tacrolimus and Autoimmune-Diseases

Anti-synthetase syndrome (ASS) is a chronic multisystemic autoimmune disease characterized by detectable anti-aminoacyl-transfer-RNA antibodies. Interstitial lung disease (ILD) in anti-synthetase syndrome patients is often severe and rapidly progressive. Anti-Zo (phenylalanyl) antibody is reported rarely in ASS. Therefore, the appropriate treatment of anti-Zo positive ASS is unclear.. Here we present a case of anti-Zo-positive ASS with rapid progressive ILD (RP-ILD) in a Chinese patient successfully treated with a combination of systemic corticosteroids and tacrolimus.. We reviewed 13 anti-Zo-positive ASS patients (including our case) and summarized clinical features that have some differences with other ASS. Anti-Zo-positive ASS is a rare autoimmune disease with a high burden of ILD, is often severe and rapidly progressive. Corticosteroids with tacrolimus may improve patient outcomes in anti-Zo antibody positive ASS with RP-ILD.

Topics: Autoimmune Diseases; Humans; Ligases; Lung Diseases, Interstitial; Tacrolimus

The specific regulation of inflammatory processes by steroid hormones has been actively studied in recent years, especially by progesterone (P

Topics: Anti-Inflammatory Agents; Anti-Obesity Agents; Autoimmune Diseases; Cyclosporins; Cytokines; Estrogen Receptor beta; Humans; Immunosuppressive Agents; Inflammation; Ligands; NF-kappa B; Peptidylprolyl Isomerase; Progesterone; Progestins; Prostaglandins; Receptors, Progesterone; Tacrolimus

From the current trends, tacrolimus (TAC) has become an important therapeutic option for the optimal individualization of immunosuppressive therapy especially in case of transplant recipients. TAC is used most frequently in comparison to other immunosuppressants because it offers better safety profile with increased long-term survival in patients especially in children and adolescents. This drug has developed an immense interest in the research field owing to its potential pharmacological scope but due to its poor water solubility, need of concomitant steroids and higher incidences of nephrotoxicity, there comes a need for future research to minimize such limitations and decipher maximum use of the drug. In addition, there are number of formulations attempted to enhance its erratic bioavailability through various techniques namely solid dispersions, inclusion complexes, prodrug approach, SMEDDS etc. The present review aims to acknowledge the TAC pharmacokinetic profile and novel drug delivery systems in multiple diseased conditions by particularly enhancing its poor biopharmaceutical issues as well as dose related toxicity. Collectively, we have updated the data pertaining to the drug delivery prospects of TAC for the period of last 8-10years.

Topics: Animals; Autoimmune Diseases; Drug Delivery Systems; Graft Rejection; Humans; Immunosuppressive Agents; Tacrolimus

Topics: Antibodies, Anti-Idiotypic; Antibodies, Monoclonal, Humanized; Autoimmune Diseases; Chronic Disease; Cyclosporine; Disease Management; Female; Histamine Antagonists; Humans; Immunosuppressive Agents; Male; Omalizumab; Prevalence; Tacrolimus; Urticaria

Some day we will have powerful targeted therapies for autoimmune diseases. Remission will be induced efficiently. Side effects will be mere ripples. Unfortunately, that day is not imminent. Current therapies are powerful but with unintended targets and side effects that can be equivalent to a sea change. For SLE, the current competition to select the 'gold standard' immunosuppressant has come down to two regimens: intravenous cyclophosphamide (IVCY, standard NIH protocol or its variations) versus oral mycophenolate (MMF). Until recently, IVCY reigned as the gold standard, a title it achieved through a curious journey that did not involve rigorous head-to-head competition. Oral cyclophosphamide (POCY) has not been invited to the current competition to select the gold standard immunosuppressant despite the substantial evidence that POCY can perform at least as well as IVCY or mycophenolate, and compared to IVCY, is far less expensive, easier for the patient, and maybe more effective in African-Americans. Here, we state the case for POCY as therapy for severe autoimmune diseases. We suggest that if POCY is allowed to compete, it will not disappoint.

Topics: Autoimmune Diseases; Cyclophosphamide; Cyclosporine; Humans; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid; Tacrolimus

The treatment of auto-immune diseases is evolving and newer agents become available. This review will outline treatment options in children with auto-immune disorders. Treatment with current corticosteroids and azathioprine works in majority but issues of intolerance and incomplete response arise, which led to window of newer immunosuppressants including mycophenolate mofetil, cyclosporine, tacrolimus, sirolimus, and various antibodies of human and animal origin. The newer agents have been studied in fewer numbers of children, so they are not first-line treatment yet but do have a clear role in patients with intolerance or incomplete response to standard therapy.

Topics: Antilymphocyte Serum; Autoimmune Diseases; Azathioprine; Child; Cyclophosphamide; Cyclosporine; Glucocorticoids; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Isoxazoles; Leflunomide; Mercaptopurine; Methotrexate; Mycophenolic Acid; Nitriles; Sirolimus; Tacrolimus

Paraneoplastic pemphigus (PNP) or paraneoplastic autoimmune multiorgan syndrome (PAMS) is a life-threatening autoimmune blistering disease commonly associated with lymphoproliferative neoplasms. This article focuses on current management strategies in PNP/PAMS, and reported instances of their treatment successes and failures. Due to the rarity of the condition and the high rates of treatment failure, no randomized control trials exist to guide the evidence-based treatment of this condition; all evidence to date on the efficacy of therapeutic modalities has been gained from individual case reports, small case series, and expert recommendations.

Topics: Adrenal Cortex Hormones; Alemtuzumab; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antibodies, Neoplasm; Autoimmune Diseases; Azathioprine; Cyclophosphamide; Cyclosporine; Dermatologic Agents; Female; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Male; Multiple Organ Failure; Mycophenolic Acid; Paraneoplastic Syndromes; Pemphigus; Plasmapheresis; Rituximab; Tacrolimus

Topical tacrolimus is an immunosuppressant that acts through the inhibition of calcineurin and thus of the T cells. This causes a decrease in the production of interleukins, the granulocyte colony stimulating factor, alpha interferon and tumor necrosis factor. Although the use of topical tacrolimus is only indicated for the treatment of moderate or severe atopic dermatitis, its immunosuppressant effect and fewer side effects regarding topical corticosteroids have lead to the increase of its use in other types of inflammatory skin diseases. The purpose of this article is to review the use of tacrolimus in this group of diseases other than atopic dermatitis, this use not being authorized within the data sheet of the drug.

Topics: Adult; Autoimmune Diseases; Child; Clinical Trials as Topic; Dermatitis; Graft vs Host Disease; Humans; Immunosuppressive Agents; Lichenoid Eruptions; Multicenter Studies as Topic; Off-Label Use; Pruritus; Psoriasis; Pyoderma Gangrenosum; Skin Diseases; Tacrolimus; Uremia; Vitiligo

Experimental autoimmune uveoretinitis (EAU) induced by immunization with retinal antigen (Santigen or interphotoreceptor retinoid-binding protein; IRBP) serves as an animal model of human uveoretinitis. As the first stage, we demonstrated the similarities between EAU and ocular inflammation in Behçet's disease by investigating anti-retinal antibodies, leukocyte migration inhibition by retinal antigen, immunogenic antigens, aberrant functions of neutrophils, and dominant Th1 lymphocyte reaction. From these findings, we verified that EAU, which is not associated with the systemic disorders observed in Behçet's disease, is an appropriate model for translational research targeting ocular inflammation. In the second stage, we set 3 therapeutic strategies for uveitis in Behçet's disease to be conducted in the translational research: (1) intraocular administration of an immunosuppressive drug; (2) inhibition of Th1 lymphocytes; and (3) activation of immunoregulatory cells. In strategy 1, our studies indicated that intravitreal injection of 10 microg of tacrolimus (FK 506) was not harmful to the retina and was predominantly effective in suppressing ongoing EAU in rats. In strategy 2, two approaches were adopted to prevent differentiation of Thl cells. One is anti-cytokine antibody therapy using anti-IL-12 monoclonal antibodies(mAb). The other is blockade of co-stimulatory signals, especially the ICOS-B7RP-1 pathway. Administration of anti-IL-12 mAb at the time of IRBP immunization completely inhibited development of EAU, and antagonistic anti B7RP-1 mAb suppressed the severity of EAU even when administered after development of EAU. In strategy 3, adoptive transfer of antigen presenting cells treated with a neuropeptide (vasoactive intestinal peptide or calcitonin gene-related peptide) or CD 4+ CD 25+ regulatory T cells suppressed EAU. We look forward to the day when therapies that are being developed in our translational research using EAU will become available for treating intraocular inflammation in Behçet's disease.

Topics: Adoptive Transfer; Animals; Antibodies, Monoclonal; Antigens, Differentiation, T-Lymphocyte; Autoimmune Diseases; Behcet Syndrome; CD28 Antigens; CD4-Positive T-Lymphocytes; Disease Models, Animal; Humans; Inducible T-Cell Co-Stimulator Protein; Interleukin-12; Interleukin-2 Receptor alpha Subunit; Neuropeptides; Rats; Retinitis; Tacrolimus; Th1 Cells; Uveitis

An elusive goal in hematology is a detailed understanding of autoimmune blood disorders including idiopathic (immune) thrombocytopenic purpura (ITP), autoimmune hemolytic anemia (AIHA), and Evans Syndrome. While it is clear that these disorders have an autoimmune pathophysiology, the exact mechanisms are not clear. Agents that target the immune system specifically, such as rituximab and tacrolimus, are currently being used clinically with favorable results. Targeted therapy may be useful not only in treating these difficult diseases, but also may provide clues to the underlying disease pathophysiology. Carefully designed studies using targeted therapy may provide biologic predictors of disease severity, as well as predictors of response to therapy.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antirheumatic Agents; Autoimmune Diseases; Cyclosporine; Humans; Lymphocyte Depletion; Purpura, Thrombocytopenic, Idiopathic; Rituximab; Tacrolimus

Alopecia areata is a common disease, but for ethical reasons it seems difficult to perform large-scale studies to elucidate the pathogenesis and to develop new therapeutic approaches in man. It is therefore helpful to develop appropriate animal models. The Dundee experimental bald rat (DEBR) and the C3H/HeJ mouse are well-established animal models for alopecia areata and can be used for the study of genetic aspects, pathogenesis and therapy of the disease. In C3H/HeJ mice alopecia areata can be experimentally induced by grafting lesional skin from an affected mouse to a histocompatible recipient which offers the possibility to study the influence of various factors on the development of the disease. Studies on the C3H/HeJ mouse and the DEBR have corroborated the concept that alopecia areata is a T-cell mediated autoimmune disease and various steps and aspects of the pathogenesis have been elucidated. Based on this knowledge new therapeutic options may be developed such as inhibition of lymphocyte-homing by an anti-CD44v10 antibody, or inhibition of costimulation by monoclonal antibodies. Therapeutic studies in the C3H/HeJ mouse and the DEBR suggest that alopecia areata can be treated by topical tacrolimus but treatment in humans may only be successful after development of an improved vehicle that facilitates penetration of tacrolimus down to the hair bulb. Current investigations in mice are designed to elucidate the mechanisms how contact sensitizers act in the treatment of alopecia areata, and this will hopefully lead to the development of more specific approaches based on the beneficial effect of contact sensitizers.

Topics: Alopecia Areata; Animals; Autoimmune Diseases; Disease Models, Animal; Immunosuppressive Agents; Immunotherapy; Mice; Mice, Inbred C3H; Models, Immunological; Rats; Species Specificity; T-Lymphocytes; Tacrolimus; Treatment Outcome

This article examines immunosuppressant transplant agents used to treat the various rheumatic diseases. The older drugs of this type have been used in this dual role for decades. There is a new generation of immunosuppressant drugs with established use in the arena of transplantation medicine. Only recently have the potential rheumatologic applications for these agents been investigated. The authors review in depth the published experience with the newer agents. The authors also discuss novel rheumatologic uses for the older agents that have been described within the past year.

Topics: Autoimmune Diseases; Azathioprine; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Isoxazoles; Leflunomide; Male; Mycophenolic Acid; Rheumatic Diseases; Severity of Illness Index; Sirolimus; Tacrolimus; Transplants; Treatment Outcome

Alopecia areata is considered to be a T-cell mediated autoimmune disease of the hair follicle. Current immunosuppressive approaches and immunomodulatory treatment with contact sensitizers such as diphenylcyclopropenone and squaric acid dibutylester are dealt with in this review article. The efficacy of the various modes of treatment is evaluated by a review of literature and their mode of action is discussed. In accordance with the mechanism of autoimmune pathogenesis of AA, improved future treatments may be immunosuppressive or immunomodulatory, or they should otherwise protect the hair follicle from the injurious effects of the inflammation. Such possible future therapeutic approaches include the use of liposomes as an improved vehicle, application of immunosuppressive cytokines like TGF-beta and IL-10, inhibition of apoptosis mediated by the Fas-FasL system, inhibition of the lymphocyte homing receptor CD44v10, induction of tolerance as well as principles of gene therapy.

Topics: Adjuvants, Immunologic; Adrenal Cortex Hormones; Alopecia Areata; Animals; Autoimmune Diseases; Female; Hair Follicle; Haptens; Humans; Immunosuppressive Agents; Male; PUVA Therapy; Tacrolimus

During the last decades, systemic and topical glucocorticosteroids assumed a dominant role in immunosuppressive therapy in dermatology. However, their administration is limited because of numerous adverse effects. Consequently, there is a large need for alternative non-steroidal anti-inflammatory therapeutics with a superior risk/benefit ratio. In recent years, a new class of anti-inflammatories, the macrolide lactones, has attracted special interest. During the last decade, a member of this class, tacrolimus, proved to be a powerful suppressor of the immune system. Introduced into clinical practice to prevent allograft rejection, it is now routinely used in organ transplantation. Recently, several placebo-controlled multicenter studies showed the therapeutic efficiency of systemic and topical tacrolimus in common inflammatory skin diseases such as psoriasis and atopic eczema.Short-term tacrolimus ointment therapy disclosed significant efficacy vs. placebo and a safety profile with only few local side effects in patients with atopic eczema. Further clinical trials including greater extent of exposure (experienced by children), and comparison between tacrolimus ointment and glucocorticosteroids are being conducted and the results will show whether this drug opens a new era in the treatment of inflammatory skin disorders. The aim of this review is to summarize the current knowledge regarding the pharmacokinetic properties, adverse effects and therapeutic indications of tacrolimus in dermatology.

Topics: Administration, Topical; Autoimmune Diseases; Female; Humans; Immunosuppressive Agents; Male; Signal Transduction; Skin Diseases; Tacrolimus

Topics: Apoptosis; Autoimmune Diseases; Calcineurin Inhibitors; Cell Adhesion Molecules; Cyclosporins; Cytokines; Epitopes; HLA Antigens; Humans; Immunosuppressive Agents; Tacrolimus

Cyclosporine and tacrolimus are potent immunosuppressant agents that have been used extensively in humans, primarily for prevention of transplant rejection but also for the treatment of autoimmune disorders. Both agents have similar mechanisms of action and pharmacokinetic profiles. However, the expected toxicity of the agents is dissimilar. Although cyclosporine usage in veterinary medicine is limited, it has been used enough for therapeutic guidelines to be established. Tacrolimus, however, has undergone limited use in veterinary medicine. The drug is too toxic in dogs for its use to be recommended in most clinical situations. This article reviews the mechanism of action, pharmacokinetics, expected drug interactions and toxicities, and clinical usage of cyclosporine and tacrolimus in veterinary medicine.

Topics: Animals; Autoimmune Diseases; Cat Diseases; Cats; Cyclosporine; Dog Diseases; Dogs; Dose-Response Relationship, Drug; Drug Interactions; Eye Diseases; Glomerulonephritis; Graft Rejection; Immunosuppressive Agents; Skin Diseases; Tacrolimus; Transplantation

Tacrolimus hydrate (FK506), a novel 23-membered macrolide, is an immunosuppressant isolated from Streptomyces tsukubaensis using extensive screening of fermentation products to identify a compound inhibiting the mixed lymphocyte reaction (MLR). The in vitro and in vivo immunosuppressive activities of FK506 were found to be more potent than those of cyclosporine (CyA). The superior immunosuppression with FK506 treatment was also confirmed in the skin allograft model in rats and liver transplantation in dogs. Clinical studies were initiated by Prof. Starzl at the University of Pittsburgh in 1989, and he demonstrated that FK506 surpassed CyA in the incidence of graft survival and the frequency of graft rejection. Multicenter randomized clinical studies, comparing FK506 to CyA corroborated the efficacy of FK506 on the survival of patients and of grafts, and especially on the appearance of severe refractory graft rejection. FK506 was marketed in 1993 in Japan, and was followed in 1994 in the U.S.A., U.K. and Germany. The mechanism of action of this compound was clarified by the endeavors of Prof. Schreiber, who demonstrated the existence of a binding protein for FK506 called FKBP, similar to cyclophilin for CyA. The FK506/FKBP complex binds with calcineurin, a serine/threonine phosphatase to inhibit the translocation of NFAT into the nucleus, resulting in inhibition of transcription of IL-2 mRNA. FK506 displays potent immunosuppressant activity, and contributes not only to the progress of transplantation therapy for clinical studies, but also to the clarification of signal transduction in T cell activation for basic science.

Topics: Animals; Autoimmune Diseases; Clinical Trials as Topic; Dogs; Drug Evaluation, Preclinical; Graft Rejection; Immunosuppressive Agents; Liver Transplantation; Molecular Structure; Rats; Tacrolimus

Microbial products have amazing diversity and complexity in their chemical structures as well as in their biological activities. The successful discovery and development of FK506 (Tacrolimus) adds a new example showing that microbial products are agents with potential therapeutic benefits. In 1984, we found a novel immunosuppressant FK506 during the course of our research program for discovery of specific inhibitors on IL-2 production in the microbial products. FK506, a new class of 23-membered macrolide lactone, was isolated the fermentation broth of Streptomyces tsukubaensis No.9993. This agent strongly inhibited the proliferative response of lymphocytes to alloantigen stimulation, and a variety of T cell associated immune reaction. FK506 also suppressed immune responses in vivo as well as in vitro and this immunosuppressive effect was more highly potent than cyclosporin, a well-known fungal metabolite. The profound immunosuppressive properties of FK506 were subsequently explored in organ transplantation in animal models. Clinical trials of FK506 were begun in 1989 by Professor Stazl and his colleagues at the University of Pittsburgh. Since then wider evaluation of FK506 in a variety of transplantation fields has been performed globally; in North America, Europe and Japan. In 1993, FK506 was commercialized in Japan for prevention of liver transplant rejection. FK506 is also undergoing extensive evaluation as an agent for the treatment of various autoimmune diseases.

Topics: Animals; Autoimmune Diseases; Clinical Trials as Topic; Cytokines; Disease Models, Animal; Drug Evaluation, Preclinical; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; T-Lymphocytes; Tacrolimus

Among all the new immunosuppressive molecules being investigated either preclinically or clinically, four stand out: tacrolimus (FK506), sirolimus (rapamycin), mycophenolate mofetil and leflunomide (and its malononitriloamide analogs). Each drug has distinct mechanisms of immunosuppressive action, and in the past year significant advances have been made in our understanding of the actions of these drugs at the molecular and even atomic levels. Data from recent clinical trials demonstrate that these drugs very effectively suppress graft rejection or autoimmune diseases, validating the pivotal role played by each of their distinct molecular targets in the normal functioning of immune cells.

Topics: Animals; Autoimmune Diseases; Graft Rejection; Humans; Immunosuppressive Agents; Isoxazoles; Leflunomide; Mycophenolic Acid; Polyenes; Pyrimidine Nucleotides; Sirolimus; Tacrolimus; Xenobiotics

Most experience of the therapeutic drug monitoring of immunosuppressive agents has been acquired in the field of solid organ transplantation; however, agents such as cyclosporin (cyclosporin A) are being increasingly utilised for the management of autoimmune diseases. Cyclosporin is the most widely studied immunosuppressant, but in spite of this many controversies still exist as to the optimum strategy for monitoring this drug. Owing to its widely variable pharmacokinetics and metabolism, and the absence of a simple method to measure therapeutic effectiveness, many factors should be considered. In most circumstances, measuring whole blood through concentrations of cyclosporin with a specific assay methodology is warranted. In addition, knowledge of other factors that may alter the pharmacokinetics (such as liver function, concomitant food or medications, gastrointestinal status, and time since transplantation) should be taken into account so that therapy can be appropriately adjusted. Other methods of monitoring have been investigated, such as AUC (area under the concentration-time curve) monitoring and immunological monitoring. However, further refinement of these techniques and greater experience with their efficacy must be accumulated before their role in the monitoring of cyclosporin can be defined. Tacrolimus, like cyclosporin, shares many of the difficulties in monitoring for efficacy and toxicity due largely to the variable pharmacokinetics; similarly to cyclosporin, whole blood through concentration monitoring should be utilised in combination with knowledge of the factors that may affect the pharmacokinetics. Muromonab CD3 (OKT3) is a monoclonal antibody used for the treatment and prophylaxis of acute allograft rejection. Several immunological monitoring techniques have been investigated for this agent. Monitoring CD3+ levels can assist clinicians in determining therapeutic efficacy, while measuring antimuromonab CD3 antibody titres can help determine if xenosensitisation has occurred, causing therapeutic ineffectiveness. The clinical monitoring of azathioprine, one of the first immunosuppressive agents used in transplantation, has historically been limited to monitoring complete blood counts for bone marrow suppression. However, newer techniques measuring intracellular DNA nucleotides appear to be promising. The new immunosuppressants on the horizon include mycophenolate mofetil and rapamycin. The clinical experience with therapeutic drug monito

Topics: Autoimmune Diseases; Azathioprine; CD3 Complex; Chromatography, High Pressure Liquid; Cyclosporine; Drug Delivery Systems; Drugs, Investigational; Enzyme-Linked Immunosorbent Assay; Humans; Immunosuppressive Agents; Monitoring, Immunologic; Radioimmunoassay; Structure-Activity Relationship; Tacrolimus

Topics: Adrenal Cortex Hormones; Adult; Anti-Inflammatory Agents; Autoimmune Diseases; Azathioprine; Budesonide; Cyclosporins; Diagnosis, Differential; Drug Therapy, Combination; Female; Hepatitis; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Prednisolone; Pregnenediones; Prognosis; Tacrolimus; Time Factors

Topics: Adult; Animals; Autoimmune Diseases; CD4-Positive T-Lymphocytes; Cholangitis; Cyclosporine; Diabetes Mellitus, Type 1; Digestive System Diseases; Disease Models, Animal; Drug Evaluation; Drug Evaluation, Preclinical; Female; Humans; Kidney Diseases; Male; Mice; Multiple Sclerosis; Nephrotic Syndrome; Psoriasis; Rats; Swine; Tacrolimus

Topics: Animals; Autoimmune Diseases; Clinical Trials as Topic; Graft Rejection; Humans; Molecular Structure; Organ Transplantation; Tacrolimus

Topics: Animals; Autoimmune Diseases; Calcineurin; Calmodulin-Binding Proteins; Carrier Proteins; Cyclosporine; Graft Rejection; Humans; Lymphocyte Activation; Molecular Conformation; Phosphoprotein Phosphatases; Polyenes; Sirolimus; T-Lymphocytes; Tacrolimus; Tacrolimus Binding Proteins

Immunosuppressive agents have proved to be remarkably successful in controlling the course of a growing number of autoimmune diseases. The usual occurrence of relapses when the treatment is stopped and the persisting risk of long term complications linked to over-immunosuppression have prompt the search for new approaches, aiming at more rapid and selective intervention and earlier onset of therapy. New chemicals and monoclonal antibodies presently represent the main clinical orientations, while at the experimental level major efforts are directed towards peptide therapy (autoantigen, T cell receptor) and tolerance induction.

Topics: Animals; Antibodies, Monoclonal; Autoimmune Diseases; Cyclosporine; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Mice; Tacrolimus

Topics: Animals; Autoimmune Diseases; Humans; Tacrolimus

FK 506 is a superior immunosuppressive agent that should improve patient survival after the commonly performed transplant procedures, make feasible transplantations that have been previously impractical, allow immune intervention for serious autoimmune diseases, and create a better spin-off understanding of basic biologic processes including signal transduction.

Topics: Autoimmune Diseases; Bone Marrow Transplantation; Female; Graft Rejection; Graft vs Host Disease; Heart Transplantation; Humans; Kidney Transplantation; Liver Transplantation; Male; Nephrotic Syndrome; Psoriasis; Tacrolimus

FK-506 is a recently discovered immunosuppressive agent that, although structurally quite distinct from cyclosporin A (CsA), shares many of its properties. These include interference with production of interleukin 2 (IL-2) and other lymphokines, lack of myelotoxicity and the induction of transplantation tolerance following administration of short courses to allografted rats. Compared with CsA, however, FK-506 is much more potent and the two agents can act synergistically both in vivo and in vitro. However, severe side effects of FK-506 have been reported in dogs and baboons, although not in rats. On the basis of recently published findings. Angus Thomson reviews the immunological properties of FK-506 and assesses its potential in the light of the impact already made by CsA in both the laboratory and clinic.

Topics: Animals; Autoimmune Diseases; Cyclosporins; Drug Evaluation, Preclinical; Drug Synergism; Graft Survival; Immunosuppressive Agents; Mice; Molecular Conformation; Primates; Pyridines; Rats; Structure-Activity Relationship; Tacrolimus

Lichen sclerosus is a chronic inflammatory autoimmune disease causing significant sclerosis, atrophy and pruritus. Treatment remains unsatisfactory, with potent corticosteroids being the most effective therapy.. To conduct a multicentre, phase II trial to assess the safety and efficacy of tacrolimus ointment 0.1% for the treatment of lichen sclerosus with a follow-up period of 18 months at 10 university and teaching hospitals in Germany and Austria.. Eighty-four patients (49 women, 32 men and three girls) aged between 5 and 85 years with long-standing, active lichen sclerosus (79 with anogenital and five with extragenital localization) were treated with topical tacrolimus ointment 0.1% twice daily for 16 weeks. Computerized analysis of the lesional area was performed. The primary endpoint was clearance of active lichen sclerosus. Secondary endpoints were time to optimal response, reduction of sclerosis and duration of remission.. The primary endpoint (clearance of active lichen sclerosus) was reached by 43% of patients at 24 weeks of treatment. Partial resolution was reached in 34% of patients. Maximal effects occurred between week 10 and 24 of therapy. Treatment led to a significant reduction of the total lesional area (P < 0.01) and to a significant decline in the total symptom score (P < 0.005). Symptoms (e.g. itching) and findings (erythema, erosions and induration) showed significant improvement. No serious adverse events were observed. There were three (9%) recurrences during the follow-up period.. Topical tacrolimus ointment 0.1% was safe and effective for the treatment of long-standing active lichen sclerosus.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Autoimmune Diseases; Child; Child, Preschool; Female; Genital Diseases, Female; Genital Diseases, Male; Humans; Immunosuppressive Agents; Lichen Sclerosus et Atrophicus; Male; Middle Aged; Ointments; Severity of Illness Index; Tacrolimus; Treatment Outcome

Autoimmune chronic active hepatitis (CAH-A) is a chronic liver disease of unknown etiology that is believed to have an autoimmune pathogenesis. The disease is slowly progressive until hepatic failure and portal hypertension develop and either death or liver transplantation occur. Currently, the only widely recognized therapy is the administration of glucocorticoids, which have both anti-inflammatory and immunosuppressive actions. Many patients cannot tolerate such therapy because of the psychiatric, osteoporotic, and weight-enhancing actions of steroids. Tacrolimus (FK 506) is a new macrolide antibiotic that has an immunosuppressive activity that is estimated to be 10-200 times greater than that of cyclosporine. Because of its greater immunosuppressive activity, we have used it in the treatment of 21 patients with autoimmune chronic active hepatitis. Before each subject was treated, a liver biopsy and a panel of hematological, serological, and biochemical parameters were assessed. The Tacrolimus was administered orally at 12-h intervals, and the dose was controlled by monitoring plasma FK trough levels. After 3 months of therapy at an oral dose of 3 mg twice a day, having achieved a median blood level of 0.5 ng/ml, the serum ALT level was reduced by 80%, and the AST level was reduced by 70%. Modest change in the white blood cell count and platelet count were noted. The median BUN level increased from a level of 12 to 18 mg/dl, and the serum creatinine increased from 0.9 to 1.3 mg/dl. These preliminary data demonstrate that: 1) Tacrolimus can be used to successfully treat CAH-A; 2) the response of CAH-A to Tacrolimus treatment is rapid and sustained; and 3) a minor increase in the serum BUN and creatinine levels occurs as a consequence of Tacrolimus treatment. It is anticipated that with continued treatment for periods of 1-2 yr, the natural history of CAH-A will be changed such that hepatic failure and the requirement for liver transplantation may be averted.

Topics: Adult; Autoimmune Diseases; Female; Hepatitis, Chronic; Humans; Male; Tacrolimus

A randomized concentration-controlled clinical trial (RCCCT) is an alternate experimental design to the standard dose-controlled study. In a RCCCT, patients are randomly assigned to predefined plasma or blood drug concentration ranges (low, medium, and high). With the caveat that concentration ranges are sufficiently separated, this design should enhance the ability to discover important concentration response relationships. FK-506, a potent and promising immunosuppressive agent for prevention and treatment of graft rejection, has shown significant clinical activity in some immune-mediated disorders. To implement the RCCCT design, a novel FK-506 intelligent dosing system (IDS) was used to guide all doses to prospectively achieve the target concentration range specific in the study protocol. Patients enrolled in these trials suffered from a variety of autoimmune disorders, including multiple sclerosis, primary biliary cirrhosis, psoriasis, autoimmune chronic active hepatitis, and nephrotic syndrome. We observed excellent predictive performance of the IDS for all patients. The accuracy (mean prediction error) of the IDS was -0.022 ng/ml and the precision (standard deviation of the prediction error) was 0.119 ng/ml. Thus, the IDS is both accurate and reproducible for autoimmune patients. We conclude that the RCCCT design, guided by an accurate and precise IDS, is an informative and cost-effective approach for evaluation of efficacy and safety of effective but highly toxic agents.

Topics: Autoimmune Diseases; Cost-Benefit Analysis; Drug Monitoring; Drug Therapy, Computer-Assisted; Enzyme-Linked Immunosorbent Assay; Humans; Randomized Controlled Trials as Topic; Research Design; Tacrolimus

The accuracy and precision of an intelligent dosing system (IDS) for FK506 in predicting doses to achieve target drug levels has been prospectively evaluated in transplant and autoimmune patients. For dose individualization, the knowledge base is updated with patient-specific feedback including the current dose, drug level, and the new target level. The study population of 147 patients consisted of 97 transplant patients (liver and kidney) and 50 patients with autoimmune disorders. Patients in the transplant study group were entered sequentially and followed as a cohort. Patients in the autoimmune study group were randomly assigned to one of three predefined FK506 concentration windows (low, 0.1-.3; medium, 0.4-.7; and high, 0.8-1.3 ng/mL) as part of a concentration controlled clinical trial. Predictions of steady-state plasma drug levels were made throughout the clinical course of autoimmune patients and during the first 6 weeks post-transplant in liver and kidney recipients. FK506 concentration in plasma was measured by a monoclonal antibody based ELISA assay. Accuracy was computed as the mean prediction error (mpe). Precision was computed as the root mean squared prediction error (rmspe). The accuracy of the IDS in each study group was as follows: 0.016 ng/mL (liver), -0.034 ng/mL (kidney), and -0.022 ng/mL (autoimmune). Because the 95% confidence interval included zero in each case, the IDS showed no bias. The precision of the IDS in each study group was as follows: 0.133 ng mL (liver), 0.1903 ng/mL (kidney), and 0.1188 ng/mL (autoimmune). These results indicate that the FK506 IDS is both accurate and very precise (reproducible) in transplant and autoimmune patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Autoimmune Diseases; Cohort Studies; Cost-Benefit Analysis; Dose-Response Relationship, Drug; Drug Therapy, Computer-Assisted; Female; Humans; Male; Middle Aged; Organ Transplantation; Sensitivity and Specificity; Tacrolimus

Efficacy of a new immunosuppressive agent, FK506, in refractory uveitis was studied in 8 patients: 5 with Behcet's disease and 3 with idiopathic retinal vasculitis. The agent was given by oral administration every 12 hours. The previous therapy with systemic corticosteroids or immunosuppressive agents including cyclosporine failed to subside uveitis in these cases. During the observation period of 21.6 +/- 7.8 weeks (mean +/- SD) under FK506 at doses with 0.05, 0.1, 0.15 or 0.2 mg/kg/day, the visual acuity was increased in 44% of treated eyes, unchanged in 44% and decreased in 12%. The inflammatory activity in the ocular fundus was improved in 69% and unchanged in 6% of treated eyes. The effects of FK506 on uveitis by the criteria of improvement of visual acuity and uveitis activity was dose-dependent: 0.05 and 0.1 mg/kg/day were ineffective but 0.15 and 0.2 mg/kg/day were effective in most cases. One patient with Behcet's disease converted from cyclosporine developed moderate renal impairment in 4 weeks under FK506 and the therapy was discontinued in 8 weeks, though the uveitis activity as well as visual acuity was markedly improved. Other 7 cases had no side effect of FK506. Although the number of cases was small and observation period was short, the present clinical data indicate that FK506 is effective to treat refractory uveitis.

Topics: Administration, Oral; Adult; Aged; Animals; Antigens; Arrestin; Autoantigens; Autoimmune Diseases; Behcet Syndrome; Drug Evaluation, Preclinical; Eye Proteins; Female; Humans; Injections, Intraperitoneal; Male; Middle Aged; Rats; Rats, Inbred Lew; Tacrolimus; Uveitis; Vasculitis; Visual Acuity

Currently, no standard treatment strategy has been established for immune-mediated necrotizing myopathy (IMNM). Here we present a case of IMNM which was successfully treated with intensive combined therapy with high-dose glucocorticoids, tacrolimus, and intravenous immunoglobulins. Her muscle weakness was rapidly progressive and severe so that she became bedridden one week after admission. She was complicated with dysphagia and had serum myogenic enzymes elevation, ventricular diastolic dysfunction, and interstitial lung disease. Serum anti-SRP antibody was positive and her muscle biopsy revealed many necrotic fibers with minimal inflammation. Further histological analysis demonstrated infiltration of phagocytic macrophages with deposition of membrane attack complex (C5b-9) in the necrotic muscle fibers, suggesting activation of complement pathway and macrophages as a pathomechanism of this disease. She was diagnosed as IMNM and was immediately initiated a combination therapy described above, which led to dramatic clinical improvements. Recent studies suggest that intravenous immunoglobulins and tacrolimus can inhibit the activation of complement pathway and macrophages. Our present case suggests that early initiation of intensive combined therapy including intravenous immunoglobulins and tacrolimus might be effective for preventing irreversible muscle damages by disrupting a pathogenic activation of complement and macrophages in IMNM.

Topics: Autoantibodies; Autoimmune Diseases; Complement Membrane Attack Complex; Female; Glucocorticoids; Humans; Immunoglobulins, Intravenous; Muscle Fibers, Skeletal; Muscular Diseases; Myositis; Tacrolimus

The pharmacokinetics of drugs, such as immunosuppressants, justify the need of measuring their blood concentrations in order to adjust their dosage. Therapeutic Drug Monitoring (TDM) of ciclosporin, tacrolimus and mycophenolate mofetil has shown its benefit particularly in the management of renal transplantees, in order to prevent graft rejection. When prescribed in autoimmune diseases, their pharmacokinetic variability and the variability of clinical response would justify TDM in practice. TDM may be useful in systemic lupus, for hydroxychloroquine, in order to monitor patient compliance. Despite insufficient data in the literature, for mycophenolate mofetil, TDM would permit to maintain clinical remission in adults and children with lupus nephritis, as well as in mucosal pemphigoid and idiopathic nephrotic syndrome in children. Studies are still necessary to validate the thresholds and TDM conditions. For azathioprine, TPMT phenotyping is recommended before prescription. For methotrexate, tacrolimus and ciclosporin, data are still sparse on the benefit of TDM, although it may improve tolerance to tacrolimus in lupus. Finally, for infliximab, in case of loss of response in maintenance, TDM may be proposed in parallel with detection of anti-drug antibodies.

Topics: Adult; Autoimmune Diseases; Child; Cyclosporine; Drug Monitoring; Humans; Immunosuppressive Agents; Mycophenolic Acid; Tacrolimus

The standard therapies for autoimmune cytopenias, including idiopathic thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA) and Evans syndrome (ES), are corticosteroids and intravenous immunoglobulin G. However, the recurrence rate is high.. Data from 80 patients with ITP, AIHA and ES who were refractory to corticosteroids/relapsed and were treated with tacrolimus from January 2018 to January 2019 in Peking Union Medical Colleague Hospital were reviewed retrospectively.. Tacrolimus can achieve a durable response with mild side effects in patients with steroid-refractory/relapsed autoimmune cytopenias. Patients with younger age had a better response.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Autoimmune Diseases; Biomarkers; Drug Resistance; Duration of Therapy; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Pancytopenia; Recurrence; Retrospective Studies; Risk Factors; Tacrolimus; Treatment Outcome; Young Adult

Allergy and other immune-mediated diseases are more frequently reported in children who have undergone liver transplantation. Furthermore, autoantibodies are also prevalent, suggesting a state of immune dysregulation in these patients. Whether or not these processes occur simultaneously in the same individual has not been studied previously.. A cohort of 43 children who had undergone liver transplantation for nonautoimmune liver disease at median age of 1.3 years was investigated for allergy and autoimmune disease. Sensitization to food and inhalant allergens was assessed, and autoantibodies were measured.. The prevalence of food allergy was 26% and that of respiratory allergy was 23%, whereas 33% and 26% of the subjects were sensitized to food and inhalant allergens, respectively. Autoimmune disease (ie, autoimmune hepatitis) occurred in a single individual (2%), whereas autoantibodies were present in 44% of the children. Food allergy and autoantibodies occurred concomitantly in 19% of the children, which was almost twice the frequency expected by chance (11%, P = 0.04). Respiratory allergy and the presence of autoantibodies were unrelated (12% concurrence versus the expected 10%, P = 0.73). In the logistic regression analysis, autoantibody formation was associated with discontinued immunosuppression and food allergy, with odds ratios of 13 (P = 0.01) and 7.1 (P = 0.03), respectively.. In contrast to respiratory allergy, food allergy and autoantibody formation occurred together in the same children who underwent liver transplantation at a frequency higher than would be expected by chance. This may reflect an underlying immune dysregulation that impairs immune tolerance to both food allergens and autoantigens.

Topics: Adolescent; Allergens; Autoantibodies; Autoantigens; Autoimmune Diseases; Biliary Atresia; Child; Child, Preschool; Cross-Sectional Studies; End Stage Liver Disease; Female; Follow-Up Studies; Food Hypersensitivity; Humans; Immunosuppression Therapy; Infant; Liver Transplantation; Male; Odds Ratio; Postoperative Complications; Prevalence; Tacrolimus

Different measured values for tacrolimus were obtained with different automated immunoassays. We aimed to examine the differences in the blood tacrolimus concentrations measured by the major immunoassay systems commercially available in Japan.. Whole-blood samples from 118 patients were assayed by 3 commercial assays: chemiluminescent enzyme immunoassay (CLIA), affinity column-mediated immunoassay (ACMIA), and enzyme-multiplied immunoassay technique (EMIT). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used for reference.. The correlation coefficient of immunoassay vs LC-MS/MS was excellent for ACMIA (.83) and CLIA (.81) and good for EMIT (.71). The mean error was negative for ACMIA and positive for CLIA and EMIT. The mean absolute error and root-mean-square error were almost the same for ACMIA and CLIA and lower than those for EMIT.. The ACMIA and CLIA yield considerably better results than the EMIT for monitoring blood tacrolimus concentrations.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Autoimmune Diseases; Chromatography, Liquid; Enzyme Multiplied Immunoassay Technique; Female; Humans; Immunoassay; Male; Middle Aged; Regression Analysis; Tacrolimus; Tandem Mass Spectrometry; Young Adult

Although tacrolimus (TAC) can induce remission in children with refractory inflammatory bowel disease (IBD) or autoimmune gastroenteropathy (AGE), its use in maintenance therapy remains controversial. The aim of this study was to investigate the potential nephrotoxic nature of prolonged TAC use.. This retrospective study reviewed children with gastrointestinal disorder who underwent kidney biopsy for the evaluation of renal damage during TAC therapy for >1 year. The clinical and histological features of renal damage were evaluated in this single-institution cohort.. Eighteen of 121 children with IBD and two children with AGE followed at a national children hospital in Tokyo, Japan, received TAC between August 2006 and April 2013. Among them, five (Crohn's disease, n = 3; autoimmune gastropathy, n = 1; autoimmune enteropathy, n = 1) received TAC for >1 year, and underwent kidney biopsy. All five had achieved remission on TAC, but had histological evidence of chronic nephrotoxicity. Renal damage in one patient with relatively low TAC trough level remained mild. Estimated glomerular filtration rate (eGFR) at the time of kidney biopsy was lower than at the initiation of TAC in all four available patients. Among them, eGFR improved in one patient after the decrease or discontinuation of TAC.. TAC appeared to be effective in children with refractory gastrointestinal disorder, but long-term use seems to cause irreversible renal damage. Rigorous monitoring of eGFR and kidney biopsy in selected cases should be considered for the proper adjustment of TAC.

Topics: Autoimmune Diseases; Biopsy; Child; Crohn Disease; Female; Gastroenteritis; Humans; Immunosuppressive Agents; Infant; Kidney; Maintenance Chemotherapy; Male; Renal Insufficiency; Retrospective Studies; Tacrolimus; Treatment Outcome

Vitiligo is a pigmentary disorder and autoimmune pathogenesis seems most likely. Decreased vitamin D levels have been related to several autoimmune diseases. Little is known about the association of vitiligo and vitamin D. We aimed to evaluate serum 25-hydroxyvitamin D [25(OH)D] levels in children with vitiligo and to determine the efficacy of oral vitamin D therapy on the repigmentation of vitamin D deficient patients.. Thirty patients aged 6-17 years with vitiligo and 30 sex- and age-matched apparently healthy controls were included in this prospective study. Size of the vitiligo representative area was estimated using the point counting method and blood samples were obtained at the beginning and month six. By the end of the study, all patients treated with topical tacrolimus for six months and the patients who were vitamin D deficient (n = 14) had been on combination treatment of oral vitamin D and topical tacrolimus. A dose of 1500 IU/day vitamin D was given if the serum 25(OH)D levels <20 ng/ml and 3000 IU/day was given if the levels <10 ng/ml for six months. Serum 25(OH)D levels were measured by high-performance liquid chromatography.. Serum 25(OH)D levels of patients and controls were not significantly different (p > 0.05). Lesion size decreased from 66.1 ± 58.3 cm. Although we did not determine decreased serum 25(OH)D levels in children with vitiligo, we showed that combination treatment with oral vitamin D and topical tacrolimus is more effective in reaching repigmentation than topical tacrolimus alone. Oral vitamin D supplementation might be useful for children with vitiligo who are also deficient in vitamin D.

Topics: Administration, Oral; Adolescent; Age Factors; Autoimmune Diseases; Blood Chemical Analysis; Body Mass Index; Child; Dietary Supplements; Female; Humans; Male; Prospective Studies; Sex Factors; Tacrolimus; Turkey; Vitamin D; Vitamin D Deficiency; Vitiligo

Topics: Acute Disease; Administration, Cutaneous; Amoxicillin-Potassium Clavulanate Combination; Autoimmune Diseases; Dermatologic Agents; Drug Hypersensitivity Syndrome; Facial Dermatoses; Female; Humans; Immunosuppressive Agents; Middle Aged; Ointments; Sinusitis; Tacrolimus; Vitiligo

Immunosuppressive agents are used for the treatment of immune-mediated myocarditis; however, the need to develop a more effective therapeutic approach remains. Nano-sized liposomes may accumulate in and selectively deliver drugs to an inflammatory lesion with enhanced vascular permeability. The aims of this study were to investigate the distribution of liposomal FK506, an immunosuppressive drug encapsulated within liposomes, and the drug's effects on cardiac function in a rat experimental autoimmune myocarditis (EAM) model. We prepared polyethylene glycol-modified liposomal FK506 (mean diameter: 109.5 ± 4.4 nm). We induced EAM by immunization with porcine myosin and assessed the tissue distribution of the nano-sized beads and liposomal FK506 in this model. After liposomal or free FK506 was administered on days 14 and 17 after immunization, the cytokine expression in the rat hearts along with the histological findings and hemodynamic parameters were determined on day 21. Ex vivo fluorescent imaging revealed that intravenously administered fluorescent-labeled nano-sized beads had accumulated in myocarditic but not normal hearts on day 14 after immunization and thereafter. Compared to the administration of free FK506, FK506 levels were increased in both the plasma and hearts of EAM rats when liposomal FK506 was administered. The administration of liposomal FK506 markedly suppressed the expression of cytokines, such as interferon-γ and tumor necrosis factor-α, and reduced inflammation and fibrosis in the myocardium on day 21 compared to free FK506. The administration of liposomal FK506 also markedly ameliorated cardiac dysfunction on day 21 compared to free FK506. Nano-sized liposomes may be a promising drug delivery system for targeting myocarditic hearts with cardioprotective agents.

Topics: Acute Disease; Animals; Autoimmune Diseases; Cytokines; Disease Models, Animal; Immunosuppressive Agents; Liposomes; Male; Myocarditis; Nanoparticles; Rats; Rats, Inbred Lew; Tacrolimus

To investigate the clinical characteristics and histopathological features of kidney disease in elderly patients.. We retrospectively analyzed the results of 4,185 consecutive renal biopsies, and 288 patients aged >60 years at the Second Hospital of Jilin University from January 1998 to December 2013 were finally included. All patients had been clinically and histologically diagnosed with kidney disease.. Nephrotic syndrome was the main clinical indication for biopsy. Twenty-four patients (8.33 %) experienced a minor complication related to their biopsy procedure. Among patients diagnosed as primary glomerulonephritis (GN), membranous nephropathy (MN) was the most frequent subclassification (24.7 %), followed by mesangioproliferative glomerulonephritis (MsPGN, 11.1 %) and IgA nephropathy (IgAN, 8.0 %). Amyloidosis (8.7 %) was the most common secondary GN, followed by antineutrophil cytoplasmic autoantibody (ANCA)-associated pauci-immune GN (5.2 %) and diabetic nephropathy (DN, 3.8 %). Based on renal biopsies results, 143/288 patients received immunosuppressive therapy and showed an overall remission rate (complete plus partial remissions) of 74.1 %. Among 71 MN patients, 29 patients received steroids plus cyclophosphamide and showed a remission rate of 79.3 %, while 42 patients received steroids and tacrolimus and showed a remission rate of 90.5 %. Among 25 patients with amyloidosis, 22 cases received melphalan plus dexamethasone and showed a remission rate of 40.9 %, while three patients received vincristine, adriamycin, and dexamethasone and showed a remission rate of 66.7 %.. Making an accurate pathologic diagnosis by renal biopsy is crucial for selecting the proper treatment for elderly patients with kidney disease.

Topics: Aged; Aged, 80 and over; Amyloidosis; Anti-Inflammatory Agents; Antibodies, Antineutrophil Cytoplasmic; Antineoplastic Agents, Alkylating; Autoimmune Diseases; Biopsy; Cyclophosphamide; Dexamethasone; Diabetic Nephropathies; Female; Glomerulonephritis, IGA; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Male; Melphalan; Middle Aged; Nephrotic Syndrome; Retrospective Studies; Tacrolimus; Treatment Outcome

Topics: Anticonvulsants; Autoimmune Diseases; Early Medical Intervention; Epilepsy; Humans; Infusions, Intravenous; Tacrolimus

Calcineurin inhibitors (CNIs) revolutionized the field of organ transplantation and remain the standard of care 40 years after the discovery of cyclosporine. The early impressive results of cyclosporine in kidney transplant recipients led to its subsequent use in other organ transplant recipients and for treatment of a variety of autoimmune diseases as well. In this review, we examine the discovery of CNIs, their mechanism of action, preclinical and clinical studies with CNIs, and the usage of CNIs in nontransplant recipients. We review the mechanisms of renal toxicity associated with CNIs and the recent efforts to avoid or reduce usage of these drugs. Although minimization strategies are possible, safe, and of potential long-term benefit, complete avoidance of CNIs has proven to be more challenging than initially thought.

Topics: Animals; Autoimmune Diseases; Calcineurin; Calcineurin Inhibitors; Clinical Trials as Topic; Cyclosporine; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Drug Therapy, Combination; Forecasting; Graft Rejection; History, 20th Century; History, 21st Century; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Lymphocyte Activation; Meta-Analysis as Topic; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; T-Lymphocytes; Tacrolimus

We aimed to compare the effects of intraperitoneal ghrelin and tacrolimus on vitreous levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6) in an experimental autoimmune uveitis model.. Twenty-four male rats, each weighing 300 g, were assigned into four groups, six rats in each. All the rats, except for those in group 1, were injected intravitreally with concanavalin a to induce experimental uveitis. The development of uveitis was confirmed by the histopathologic examination of two rat globes from each group. The rats in group 2 were not given any treatment after uveitis was induced. The rats in group 3 were administered 1 mg/kg/day of intraperitoneal tacrolimus on days 0, 1, 3, 5 and 7 following the induction of uveitis (on the 14th day of study). The rats in group 4 were given 10 ng/kg/day of intraperitoneal ghrelin for 7 days following the induction of uveitis. On the 21st day of the study, all rats were sacrificed, and the eyes enucleated were subjected to histopathologic examination. Vitreous levels of TNF-α, IL-1 and IL-6 were measured by the enzyme-linked immunosorbent assay method.. The histopathologic evaluation carried out to confirm the development of uveitis revealed destruction in the retinae and ciliary bodies of the immunized rats. The mean vitreous levels of TNF-α, IL-1 and IL-6 were significantly higher in the sham group than in the control group (p < 0.05). The levels of these three cytokines showed a significant decrease in the tacrolimus treatment group (p < 0.05). Cytokine levels decreased in the ghrelin treatment group relative to the control group; however, the decrease was not found statistically significant (p > 0.05).. Tacrolimus could be effective in uveitis treatment by neutralizing or decreasing the levels of cytokines such as TNF-α, IL-1 and IL-6 that have a critical part in the pathogenesis of uveitis. However, ghrelin failed to produce the desired effect. Further studies using different doses and different ways of administration are needed to determine the effective dose of ghrelin in uveitis.

Topics: Animals; Autoimmune Diseases; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Ghrelin; Immunosuppressive Agents; Injections, Intraperitoneal; Interleukin-1; Interleukin-6; Male; Rats; Tacrolimus; Tumor Necrosis Factor-alpha; Uveitis; Vitreous Body

DNA vaccines have been widely used to induce immune responses against molecular targets. In this study, we explored the possibility of using DNA vaccine combined with the immunosuppressant FK506 (tacrolimus) to antigen-specifically suppress unwanted immune responses and prevent autoimmune ovarian disease. To that end, we immunized C57BL/6 mice with a DNA vaccine encoding mouse zona pellucida 3 (ZP3) together with FK506. The immunization induced ZP3-specific CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg), which suppressed the induction of ZP3-specific delayed-type hypersensitivity in the animals. Significantly, the immunization also protected the animals from experimentally induced autoimmune ovarian disease. These results suggest that DNA vaccination in the presence of FK506 may be used to induce Treg cells and prevent AOD.

Topics: Animals; Autoimmune Diseases; CD4 Antigens; Cells, Cultured; Egg Proteins; Female; Forkhead Transcription Factors; Hypersensitivity, Delayed; Immune Tolerance; Immunization; Immunosuppressive Agents; Interleukin-2 Receptor alpha Subunit; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Ovarian Diseases; Receptors, Cell Surface; T-Lymphocytes, Regulatory; Tacrolimus; Vaccines, DNA; Zona Pellucida Glycoproteins

PURPOSE. To evaluate the effects of intravitreal injection of liposomes encapsulating tacrolimus (FK506) on experimental autoimmune uveoretinitis (EAU) in Lewis rats. METHODS. Liposomes containing tacrolimus were prepared by reverse-phase evaporation vesicles. EAU was induced in Lewis rats by subcutaneous injection of interphotoreceptor retinoid-binding protein R16 peptide emulsified in adjuvant. Ten days later, rats were intravitreally injected with saline, tacrolimus, tacrolimus-loaded liposomes, or unloaded liposomes. Clinical signs of inflammation and ocular histologic sections were observed and graded. Retinal function was evaluated by electroretinography (ERG). Tacrolimus concentration was determined in the vitreous body and serum by ELISA. Ocular biodistribution of rhodamine-conjugated liposomes containing tacrolimus (tacrolimus-Rh-lip) was analyzed with a laser scanning confocal microscope. To evaluate the systemic effect of intravitreally injected tacrolimus, delayed-type hypersensitivity (DTH) and lymphocyte proliferation assay (LPA) responses were detected. RESULTS. Treatment of EAU with intravitreal injection of liposomal tacrolimus significantly reduced intraocular inflammation and markedly inhibited the development of EAU, as determined in clinical and histopathologic analyses. No toxic effects could be detected as evaluated by ERG. The concentration of tacrolimus in ocular fluids remained for as long as 14 days after liposomal injection of tacrolimus. Confocal microscopy showed a transretinal distribution of the liposomal particles. DTH and LPA responses were not impaired in liposomal tacrolimus-treated rats. CONCLUSIONS. Intravitreal injection of liposomal tacrolimus was highly effective in suppressing the process of EAU without any side effects on retinal function or systemic cellular immunity. This treatment may represent a new option for the management of intraocular inflammation.

Topics: Animals; Autoimmune Diseases; Disease Models, Animal; Electroretinography; Female; Hypersensitivity, Delayed; Immunosuppressive Agents; Injections; Liposomes; Lymphocyte Activation; Microscopy, Confocal; Rats; Rats, Inbred Lew; Retinitis; T-Lymphocytes; Tacrolimus; Uveitis, Posterior; Vitreous Body

Neurologic complications are a significant cause of morbidity in children after liver transplant. In this study, we sought to evaluate the neurologic complications in children after liver transplant.. All children aged younger than 18 years old who had undergone liver transplant between June 2004 and June 2007 were included in this prospective study. There were 30 boys (62.5%) and 18 girls (37.5%) (mean age, 9.6 -/+ 4.3 years; mean duration of follow-up, 21.6 -/+ 9.4 months). The most common indications for liver transplant were biliary atresia (n=12, 25%), Wilson disease (n=7, 14.6%), tyrosinemia (n=7, 14.6%), progressive familial intrahepatic cholestasis (n=6, 12.5%), and autoimmune cirrhosis (n=5, 10.4%).. Immunosuppressive medication consisted tacrolimus (n=44, 91.7%) or cyclosporine (n=4, 8.3%) combined with mycophenolate mofetil (n=33, 68.7%) and prednisolone (n=18, 37.5%). The most-common neurologic complications were tremor (n=8, 16.7%), convulsions (n=6, 12.5%), insomnia (n=6, 12.5%), headache (n=5, 10.4%), muscle cramps (n=5, 10.4%), paresthesia (n=3, 6.2%), and weakness (n=3, 6.2%).. We conclude that the most-common neurologic complication after liver transplant in children in contrast to other studies is tremor, same as adult patients. This may be due to higher rate of use of tacrolimus in our patients.

Topics: Adolescent; Autoimmune Diseases; Child; Child, Preschool; Cholestasis, Intrahepatic; Cyclosporine; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Incidence; Liver Cirrhosis; Liver Transplantation; Male; Mycophenolic Acid; Prednisolone; Prospective Studies; Retrospective Studies; Seizures; Tacrolimus; Treatment Outcome; Tremor

Although clinical trials for new drugs are often limited in children because of safety concerns or restrictions, new therapies or novel strategies with old drugs have recently expanded dermatologic armamentarium for pediatric patients. Oral propranolol is currently the first choice in the treatment of alarming infantile hemangiomas. In atopic dermatitis, proactive strategy with topical calcineurin inhibitors can safely prevent disease exacerbation. Tacrolimus, in particular, is also useful for the treatment of vitiligo occurring in sensitive areas such as the eyelids. Among biologic drugs, use of etanercept is safe and efficient in children and adolescents with moderate-to-severe plaque psoriasis. Engineered tissues with special antimicrobial properties (silver-coated fabrics or engineered silk) are now used to treat eczema and fungal diseases in children. In athlete's foot, the use of 5-finger socks can also be helpful.

Topics: Adolescent; Adrenal Cortex Hormones; Alopecia Areata; Autoimmune Diseases; Child; Child, Preschool; Dermatitis, Atopic; Eczema; Female; Hemangioma; Humans; Immunosuppressive Agents; Male; Propranolol; Psoriasis; Randomized Controlled Trials as Topic; Skin Diseases; Tacrolimus; Therapies, Investigational; Vitiligo

For more than a decade, mycophenolate mofetil (MMF) has been used as an immunosuppressive drug in solid organ transplant recipients to prevent graft rejection. After oral administration, the prodrug MMF is rapidly hydrolyzed to the active metabolite mycophenolic acid (MPA). MMF is being used increasingly in hematopoietic stem cell transplantation (HSCTx) and autoimmune diseases (AID). The pharmacokinetics of MPA are markedly different in these patients. In comparison with renal transplant recipients (RTx), MPA clearance is increased in HSCTx patients and decreased in AIDS. The aim of this study was to characterize MPA clearance in RTx, HSCTx, and AID patients and to test whether the differences in clearance can be described by clinical chemical parameters. MPA concentration-time profiles from 19 RTx patients coprescribed cyclosporine, 17 RTx patients coprescribed tacrolimus, 38 HSCTx patients coprescribed cyclosporine, and 36 patients with AID were analyzed retrospectively with nonlinear mixed effects modeling (first-order conditional estimate). The following covariates were tested: indication for MMF treatment, sex, age, weight, plasma albumin, cyclosporine cotreatment, dose and predose blood concentration, creatinine clearance, and hemoglobin. Pharmacokinetics of MPA were described by a two-compartment model with time-lagged first-order absorption. MPA clearance was correlated in univariate analysis with plasma albumin, cyclosporine dose and predose blood concentration, creatinine clearance, hemoglobin, and indication for MMF treatment (RTx, HSCTx, or AID) (P < 0.001). All significant covariates were combined in an intermediate multivariate model followed by backward elimination. The indication for MMF treatment could be removed from the intermediate model without compromising the fit. The correlation between clearance and cyclosporine predose concentrations and plasma albumin remained significant in the final model and could describe the difference in clearance between the different indications for MMF treatment. Median clearance was 30.2, 45.6, and 10.7 L/h in RTx, HSCTx, and AID patients, respectively. In conclusion, plasma albumin concentrations and cyclosporine predose concentrations are able to describe the difference in MPA clearance among RTx, HSCTx, and AID patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Area Under Curve; Autoimmune Diseases; Cyclosporine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Graft Rejection; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Models, Biological; Mycophenolic Acid; Serum Albumin; Tacrolimus

The development of autoimmune blood cell cytopenias is a potentially life-threatening complication of solid organ transplantation, resulting from T-cell dysregulation from immunosuppressive medications. Conventional treatment with corticosteroids and IVIgG is often unsuccessful as these therapies are unlikely to overcome the T-cell dysregulation. We describe two patients who developed severe autoimmune cytopenias after solid organ transplantation. They had limited response to conventional medications, but had complete resolution of autoimmunity upon transition of immunosuppression from tacrolimus to sirolimus. Altering the immunosuppressive regimen to modify T-cell dysregulation may be beneficial for patients who develop post-transplant autoimmune disease and allow continued preservation of allograft.

Topics: Adolescent; Autoimmune Diseases; Heart Transplantation; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Organ Transplantation; Pancytopenia; Sirolimus; Tacrolimus

Haemophagocytic syndrome (HPS) is known as a relatively rare complication in autoimmune diseases. Here we analysed the clinical features of HPS in patients with systemic autoimmune diseases.. One thousand and fourteen patients with systemic autoimmune diseases admitted to Hokkaido University Hospital from 1997 to 2007 were recruited [350 SLE, 136 RA, 98 polymyositis/dermatomyositis (PM/DM), 88 SSc, 91 vasculitis syndrome, 37 primary SS, 26 adult onset Still's disease (AOSD) and 188 other diseases]. Clinical features and treatment outcomes were retrospectively analysed.. Thirty cases (3.0%) fulfilled HPS criteria (progressive cytopenia in two or more lineages and haemophagocytosis in reticuloendothelial systems). Underlying diseases were SLE (18), RA (2), PM/DM (2), SSc (2), vasculitis (1), SS (2) and AOSD (3). Nineteen patients were diagnosed as having autoimmune-associated HPS, eight infection-associated, one drug-induced and one developed HPS after haematopoietic stem cell transplantation. For the treatment of HPS, high-dose corticosteroid monotherapy was given in 26 cases, being effective in 12 (46%). Ten out of 15 patients with corticosteroid-resistant autoimmune-associated HPS were treated with CsA, cyclophosphamide or tacrolimus, leading to the remission in 80%. The overall mortality rate was 20%. Multivariate analysis showed that the presence of infections and CRP level >50 mg/l on HPS related with poor prognosis.. The prevalence of HPS among in-hospital patients with systemic autoimmunity is not ignorable. Administration of immunosuppressants was effective in cases with autoimmune-associated HPS, whereas prognosis was poor in infection-associated HPS.

Topics: Adult; Aged; Autoimmune Diseases; Bacterial Infections; Cyclophosphamide; Cyclosporine; Glucocorticoids; Humans; Immunosuppressive Agents; Lymphohistiocytosis, Hemophagocytic; Middle Aged; Prognosis; Retrospective Studies; Tacrolimus; Virus Diseases; Young Adult

To determine whether intravitreal injection of tacrolimus suppresses ongoing experimental autoimmune uveoretinitis (EAU) in rats.. Rats were immunised with interphotoreceptor retinoid-binding protein peptide (R14) and given an intravitreal injection of tacrolimus on day 12 after immunisation. Intraocular inflammation was assessed by slit-lamp biomicroscopy and histopathological examination. Interferon gamma and tumour necrosis factor alpha protein levels in the ocular tissues were measured. Gene expression of chemokines was determined in ocular tissues by reverse transcription-polymerase chain reaction. To evaluate the systemic effect of intravitreal injection of tacrolimus, delayed-type hypersensitivity was measured by ear swelling.. Clinical and pathological scores showed that ocular inflammation of tacrolimus-treated eyes was markedly less than that of vehicle-treated eyes. The amount of interferon gamma and tumour necrosis factor alpha was considerably inhibited in tacrolimus-treated eyes. The gene expression of monocyte chemattractant protein-1 (MCP-1) and regulated upon activation, normal T cell expressed and secreted (RANTES) was markedly reduced in tacrolimus-treated eyes. Delayed-type hypersensitivity responses were not impaired in tacrolimus-treated rats.. Intravitreal injection of tacrolimus was highly effective in suppressing the ongoing process of EAU without any side effects on systemic cellular immunity. This treatment may be useful in the management of patients with severe uveitis.

Topics: Animals; Autoimmune Diseases; Cells, Cultured; Chemokines; Eye; Female; Gene Expression Regulation; Hypersensitivity, Delayed; Immunity, Cellular; Immunosuppressive Agents; Injections; Interferon-gamma; Macrophages; Rats; Rats, Inbred Lew; Retinitis; RNA, Messenger; Tacrolimus; Treatment Outcome; Tumor Necrosis Factor-alpha; Uveitis; Vitreous Body

The current study was designed to determine whether intravitreal injection of tacrolimus (FK506) modulates the gene expression of neurotrophic factor-related molecules in the retina from eyes with induced experimental autoimmune uveoretinitis (EAU) in rats.. Rats were immunised with interphotoreceptor retinoid binding protein peptide (R14) and given intravitreal injection of tacrolimus on day 12 after immunisation. As control, immunised rats received intravitreal injection of vehicle. On day 15 after immunisation, changes in the genetic programme associated with neuroprotection and inflammatory responses in the retinas from both groups were determined by DNA microarray analyses and confirmed by real-time PCR analyses.. The gene expression of inflammatory responses was markedly reduced in tacrolimus-treated eyes. Genes for molecules associated with neuroprotection (oestrogen receptor, erythropoietin receptor, gamma-aminobutyric acid receptor, protein kinase C, glial cell line-derived neurotrophic factor receptor, fibroblast growth factor and neuropeptide Y receptor) were upregulated in the retinas from tacrolimus-treated eyes.. Intravitreal injection of tacrolimus modulated the genes related to neuroprotection in the retina during the ongoing process of EAU. This treatment may be useful for the neuroprotection of retina with severe uveitis as well as for immunosuppression in the uveitic eyes.

Topics: Animals; Autoimmune Diseases; Disease Models, Animal; Female; Gene Expression Profiling; Immunosuppressive Agents; Injections; Nerve Growth Factors; Oligonucleotide Array Sequence Analysis; Rats; Rats, Inbred Lew; Retinitis; RNA, Messenger; Tacrolimus; Up-Regulation; Uveitis, Anterior; Vitreous Body

We report a 17-year-old boy who was diagnosed as autoimmune encephalitis with various neurological complications such as hemiplegia, aphasia and seizures. An autoimmune process was considered to be responsible for the repeated episodes of encephalitis because the symptoms were highly responsive to steroids and anti-glutamate receptor antibodies were detected in the CSF. After administration of the immunosuppressant tacrolimus, we could taper the steroid dosage. He has had no relapse for three years to date. We demonstrated the possibility of steroid-sparing treatment with tacrolimus for a patient with steroid-responsive encephalitis. There were few reports describing tacrolimus therapy for encephalitis. Tacrolimus may be effective for selected patients with recurrent encephalitis in which an autoimmune mechanism is considered as the pathogenesis.

Topics: Adolescent; Autoimmune Diseases; Encephalitis; Humans; Immunosuppressive Agents; Male; Tacrolimus

Autoimmunity results from loss of mechanisms controlling self-reactivity. Autoimmune disorders play an increasingly important role and CD40-CD40 ligand (CD40L) interaction on immunocompentent cells is able to break established immunotolerance. To study the effects of the calcineurin-inhibitor FK506 on CD40L-induced systemic autoimmunity, CD40L transgenic (tg) mice, which spontaneously develop a mixed connective tissue-like disease, were treated with FK506 after onset of overt autoimmunity. Interestingly, FK506-treated CD40L tg mice showed significantly reduced autoimmune dermatitis scores and markedly decreased numbers of lesional infiltrating leukocytes. This finding was associated with diminished lymphadenopathy induced by FK506 treatment. Furthermore, FK506 suppressed the development of cytotoxic/autoreactive CD8(+) T cells as evidenced by the reduced expression of T cell activation markers in treated CD40L tg mice. Importantly, FK506 induced a significant reduction in autoantibody titers in the serum of CD40L tg animals. As CD40L tg mice develop nephritis leading to loss of renal function proteinuria was determined after FK506 injections. Notably, FK506 treatment re-established renal function as indicated by significantly reduced uric protein concentrations of treated CD40L tg mice. Together, these findings show the beneficial therapeutic effects of FK506 for the treatment of CD40L-induced autoimmunity. Additionally, these results demonstrate that FK506 is able to suppress ongoing severe autoimmune responses.

Topics: Animals; Autoantibodies; Autoimmune Diseases; Autoimmunity; Calcineurin Inhibitors; CD40 Ligand; Cell Nucleus; Dermatitis; Female; Immunosuppressive Agents; Mice; Mice, Transgenic; T-Lymphocytes, Cytotoxic; Tacrolimus

Dendritic cells are the coordinators of the adaptive immune response. Chronic activation of skin dendritic cells by keratinocyte expression of CD40 ligand (CD40L; CD154) leads to autoimmunity. In this issue, systemic administration of tacrolimus is shown by Loser et al. to effectively treat autoimmunity in a murine model involving transgenic keratinocyte expression of CD40L.

Topics: Animals; Autoimmune Diseases; Calcineurin Inhibitors; Dendritic Cells; Disease Models, Animal; Immunosuppressive Agents; Mice; Skin; Skin Diseases; Tacrolimus

Autoimmune enteropathy (AIE) is a rare cause of intractable diarrhea in infancy. A variant with onset in adulthood has recently been described. The immune mechanisms underlying AIE are unclear and the experience in the management of adult AIE is very limited.. A 19-year-old male patient with massive refractory diarrhea and significant weight loss was diagnosed with AIE. He did not improve with corticosteroid and azathioprine treatment and was then treated successfully with infliximab. The response to treatment was rapid and complete. Because of a severe life-threatening hypersensitivity reaction during the 4th infliximab dose, infliximab had to be discontinued and therapy with tacrolimus was initiated. A complete clinical remission has since been maintained.. Both infliximab and tacrolimus may provide a therapeutic alternative in patients with adult refractory AIE.

Topics: Administration, Oral; Adult; Antibodies, Monoclonal; Autoimmune Diseases; Biopsy; Drug Therapy, Combination; Endoscopy, Gastrointestinal; Follow-Up Studies; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Infusions, Intravenous; Intestinal Diseases; Intestinal Mucosa; Male; Severity of Illness Index; Tacrolimus; Treatment Outcome

Topics: Animals; Autoimmune Diseases; Brain; Calcineurin; Calcineurin Inhibitors; Cyclosporine; Dimerization; DNA-Binding Proteins; Graft Rejection; Humans; Mammals; NFATC Transcription Factors; Nuclear Proteins; Protein Conformation; Substrate Specificity; Tacrolimus; Transcription Factors

Topics: Absorption; Administration, Topical; Autoimmune Diseases; Bone Marrow Transplantation; Child, Preschool; Graft vs Host Disease; Humans; Male; Skin Diseases; Tacrolimus

Autoimmune recurrence and subsequent diabetes after pancreas transplantation has been described. In this cross-sectional study 91 type 1 diabetic patients were examined after successful pancreas/kidney transplantation (SPK). We studied the prevalence of autoantibodies to insulin (IAA), glutamate decarboxylase (GAD) and tyrosine phosphatase (IA-2) as well as parameters of pancreas graft function. Graft recipients were grouped according to immunoreactivity: group 1: no immunoreactivity; group 2: immunoreactivity to one antigen; group 3: immunoreactivity to two or three antigens. Twenty-five percent of graft recipients displayed no immunoreactivity, 39% displayed positivity for one antigen and 36% were positive for two or three antigens. There were no significant differences concerning fasting glucose, HbA1(c), glucose tolerance and renal function between the groups. Patients with cyclosporine (n = 42) as first-line immunosuppression displayed more often immunoreactivity to IA-2 and IAA than patients treated with tacrolimus (n = 49) (31% vs. 14%, P = 0.04; 67% vs. 47%, P = 0.04). In addition methylprednisolone therapy was related to less immunoreactivity to IA-2. Immunological markers for type 1 diabetes can be determined in the majority of pancreas graft recipients despite adequate immunosuppression. However, immunoreactivity was not associated with impaired graft function. Patients with cyclosporine for immunosuppression and withdrawal of glucocorticoids therapy were more often immunoreactive to IAA and IA-2.

Topics: Adult; Autoantibodies; Autoimmune Diseases; Blood Glucose; Female; Glucocorticoids; Glucose; Glucose Tolerance Test; Glutamate Decarboxylase; Graft Rejection; Humans; Immunosuppressive Agents; Insulin; Islets of Langerhans; Male; Methylprednisolone; Middle Aged; Models, Statistical; Pancreas; Pancreas Transplantation; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases; Recurrence; Tacrolimus; Time Factors; Treatment Outcome

Oral cicatricial pemphigoid is a chronic autoimmune blistering disease which affects predominantly the gingiva and the buccal mucosa. The pathogenesis of this disease is still incompletely understood; however, there is compelling evidence that cicatricial pemphigoid might be mediated by T lymphocytes. Therefore, we performed immunomodulatory therapy with topical tacrolimus in patients with long-standing, therapy-resistant oral cicatricial pemphigoid. Following 3 months of treatment, complete healing and ongoing remission could be achieved.

Topics: Aged; Autoimmune Diseases; Facial Dermatoses; Female; Humans; Immunosuppressive Agents; Male; Mouth Diseases; Ointments; Pemphigoid, Bullous; Tacrolimus; Time Factors; Treatment Outcome

Topics: Adjuvants, Immunologic; Age Factors; Autoimmune Diseases; Child; Humans; Immunosuppressive Agents; Tacrolimus; Vitiligo

Topics: Adolescent; Alopecia; Amenorrhea; Autoantibodies; Autoimmune Diseases; Drug Therapy, Combination; Female; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Methylprednisolone; Prednisolone; Spasm; Syndrome; Tacrolimus

Immunomodulators include both immunostimulatory and immunosuppressive agents. Obligate contact sensitizers such as diphencyprone or dinitrochlorobenzene have been used against viral and autoimmune diseases. Newer agents such as the toll-like receptor agonists imiquimod and resiquimod have been clinically used to treat viral infections and skin cancers in immunocompetent and immunosuppressed patients. On the other hand, the topical immunosuppressive agents tacrolimus and pimecrolimus have been used with great success in the treatment of chronic inflammatory diseases in children and adults. The introduction of this new class of drugs (i.e. Calcineurin inhibitors) marked the beginning of the post-cortisone era in clinical dermatology. Toll-like receptor agonists and calcineurin antagonists will supplement corticosteroids to improve specific dermatological therapy. Topical immunotherapy with both immunostimulatory and immunosuppressive agents show potential for effective and patient-friendly treatment of inflammatory, infectious and neoplastic skin diseases. Long-term evaluation will define the tolerability and the safety profile.

Topics: Adjuvants, Immunologic; Administration, Topical; Adult; Aged; Aged, 80 and over; Aminoquinolines; Asthma; Autoimmune Diseases; Bowen's Disease; Child; Cyclopropanes; Dermatitis, Atopic; Dinitrochlorobenzene; Female; Follow-Up Studies; Herpes Simplex; Humans; Imidazoles; Imiquimod; Immunity, Cellular; Immunocompromised Host; Immunoglobulin A; Immunosuppressive Agents; Lichen Sclerosus et Atrophicus; Male; Molluscum Contagiosum; Papillomavirus Infections; Precancerous Conditions; Skin Diseases; Skin Diseases, Viral; Skin Neoplasms; Tacrolimus; Time Factors; Warts

Autoimmune enteropathy is a life-threatening, chronic disease of the small bowel mucosa, which generally responds well to steroids. Treatment requires long-term immunosuppression, and steroid-sparing treatment strategies are desirable. Azathioprine and cyclosporine A have limitations, however alternatives have not been described in adults.. We present the case of a 54-year-old male patient with autoimmune enteropathy who responded initially to a standard treatment with steroids, but was dependent on 30 mg prednisolone. Medical treatment was changed to tacrolimus after renal function deteriorated under treatment with cyclosporine A. Under this regimen, small bowel histology normalized and the clinical condition is stable after 2 years of introduction of tacrolimus.. This constitutes the first report of effective treatment of adult autoimmune enteropathy with tacrolimus, a substance with a similar mode of action to cyclosporine, but with fewer side effects and improved bioavailability.

Topics: Administration, Oral; Autoimmune Diseases; Duodenum; Humans; Immunosuppressive Agents; Intestinal Diseases; Male; Middle Aged; Tacrolimus

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Autoimmune Diseases; Chronic Disease; Diarrhea; Follow-Up Studies; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infant; Infliximab; Intestinal Diseases; Male; Parenteral Nutrition; Tacrolimus

We have recently reported the accumulation of oligoclonal activated T cells in the spontaneously developed autoimmune pancreatitis in aly/aly mouse. In this study, we examined the effects of FK506 in this mouse model in preventing autoimmune pancreatitis and investigated its action on calcium signalling apoptosis of alymphoplasia (aly) lymphocytes in vitro. Mice were treated with FK506 from 8 to 25 weeks of age. At the age of 15 weeks, minimal mononuclear cell infiltration was observed in the pancreas in both the FK506 treated group and the control group. Furthermore, a marked cell infiltration associated with destruction of acini and partial fatty changes were observed in 25-week-old control mice. In contrast, FK506 treated mice showed almost no tissue destruction or mononuclear cell infiltration at the age of 25 weeks. Furthermore, at 15 weeks of age, most mononuclear cells in FK506-treated mice were TUNEL positive, whereas only a few were positive in control mice. This augmentation of T cell apoptosis by FK506 was confirmed using naive splenocytes activated by PMA and ionomycin in vitro. Finally, a suppressive effect of FK506 on Bcl-2 production but not on Bax production was confirmed by Western blotting. This unique effect of FK506 on the augmentation of T cell apoptosis is probably one of the mechanisms explaining its beneficial effect on aly autoimmune pancreatitis.

Topics: Animals; Apoptosis; Autoimmune Diseases; bcl-2-Associated X Protein; Calcium Signaling; Cells, Cultured; Immunosuppressive Agents; Mice; Pancreatitis; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Receptors, Antigen, T-Cell; T-Lymphocytes; Tacrolimus

We assessed T cell association with acinar cell apoptosis and a preventive effect of tacrolimus, a T cell suppressant, on the development of chronic pancreatitis in male Wistar Bonn/Kobori rats. At 15 wk, cellular infiltrates composed of F4/80-positive cells (monocytes/macrophages), CD4-positive cells, and CD8-positive cells were extensive in the interlobular connective tissue and parenchyma. In particular, CD8-positive cells invaded pancreatic lobules and formed close associations with acinar cells, some of which demonstrated features of apoptosis. At 20 wk, CD8-positive cells were still abundant in the fibrotic tissue formed with loss of acinar cells. Repeated subcutaneous injection of 0.1 mg x kg(-1) x day(-1) but not 0.025 mg x kg(-1) x day(-1) of tacrolimus for 10 wk completely prevented the occurrence of acinar cell apoptosis, infiltration of CD4- and CD8-positive cells, and development of pancreatitis at the age of 20 wk, but these maneuvers did not recover the decreased plasma corticosterone levels, which may be responsible for the development of disease. We demonstrated that T cells, possibly CD8-positive cells, are involved in inducing apoptosis of acinar cells, raising the possibility that tacrolimus might find clinical application in the treatment of autoimmune chronic pancreatitis.

Topics: Animals; Apoptosis; Autoimmune Diseases; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Chronic Disease; Corticosterone; Immunosuppressive Agents; In Situ Nick-End Labeling; Male; Pancreatitis; Rats; Rats, Wistar; T-Lymphocytes; Tacrolimus

Topics: Administration, Topical; Adult; Adverse Drug Reaction Reporting Systems; Animals; Autoimmune Diseases; Child; Clinical Trials as Topic; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Skin Diseases; Tacrolimus; Treatment Outcome

FTY720 is a new immunosuppressant agent and selectively decreases the number of circulating lymphocytes. In this study, we compared the effects of FTY720 with those of tacrolimus on experimental autoimmune myocarditis (EAM) in rats. A significant decrease in circulating lymphocyte counts was noted after a single administration of FTY720 in normal rats. At day 0, 7-week-old male Lewis rats were immunized with purified porcine cardiac myosin emulsified in complete Freund's adjuvant. FTY720 or tacrolimus was administered intraperitoneally daily. The number of myocarditis-affected areas in the FTY720 treatment groups with doses of 0.1 mg/kg/ day was significantly lower than those in control groups at days 14 and 28. In addition, at day 28, the myocarditis-affected areas in the FTY720 treatment group were significantly smaller than those in the tacrolimus treatment group receiving the same dose. Effects of early administration (days 0-10) and delayed administration (days 11-20) of FTY720 also were examined. At day 28, the myocarditis-affected areas in the early therapy group were significantly lower than those in the control group. In conclusion, we demonstrated that the development of EAM could be prevented by FTY720. These data also indicated that lymphocyte-mediated immunity is critically involved in the development of EAM.

Topics: Analysis of Variance; Animals; Autoimmune Diseases; Body Weight; Fingolimod Hydrochloride; Immunosuppressive Agents; Injections, Intraperitoneal; Lymphocyte Count; Lymphocytes; Male; Myocarditis; Organ Size; Propylene Glycols; Rats; Rats, Inbred Lew; Sphingosine; Tacrolimus

Topics: Adult; Autoimmune Diseases; Diabetes Mellitus; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Tacrolimus

Mercuric-chloride (HgCl2) induces a lymphoproliferative disorder and autoimmune glomerulonephritis in Brown Norway rats. The effects of a new immunosuppressant FK 506 on this model of glomerulonephritis were studied. Brown Norway rats were treated with HgCl2 according to a standard protocol (HgCl2 1 mg/kg s.c. 3 times/ week). Rats developed proteinuria at day 7, which reached a plateau level at day 14. On day 14, renal histology showed prominent mesangial cellular proliferation and the expansion of mesangial matrix. Electron microscopic study showed the effacement of visceral epithelial foot processes and the microvillous transformation of the visceral epithelium. Immunofluorescence study showed a strong linear staining for IgG and the adhesion molecule ICAM-1 in all glomeruli. Coadministration of FK 506 (1 mg/kg s.c. daily) prevented the appearance of proteinuria at day 14 (621.4 +/- 30.5 vs. 2.2 +/- 2.7 mg/day) and the morphological lesions. These findings suggest that FK 506 could be useful for the therapy of certain types of human glomerulonephritis.

Topics: Animals; Autoimmune Diseases; Blood Proteins; Disinfectants; Dose-Response Relationship, Drug; Glomerulonephritis; Immunoglobulin G; Immunosuppressive Agents; Intercellular Adhesion Molecule-1; Kidney Glomerulus; Male; Mercuric Chloride; Microscopy, Electron; Rats; Tacrolimus; Urine

Mercuric chloride (HgCl2) induces a lymphoproliferative disorder and autoimmune glomerulonephritis in Brown Norway (BN) rats. The effects of a new immunosuppressant, FK 506, on this model of glomerulonephritis were studied. BN rats were treated with HgCl2 according to a standard protocol (HgCl2 1 mg/kg s.c. 3 times/week). FK 506 was inoculated subcutaneously daily from day 15 to day 28. Animals were divided into 4 groups: group 1, rats were treated with normal saline alone and sacrificed on day 28; group 2, rats were treated with HgCl2 alone and sacrificed on day 14; group 3, rats were treated with HgCl2 alone and sacrificed on day 28, and group 4, rats were treated with HgCl2 and FK 506 (from day 15 to day 28) and sacrificed on day 28. Rats developed proteinuria by day 7, which reached a plateau level by day 14. On day 14, renal histology showed prominent mesangial cellular proliferation and the expansion of mesangial matrix. Electron microscopic study showed the effacement of visceral epithelial foot processes and the microvillous transformation of the visceral epithelium. Immunofluorescence study showed strong linear staining for IgG and the adhesion molecule ICAM-1 in all glomeruli. Treatment with FK 506 (1 mg/kg s.c. daily) resulted in a remarkable reduction in proteinuria on day 28 (493.5 +/- 48.3 vs. 24.4 +/- 13.5 mg/day) and an improvement in the morphological lesions. These findings suggest that FK 506 could be useful in the treatment of some human glomerulonephritides.

Topics: Animals; Autoimmune Diseases; Dose-Response Relationship, Drug; Fluorescent Antibody Technique; Glomerulonephritis; Immunoglobulin G; Immunosuppressive Agents; Intercellular Adhesion Molecule-1; Kidney; Kidney Function Tests; Male; Mercuric Chloride; Microscopy, Electron; Proteinuria; Rats; Rats, Inbred BN; Tacrolimus

Plasma from 126 patients with various autoimmune diseases and 118 healthy subjects were examined to determine the presence of autoantibodies to FKBP12, one of immunophilins. The frequency of IgG and/or IgM anti-FKBP12 autoantibodies detected by ELISA was as follows; SLE (15/39), SSc (11/27), CREST (4/7), RA (2/8), MCTD (0/5), Graves' disease (4/12), IDDM (2/6), PM/DM (0/3), MG (1/4), AIH (2/6), PBC (4/9), and healthy subjects (5/118). The specificity of the autoantibodies was demonstrated by absorption of the plasma samples with r-FKBP12 and other recombinant proteins. In immunoblotting, IgM anti-FKBP12 autoantibodies reacted with two bands of 12 and 24 kD, the latter representing the dimer. Anti-FKBP12 autoantibodies in some patients reacted more strongly with the dimer than the monomer, suggesting that FKBP12 may also exist as the dimer in vivo. The majority of anti-FKBP12 autoantibodies bound to two synthetic peptides corresponding to amino acid residues of FKBP12, Pro16 approximate to Tyr26 and Thr27 approximate to Phe46. These epitopes are phylogenetically well conserved and responsible for the binding to calcineurin and FK506. The autoantibodies inhibited pentamerization of FKBP12 with FK506, calcineurin, calmodulin, and Ca2+ in vitro. These data define the frequent occurrence of a novel set of autoantibodies to a cytosolic protein involved in the regulation of the immune response.

Topics: Amino Acid Sequence; Antibody Specificity; Autoantibodies; Autoimmune Diseases; Enzyme-Linked Immunosorbent Assay; Epitopes; Humans; Immunoglobulin M; Immunophilins; Molecular Sequence Data; Peptides; Tacrolimus; Tacrolimus Binding Proteins

Topics: Adrenal Cortex Hormones; Autoimmune Diseases; Cyclosporine; Data Collection; Drug Therapy, Combination; Europe; Hepatitis B; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Postoperative Complications; Renal Insufficiency; Tacrolimus

Autoimmune liver diseases (AILD) may progress to liver failure, requiring liver transplantation as definitive therapy, and these immune-mediated disorders may predispose the patient to more frequent graft rejection. The objective of this study was to determine the effect of preexisting AILD on the incidence of allograft rejection after liver transplantation. Sixty-three patients who underwent liver transplantation between March 1988 and December 1994 for AILDs that included autoimmune hepatitis (AIH; n = 33) and primary biliary cirrhosis (PBC; n = 30) were retrospectively compared with 47 patients who underwent liver transplantation for alcoholic cirrhosis during the same time period. There was a lower incidence of acute allograft rejection in patients with AILD who received tacrolimus-based compared with cyclosporine-based immunosuppression (50% v 85.5%; P = .02). However, patients with AILDs overall had a higher incidence of acute rejection than patients with alcoholic cirrhosis (81% v 46.8%; P < .001), regardless of the type of immunosuppression. In addition, steroid-resistant rejection occurred more frequently in patients with AILDs than in patients with alcoholic cirrhosis (38.1% v 12.8%; P = .003). There was also a trend toward a higher incidence of chronic rejection in patients with AILDs compared with patients with alcoholic cirrhosis (11.1% v 2.1%), but this difference did not reach statistical significance. Patient and graft survivals at 1 and 3 years were similar between patients with AILDs and alcoholic liver disease. Compared with alcoholic cirrhosis, preexisting AILDs are associated with a higher incidence of acute allograft rejection and a trend toward more frequent chronic rejection.

Topics: Adult; Autoimmune Diseases; Case-Control Studies; Chi-Square Distribution; Cyclosporine; Female; Graft Rejection; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Prednisone; Retrospective Studies; Statistics, Nonparametric; Tacrolimus; Transplantation, Homologous

Topics: Adult; Anti-Bacterial Agents; Autoantibodies; Autoimmune Diseases; Cyclosporine; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Tacrolimus

Topics: Adolescent; Autoimmune Diseases; Biopsy; Chronic Disease; Colitis; Diarrhea; Duodenum; Gastroenteritis; Humans; Immunosuppressive Agents; Male; Rectum; Tacrolimus

Conventional allogeneic bone marrow transplantation after myeloablation can prevent experimental autoimmunity and has been proposed as treatment for humans. However, trace populations of donor hematolymphoid cells persisting in solid organ allograft recipients have been associated in some circumstances with therapeutic effects similar to replacement of the entire bone marrow. We therefore examined whether inducing hematolymphoid microchimerism without myeloablation could confer the ability to resist mercuric chloride (HgCl2)-induced autoimmunity. Brown-Norway (BN) rats were pretreated with a syngeneic or allogeneic bone marrow infusion under transient FK506 immunosuppression before receiving HgCl2. They were compared with BN rats receiving either no pretreatment (naive) or FK506 alone. Administration of HgCl2 to naive BN rats induced marked autoantibody production, systemic vasculitis and lymphocytic infiltration of the kidneys, liver and skin in all of the animals and a 47% mortality. In contrast, BN rats pretreated with HgCl2-resistant allogeneic Lewis bone marrow and transient FK506 showed less clinical disease and were completely protected from mortality. More specifically, IgG anti-laminin autoantibody production was decreased by 40% (P < 0.05), and there was less histopathological tissue injury (P < 0.005), less in vitro autoreactivity (P < 0.05), less of an increase in class II MHC expression on B cells (P < 0.01), and 22% less weight loss (P < 0.01), compared with controls. Protection from the experimental autoimmunity was associated with signs of low grade activation of the BN immune system, which included: increased numbers of circulating B and activated T cells before administration of HgCl2, and less autoreactivity and spontaneous proliferation in vitro after HgCl2.

Topics: Animals; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Bone Marrow Transplantation; Cell Movement; Histocompatibility Antigens Class II; Immunosuppressive Agents; Laminin; Lewis Blood Group Antigens; Lymphocyte Activation; Lymphocytes; Male; Mercuric Chloride; Rats; Tacrolimus; Transplantation Chimera; Vasculitis; Weight Loss

Autoimmune enteropathy is characterized by chronic secretory diarrhea, villous atrophy, associated autoantibodies, and a partial response to immunosuppression. Currently available therapy (including steroids and cyclosporine) has resulted in remission only in a subset of patients. We evaluated the effects of tacrolimus (FK506) in patients with autoimmune enteropathy refractory to steroids and cyclosporine. Three patients with diagnosed autoimmune enteropathy who continued to have intractable diarrhea despite treatment with steroids and/or cyclosporine were treated with oral tacrolimus. Despite documented histological villous atrophy and poor absorption of oral cyclosporine, therapeutic tacrolimus levels were easily achieved in all 3 patients. All patients showed clinical improvement as documented by decreased stool output and ability to be weaned off parenteral nutrition; response time ranged from 1 to 4 months after tacrolimus was begun. Histological improvement was noted in all patients, and the small bowel biopsy specimens of 2 of the 3 patients showed a return to normal. All patients have been followed up for at least 6 months and are in clinical remission; 1 has received a bone marrow transplant for underlying immunodeficiency. Tacrolimus is a useful drug in the treatment of autoimmune enteropathy, even in patients who have not responded to steroids or cyclosporine. No long-term follow-up of patients with autoimmune enteropathy treated with tacrolimus is currently available.

Topics: Administration, Oral; Atrophy; Autoimmune Diseases; Biopsy; Duodenum; Female; Humans; Immunosuppressive Agents; Infant; Intestinal Diseases; Male; Remission Induction; Tacrolimus

Topics: Alopecia; Autoimmune Diseases; Graft Rejection; Hair; Humans; Liver Transplantation; Male; Middle Aged; Tacrolimus

Topics: Autoimmune Diseases; Betamethasone; Child, Preschool; Cyclosporine; Dose-Response Relationship, Drug; Drug Administration Schedule; Follow-Up Studies; Genetic Linkage; Humans; Immunosuppressive Agents; Infant; Intestinal Diseases; Male; Sex Chromosome Aberrations; Tacrolimus; X Chromosome

It has been suggested that intercellular adhesion molecule-1 (ICAM-1) may play an important role in the initiation, localization, and perpetuation of autoimmune thyroid diseases (AITD). In an effort to clarify its role, we have investigated the expression of ICAM-1 on thyroid epithelial cells (TEC) of patients with AITD, patients with nontoxic goiter (NTG), and normal subjects (PN) by flow cytometric analysis under basal conditions and after modulation with cytokines, before and after 8 weeks of thyroid tissue xenotransplantation in nude athymic mice (which lyses all passenger lymphocytes), and in severe combined immunodeficient (SCID) mice where these cells survive. Before xenografting, ICAM-1 was expressed on 56% of TEC from Hashimoto's thyroiditis (n = 5), 54% of Graves' disease (n = 6), 15% of NTG (n = 5), and 12% of PN TEC. After the xenografts had been 8 weeks in nude mice, ICAM-1 expression decreased markedly in AITD TEC [from 56% to 10% in Hashimoto's thyroiditis (P < 0.001) and from 54% to 8% in Graves' disease (P < 0.01)], but did not change significantly in NTG or PN. After the xenografts had been 8 weeks in SCID mice, the expression of ICAM-1 was significantly higher on TEC of AITD compared with the same tissue in nude mice. When the SCID mice engrafted with AITD tissue were treated with the anti-CD4+ T (helper) cell agent FK-506, the expression of ICAM-1 was reduced significantly compared with that in the original tissue or that in nontreated mice engrafted with the same tissue. The proportion of TEC that were ICAM-1 positive was up-regulated in all cases by certain cytokines (e.g. interferon-gamma and tumor necrosis factor-alpha applied alone or in combination). We also detected the presence of ICAM-1 in AITD frozen tissues using an immunohistochemical technique. These data suggest a role for ICAM-1 in human AITD. However, the expression of ICAM-1 appears to be a secondary phenomenon in response to the immune assault, rather than a primary event. Our results support the idea that TEC may act as passive captives to immunological events in human AITD.

Topics: Animals; Autoimmune Diseases; Cells, Cultured; Cytokines; Epithelium; HLA-DR Antigens; Humans; Immunohistochemistry; Intercellular Adhesion Molecule-1; Male; Mice; Mice, Nude; Mice, SCID; Tacrolimus; Thyroid Diseases; Thyroid Gland; Tissue Transplantation; Transplantation, Heterologous

Topics: Adolescent; Adult; Aged; Animals; Autoimmune Diseases; Bone Marrow Transplantation; Child; Child, Preschool; Cricetinae; Demography; Female; Forecasting; Graft Enhancement, Immunologic; Graft Survival; Graft vs Host Disease; Hospitals, University; Humans; Immunosuppression Therapy; Infant; Life Tables; Liver Diseases; Liver Transplantation; Male; Middle Aged; Pennsylvania; Rats; Reoperation; Retrospective Studies; Risk Factors; Survival Analysis; Tacrolimus; Transplantation, Heterologous; Treatment Outcome

Preventive effects of FK506 on autoimmune myocarditis have been demonstrated, but the therapeutic efficacy of the agent in established myocarditis yet remains to be assessed. In this study, effects of FK506 on experimental autoimmune myocarditis were investigated by the use of the agent after the onset of the disease. Lewis rats were immunized with either cardiac myosin or bovine serum albumin (BSA) in complete Freund's adjuvant. The onset of the disease was ascertained by examining randomly chosen cardiac myosin-immunized rats. Animals were divided into four groups: the BSA-immunized saline-treated group (group A, n = 6); the BSA-immunized FK506-treated group (group B, n = 6); the myosin-immunized saline-treated group (group C, n = 6); and the myosin-immunized FK506-treated group (group D, n = 11). Saline or 1.0 mg/kg/day of FK506 were intramuscularly injected from day 16 to day 27. All the rats were put to death on day 28. Rats of group C became severely ill by the third week, while in contrast, rats of group D remained active, as did rats of groups A and B. The heart weight/body weight ratio was significantly lower in group D than in group C rats. Group mean values were 3.48 +/- 0.10 gm/kg for group A, 3.48 +/- 0.16 gm/kg for group B, 4.94 +/- 0.66 gm/kg for group C, and 3.88 +/- 0.43 gm/kg for group D. Rats of group C showed severe myocarditis with mononuclear cell infiltration, myocardial necrosis, and interstitial edema.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Autoimmune Diseases; Body Weight; Heart; Myocarditis; Myocardium; Organ Size; Random Allocation; Rats; Rats, Inbred Lew; Tacrolimus

It is well recognized that FK506 (Tacrolimus) is a powerful inhibitor of CD4+ T-cell activation and proliferation in vitro. In this study, immunophenotypic and functional analyses were performed on peripheral blood mononuclear cells from a total of 30 patients with various autoimmune disorders before and whilst the patients were receiving systemic FK506 therapy. The expression of cell surface IL-2R alpha and -beta on CD4+ and CD8+ cells, cytokine message (IL-2, IFN-gamma, IL-4, IL-10) and the proliferative activity of lymphocytes in response to rIL-2 were examined. Despite plasma levels of FK506 compatible with the blockade of IL-2 production by stimulated T cells in vitro, cells from patients on FK506 treatment cultured ex vivo with either ConA or IL-2 did not differ from normal cells in their expression of cytokine mRNA or their proliferative responses. These data indicate that the presumed in vivo suppression of T-cell function by FK506 is rapidly reversible ex vivo. Alternatively/additionally, they suggest that FK506 may mediate its in vivo action primarily by mechanisms other than blockade of T-cell function.

Topics: Adolescent; Adult; Aged; Autoimmune Diseases; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes; CD8 Antigens; Cytokines; Female; Gene Expression; Humans; Interleukin-2; Lymphocyte Activation; Male; Middle Aged; Polymerase Chain Reaction; T-Lymphocytes; Tacrolimus

A new immunosuppressive compound, FK-506, is a macrolide produced by Streptomyces tsukubaensis. It is reported that FK-506 prolongs the viability of allogenic grafts of the heart and kidney in vivo and inhibits the development of autoimmune diseases. Furthermore, immunosuppressive therapy of myocarditis in humans has been given special attention by various observers; however, it is controversial. This study investigates the effects of FK-506 on experimental autoimmune myocarditis in rats. We performed two experiments. In Experiment 1, FK-506 was given intramuscularly on Days 11-20 after the first immunization. The rats were immunized twice (on Day 0 and Day 7). They were injected subcutaneously in the footpads with 1.0 mg of human cardiac myosin in equal volumes of complete Freund's adjuvant supplemented with Mycobacterium tuberculosis. They were divided into four groups: Control (six rats, saline), group 1 (six rats, FK-506: 0.1 mg/kg/day), group 2 (seven rats, FK-506: 0.32 mg/kg/day), and group 3 (six rats, FK-506: 1.0 mg/kg/day). To investigate the histologic extent of myocarditis, we formulated a histologic score (0-3). Histologic scores were: Control, 1.90 +/- 0.14; group 1, 0.97 +/- 0.46; group 2, 0.03 +/- 0.05; and group 3, 0 +/- 0. The indices of heart weight/body weight were: Control, 0.74 +/- 0.10%; group 1, 0.45 +/- 0.05%; group 2, 0.35 +/- 0.03%; and group 3, 0.35 +/- 0.03%. In Experiment 2, FK-506 was given on Days 1-10 after the first immunization, earlier than in Experiment 1. The rats were similarly divided into four groups. Each group was given the same dose of FK-506 as in Experiment 1. Histologic scores were: Control 1.49 +/- 0.24; group 1, 1.60 +/- 0.22; group 2, 0.29 +/- 0.41; and group 3, 0.03 +/- 0.03. The indices of heart weight/body weight were: Control, 0.69 +/- 0.15%; group 1, 0.76 +/- 0.09%; group 2, 0.42 +/- 0.08%; and group 3, 0.37 +/- 0.03%. Accordingly, in Experiments 1 and 2, the effects of FK-506 on autoimmune myocarditis were dose-dependent. On the other hand, in Experiments 1 and 2, not only in the control group but also in all treated groups, the titers of anti-myosin IgG were high. In conclusion, even if it is administered just before the onset of myocarditis, FK-506 is extremely effective at suppressing autoimmune myocarditis, despite a high titer of anti-myosin IgG.

Topics: Animals; Antibodies; Autoimmune Diseases; Body Weight; Male; Myocarditis; Myosins; Organ Size; Rats; Rats, Inbred Lew; Tacrolimus

Topics: Animals; Animals, Newborn; Autoimmune Diseases; Diabetes Mellitus, Type 1; Graft Survival; Islets of Langerhans; Mice; Mice, Inbred NOD; Pancreas; Pancreas Transplantation; Pancreatic Diseases; Tacrolimus

Topics: Animals; Autoimmune Diseases; Immunization; Kidney; Liver; Liver Function Tests; Macaca mulatta; Mycobacterium tuberculosis; Retinitis; Tacrolimus; Uveitis; Weight Loss

Topics: Animals; Autoimmune Diseases; Carrier Proteins; Cyclosporine; Drug Monitoring; Humans; Tacrolimus; Tacrolimus Binding Proteins; Transplantation Immunology

We have examined the effects of FK-506 and of the struturally related macrolide rapamycin, which bind with high affinity to a specific binding protein (FKBP), to evaluate the involvement of this protein in the release of preformed (histamine) and de novo synthesized inflammatory mediators (sulfidopeptide leukotriene C4 and prostaglandin D2) from mast cells isolated from human lung parenchyma. FK-506 (0.1 to 300 nM) concentration dependently inhibited histamine release from lung parenchymal mast cells activated by anti-IgE. FK-506 was more potent in lung mast cells than in basophils (IC50 = 1.13 +/- 0.46 nM vs 5.28 +/- 0.88 nM; p less than 0.001), whereas the maximal inhibitory effect was higher in basophils than in lung mast cells (88.4 +/- 2.5% vs 76.4 +/- 3.8%; p less than 0.01). FK-506 had little or no inhibitory effect on histamine release from lung mast cells challenged with compound A23187, whereas it completely suppressed A23187-induced histamine release from basophils. FK-506 also inhibited the de novo synthesis of 5-lipoxygenase (sulfidopeptide leukotriene C4) and cyclo-oxygenase (prostaglandin D2) metabolites of arachidonic acid from mast cells challenged with anti-IgE. Unlike in basophils, Il-3 (3 to 30 ng/ml) did not modify anti-IgE- or A23187-induced histamine release from lung mast cells nor did it reverse the inhibitory effect of FK-506. Rapamycin (3 to 300 nM) had little or no effect on the release of histamine from lung mast cells, but it was a competitive antagonist of the inhibitory effect of FK-506 on anti-IgE-induced histamine release from human mast cells with a dissociation constant of about 12 nM. These data indicate that FK-506 is a potent anti-inflammatory agent that acts on human lung mast cells presumably by binding to a receptor site (i.e., FKBP).

Topics: Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Autoimmune Diseases; Calcimycin; Cells, Cultured; Histamine Release; Humans; Immunoglobulin E; Interleukin-3; Leukotrienes; Mast Cells; Polyenes; Sirolimus; Tacrolimus

The effect of the immunosuppressant FK-506 on the development of diabetes in BB/Wor rats was investigated. Using a treatment schedule (25 micrograms i.m. from day 27 to 120), not associated with detectable general ill effects, this drug was found to completely inhibit the appearance hyperglycemia and to reduce the histological signs of pancreatic insulitis. The treatment was also able to reduce the percentages of Ia+ T-lymphocytes and to block the appearance of detectable serum levels of gamma interferon (IFN).

Topics: Animals; Autoimmune Diseases; Diabetes Mellitus, Type 1; Female; Interferon-gamma; Lymphocyte Activation; Male; Rats; Rats, Inbred BB; T-Lymphocyte Subsets; Tacrolimus

A newly developed immunosuppressive drug, FK506 (Fujisawa, Japan) is known to inhibit T-cell immunity. We have evaluated the action of this compound in MRL/lpr mice which develop a severe autoimmune disease. Eight-week-old female MRL/lpr of mice were treated subcutaneously with 2 mg/kg (high dose), 0.8 mg/kg (medium dose), 0.2 mg/kg (low dose) or solvent only (control) six times per week. Survival times of the mice were prolonged in the medium and the high dose treatment groups. The lymph node swelling was dramatically prevented with the high dose treatment. The increasing footpad swelling seemed to be also suppressed with the treatment. FACS analyses of the spleen cells revealed that FK506 reduced the percentage of double negative T cells (Thy-1.2+, Lyt-2-, L3T4-). Serological studies showed that anti-ssDNA and anti-dsDNA activities were significantly reduced by the high dose treatment, which is different from recent findings with Cyclosporine A. The high dose treatment also suppressed the total amount of IgG, even though the IgG concentration was rather increased by the medium dose treatment. Decreased proteinuria as well as pathological evaluations of the kidneys and lungs indicated that there were marked ameliorations in these organs with the treatment. These results suggest that FK506 could be potentially used for the treatment of autoimmune diseases.

Topics: Animals; Anti-Bacterial Agents; Arthritis; Autoimmune Diseases; Female; Immunoglobulin G; Immunosuppressive Agents; Lupus Nephritis; Lymphatic Diseases; Mice; Mice, Mutant Strains; Pulmonary Fibrosis; T-Lymphocytes; Tacrolimus

From days 30-120 after birth, 59 BB rats were treated with water (n = 20) or FK 506 in intragastric doses of 1 mg.kg-1.day-1 (n = 19) or 2 mg.kg-1.day-1 (n = 20). Diabetes developed in 75, 15, and 0% of the 3 groups, respectively. Animals protected from diabetes by FK 506 had normal intraperitoneal glucose tolerance tests, virtual absence histopathologically of autoimmune insulitis, and normal pancreatic insulin content. Forty-five to 75 days after stopping FK 506, approximately 75% of the rats that were diabetes free at 120 days remained so.

Topics: Animals; Anti-Bacterial Agents; Autoimmune Diseases; Blood Glucose; Cyclosporins; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Glucose Tolerance Test; Guinea Pigs; Immunosuppressive Agents; Insulin; Interleukin-2; Interleukin-3; Pancreas; Radioimmunoassay; Rats; Rats, Inbred BB; Rats, Inbred Strains; RNA, Messenger; Tacrolimus; Transcription, Genetic

The effects of a novel immunosuppressant, FK 506, on the efferent limb of the immune response were studied in the experimental autoimmune uveoretinitis (EAU) in the rat, using two different treatment schedules. First, rats actively immunized with S-antigen were treated with FK 506 only after the onset of EAU. FK 506 (1 or 3 mg kg-1 day-1) reduced the intensity of EAU as compared to that of non-treated rats. Especially, a daily dose of 3 mg kg-1 completely suppressed further development of EAU. It is, therefore, suggested that FK 506 treatment is effective in suppressing the ongoing process of the immune response, even after the disease has been initiated. Second, FK 506 (0.3 mg kg-1 day-1) was given only to the recipient rats which received IRBP-sensitized lymphocytes. None of FK 506-treated recipients developed EAU, while all control recipients developed the disease approximately 4 days after the cell transfer. The immune responses of FK 506-treated rats in the two experiments were also significantly suppressed. The antibody levels to S-antigen, the antigen-specific proliferative responses of lymphocytes, and even the proliferative responses to Con A were markedly suppressed in the rats in which FK 506 was given only during the efferent limb of the immune response.

Topics: Animals; Anti-Bacterial Agents; Antigens; Arrestin; Autoantigens; Autoimmune Diseases; Cell Division; Disease Models, Animal; Eye; Eye Proteins; Immunosuppressive Agents; Lymphocytes; Male; Rats; Rats, Inbred Lew; Retinitis; Tacrolimus; Uveitis

The authors previously reported that FK506 effectively suppressed the induction of experimental autoimmune uveoretinitis (EAU) in rats with much lower doses than cyclosporine A. This study was aimed at analyzing the immune status of the FK506-treated and EAU-suppressed rats and examining the hypothesis whether the agent could induce antigen-specific suppressor T (Ts) cells. It was found that spleens from S-antigen-immunized and FK506-treated rats contained a population of Ts cells inhibiting the proliferative responses of S-antigen-sensitized lymphocytes to S-antigen, yet these cells did not affect the proliferative responses of interphotoreceptor retinoid-binding protein (IRBP)-sensitized lymphocytes to IRBP. The helper T (Th) cells did not exhibit such suppressor activities. Furthermore, transfer of Ts cells from S-antigen-immunized and FK506-treated rats to naive syngenic rats induced partial inhibition of EAU induction or delay of EAU onset after immunizing the recipient rats with S-antigen. Lymphocytes from the EAU-suppressed recipients showed low proliferative response to S-antigen and low levels of antibody to S-antigen. These data thus indicate that FK506 treatment after S-antigen immunization induces an activation of Ts cells specific to S-antigen and that the Ts cells might contribute, at least in part, to the uniquely prolonged and intensive immunosuppression by FK506.

Topics: Animals; Anti-Bacterial Agents; Antigens; Arrestin; Autoimmune Diseases; Concanavalin A; Epitopes; Eye Proteins; Immunization; Immunosuppressive Agents; Immunotherapy, Adoptive; Lymphocyte Activation; Male; Rats; Rats, Inbred Lew; Retinitis; Retinol-Binding Proteins; Spleen; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Tacrolimus; Uveitis

The effects of two novel immunosuppressants, FK506 and 15-deoxyspergualin (15-DSG), on experimental autoimmune uveoretinitis (EAU) were evaluated in the rat. Rats were immunized with retinal soluble antigen (S-antigen) and treated with FK506 or 15-DSG, and the disease induction as well as the immune responses to the antigen were examined. The results were compared with animals treated with cyclosporine (CsA) which has been widely used to treat refractory uveitis in humans. A dose-response study showed that FK506 suppressed EAU induction at doses 10-30 times lower CsA when given on days 0-14 postimmunization, while 15-DSG suppressed the disease development at doses very similar to CsA. As with CsA, FK506 suppressed EAU induction when given only in the induction phase (days 0-5 postimmunization) or in the effector phase (days 7-12), but at doses much lower than CsA. On the other hand, 15-DSG suppressed EAU only at toxic doses with these schedules. The antigen specific mitotic response of lymphocytes was markedly suppressed by the three agents, while the antigen specific antibodies in sera were suppressed by 15-DSG and FK506 but not by CsA at doses effective in suppressing the disease induction. More significant findings were uniquely prolonged immunosuppressive effects of FK506: EAU induction as well as the immune responses to S-antigen were suppressed long after the cessation of drug treatment.

Topics: Animals; Antibodies; Antigens; Arrestin; Autoimmune Diseases; Body Weight; Cyclosporine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation, Preclinical; Enzyme-Linked Immunosorbent Assay; Eye; Eye Proteins; Guanidines; Immunosuppressive Agents; Male; Rats; Rats, Inbred Lew; Tacrolimus; Uveitis

In order to evaluate two new immunosuppressive agents, FR900506 (FK 506) and 15-Deoxyspergualine (15-DSG), the kinetics of infiltrating cells in the eyes of Lewis rats with experimental autoimmune uveoretinitis (EAU) were studied. Rats were immunized with retinal S-antigen and treated with different doses of either FK 506 or 15-DSG. The inflammatory ocular tissues obtained at various intervals during the process of EAU were examined using an immunoperoxidase technique. The results were compared with those eyes developing EAU without treatment or with suboptimal doses or a suboptimal dose of Cyclosporine (CsA). Both FK 506 and 15-DSG, like CsA, delayed the cellular kinetics during the course of EAU. However, FK 506 had the greatest effect on the kinetics of T lymphocyte subsets by causing the greatest increase in the recruitment time of the T suppressor/cytotoxic population. FK506 treatment resulted not only in the highest inhibition of expression of IL-2 receptors on T cells, but also in the prevention of the expression of MHC class II antigens on ocular resident cells. Treatment with 15-DSG resulted in general immunosuppression on various infiltrating inflammatory cells.

Topics: Animals; Antigens; Arrestin; Autoimmune Diseases; Cyclosporine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation; Eye Proteins; Guanidines; Immunoenzyme Techniques; Immunosuppressive Agents; Macrophages; Male; Rats; Rats, Inbred Lew; Retina; T-Lymphocyte Subsets; Tacrolimus; Uveitis

FK506, a new immunosuppressive agent, was given intramuscularly to rats for 12 days, starting on the day of type II collagen immunization. FK506 in doses of 0.32 mg/kg or more suppressed arthritis and also suppressed humoral and skin test response to type II collagen. FK506 suppressed arthritis only when given during the afferent limbs of immune response (0-4 days), whereas the drug was only marginally effective when treatment was started during the efferent limbs of immune response (7-11 days). FK506-induced immunosuppression continued and/or was maintained throughout the experiments (50 days). These rats immunized with type II collagen and treated with FK506 failed to develop arthritis even following a secondary immunization 50 days later but were fully capable of developing experimental allergic encephalomyelitis. This result suggest that FK506-treated rats develop specific unresponsiveness toward the type II collagen. It is concluded that FK506 is a strong immunosuppressive drug on collagen-induced arthritis.

Topics: Animals; Arthritis; Arthus Reaction; Autoantibodies; Autoimmune Diseases; Collagen; Encephalomyelitis, Autoimmune, Experimental; Female; Hypersensitivity, Delayed; Immunosuppressive Agents; Pyridines; Rats; Rats, Inbred Lew; Tacrolimus

A comparative study was carried out between cyclosporine and a new immunosuppressive agent, FK506, isolated from the Streptomyces organism. This agent has the capacities to suppress the development of S-antigen-induced experimental autoimmune uveoretinitis (EAU) as well as immune responses to S-antigen in rats immunized with the antigen. When administered daily beginning on the day of immunization and for 14 days thereafter, FK506 at doses between 0.1 and 1 mg/kg suppressed EAU in a dose-dependent manner. Complete inhibition of EAU was achieved at doses of 1, 3 and 10 mg/kg. Cyclosporine (1-20 mg/kg) also produced a dose-dependent suppression of EAU and only the highest dose (20 mg/kg) caused complete inhibition of the disease. On the basis of the dose-response study, the capacity of FK506 in preventing EAU induction is 10-30 times more intense than that of cyclosporine. In addition, the FK506 (1 and 3 mg/kg) was found to be effective in preventing EAU even when administered only in the early induction phase (days 0-5) or late effector phase (days 7-12). Similar effects were obtained by cyclosporine at a daily dose of 30 mg/kg. Furthermore, none of the rats immunized with S-antigen and treated with FK506 (1 mg/kg) on days 0-14 developed EAU when reimmunized with S-antigen on day 30. In contrast, similarly treated rats were fully susceptible to the induction of experimental allergic encephalomyelitis, or even to EAU when immunized with another retinal antigen, interphotoreceptor retinoid-binding protein. Therefore, as with cyclosporine, as demonstrated in our previous study, FK506 has the capacity to induce immunological unresponsiveness specific to the S-antigen.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antibody Formation; Antigens; Arrestin; Autoimmune Diseases; Cyclosporins; Eye Proteins; Immunization; Immunosuppressive Agents; Male; Pyridines; Rats; Rats, Inbred Lew; Retinitis; Tacrolimus; Time Factors; Uveitis