tacrolimus and Vasculitis

IgA vasculitis (IgAV), previously known as Henoch-Schönlein purpura, is the most common vasculitis of childhood but may also occur in adults. This small vessel vasculitis is characterised by palpable purpura, abdominal pain, arthritis or arthralgia and kidney involvement. This is an update of a review first published in 2009 and updated in 2015.. To evaluate the benefits and harms of different agents (used singularly or in combination) compared with placebo, no treatment or any other agent for (1) the prevention of severe kidney disease in people with IgAV with or without kidney involvement at onset, (2) the treatment of established severe kidney disease (macroscopic haematuria, proteinuria, nephritic syndrome, nephrotic syndrome with or without acute kidney failure) in IgAV, and (3) the prevention of recurrent episodes of IgAV-associated kidney disease.. We searched the Cochrane Kidney and Transplant Register of Studies up to 2 February 2023 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.. Randomised controlled trials (RCTs) comparing interventions used to prevent or treat kidney disease in IgAV compared with placebo, no treatment or other agents were included.. Two authors independently determined study eligibility, assessed the risk of bias and extracted data from each study. Statistical analyses were performed using the random-effects model, and the results were expressed as risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.. Twenty studies (1963 enrolled participants) were identified; one three-arm study has been assessed as two studies. Nine studies were at low risk of bias for sequence generation (selection bias), and nine studies were at low risk of bias for allocation concealment (selection bias). Blinding of participants and personnel (performance bias) and outcome assessment (detection bias) was at low risk of bias in four and seven studies, respectively. Nine studies reported complete outcome data (attrition bias), while 10 studies reported expected outcomes, so were at low risk of reporting bias. Five studies were at low risk of other bias. Eleven studies evaluated therapy to prevent persistent kidney disease in IgAV with or without kidney involvement at presentation. There was probably no difference in the risk of persistent kidney disease any time after treatment (5 studies, 746 children: RR 0.74, 95% CI 0.42 to 1.32) or at one, three, six and 12 months in children given prednisone for 14 to 28 days at presentation of IgAV compared with placebo or supportive treatment (moderate certainty evidence). There may be no differences in the risk of any persistent kidney disease with antiplatelet therapy (three studies) or heparin (two studies) in children with or without any kidney disease at study entry, although heparin may reduce the risk of proteinuria by three months compared with placebo or no specific treatment (2 studies, 317 children: RR 0.47, 95% CI 0.31 to 0.73). One study comparing montelukast with placebo found no differences in outcomes as assessed by severity scale scores. Nine studies examined the treatment of severe IgAV-associated kidney disease. In two studies (one involving 56 children and the other involving 54 adults), there may be no differences in efficacy outcomes or adverse effects with cyclophosphamide compared with placebo or supportive treatment. In two studies, there may be no differences in the numbers achieving remission of proteinuria with intravenous (IV) cyclophosphamide compared with mycophenolate mofetil (MMF) (65 children evaluated) or tacrolimus (142 children evaluated). In three small studies comparing cyclosporin with methylprednisolone (15 children), MMF with azathioprine (26 children), or MMF with leflunomide (19 children), it is unclear whether the treatment had any effect on the numbers in remission or the degree of proteinuria between treatment groups because of small numbers of included participants. In one study comparing plas. There are no substantial changes in conclusions from this update compared with the initial review or the previous update despite the addition of five studies. From generally low to moderate certainty evidence, we found that there may be little or no benefit in the use of corticosteroids or antiplatelet agents to prevent persistent kidney disease in children with IgAV in participants with no or minimal kidney involvement at presentation. We did not find any studies which evaluated corticosteroids in children presenting with IgAV and nephritic and/or nephrotic syndrome, although corticosteroids are recommended in such children in guidelines. Though heparin may be effective in reducing proteinuria, this potentially dangerous therapy is not justified to prevent serious kidney disease when few children with IgAV develop severe kidney disease. There may be no benefit of cyclophosphamide compared with no specific treatment or corticosteroids. While there may be no benefit in the efficacy of MMF or tacrolimus compared with IV cyclophosphamide in children or adults with IgAV and severe kidney disease, adverse effects, particularly infections, may be lower in MMF or tacrolimus-treated children. Because of small patient numbers and events leading to imprecision in results, it remains unclear whether cyclosporin, MMF or leflunomide have any role in the treatment of children with IgAV and severe kidney disease. We did not identify any studies which evaluated corticosteroids.

Topics: Adult; Child; Fosinopril; Humans; IgA Vasculitis; Kidney Diseases; Leflunomide; Proteinuria; Tacrolimus; Vasculitis

Several novel immunosuppressive agents have been developed in recent years. They exhibited not only remarkable immunosuppressive potency but also side effects. They are still short of the final goal in terms of immunosuppression for organ transplantation. Combination treatment is more effective and safer to use, and it will prevail in the future.

Topics: Amylases; Animals; Antibodies, Monoclonal; Cell Adhesion Molecules; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Polyenes; Sirolimus; Tacrolimus; Transplantation, Heterologous; Vasculitis

We studied the clinical effects of the immunosuppressive agent FK506 in patients with noninfectious uveitis.. This study was designed as a multicenter open clinical trial in Japan. Sixteen patients with noninfectious uveitis who had visited the Uveitis Survey Clinic of the Yokohama City University Hospital were given FK506. Eight had Behçet's disease; five, Vogt-Koyanagi-Harada syndrome; one, sympathetic ophthalmia; one, retinal vasculitis; and one, sarcoidosis. In patients with Behçet's disease, ocular attack score before and after therapy was compared to judge clinical status. For the other diseases, the ocular inflammatory symptoms were observed after the initiation of FK506 treatment. All patients underwent blood and urine examinations, electrocardiography, and chest x-rays before and after FK506 treatment.. Of the patients with Behçet's disease, five improved, one remained unchanged, one deteriorated, and the status of one could not be determined. Of the patients with Vogt-Koyanagi-Harada syndrome, four improved, and one remained unchanged. The patient with sympathetic ophthalmia improved, the patient with retinal vasculitis remained unchanged, and the status of the patient with sarcoidosis could not be determined. Major adverse effects were sensations of warmth, hypomagnesemia, renal dysfunction, glucose intolerance, nausea, vomiting, and disorders of the central nervous system. All adverse effects disappeared or improved when FK506 was stopped or when the dosage was decreased. Renal dysfunction and glucose intolerance appeared when the blood level of FK506 was high.. FK506 was effective in patients with uveitis, but it is important to monitor the occurrence of adverse effects.

Topics: Adult; Aged; Behcet Syndrome; Endophthalmitis; Female; Humans; Male; Middle Aged; Retinitis; Tacrolimus; Uveitis; Uveomeningoencephalitic Syndrome; Vasculitis

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

Histologic criteria for diagnosing acute rejection in vascularized composite tissue allograft (VCA) have been established by the Banff 2007 Working Classification of Skin-Containing Composite Tissue Allograft, but the role of early vascular lesions in graft rejection warrants additional analysis.. We performed a retrospective study of 34 skin biopsies performed over 430 d for rejection surveillance, in Canada's first face allotransplant recipient. Three observers reviewed all biopsies to assess the nature and intensity of the inflammatory skin infiltrate. A complete histological and immunohistochemical review of the vascular components was performed with a focus on lymphocytic vasculitis, intravascular fibrin, vessel caliber, extent of injury, C4d positivity, and inflammatory cell phenotyping. We then correlated these data points to clinical and immunosuppression parameters.. Acute vascular damage in biopsies that would be classified as mild acute rejection correlates with troughs in immunosuppression and subsides when immunosuppressive tacrolimus doses are increased. Grade 0 Banff rejection and Grade I without lymphocytic vasculitis were almost indistinguishable, whereas Grade I with lymphocytic vasculitis was an easy and reproducible histologic finding.. Our results highlight the possible relevance of vascular injury in the context of VCA, as its presence might underlie a more aggressive form of immune rejection. If these findings are validated in other VCA patients, vascular injury in mild rejection might warrant a different clinical approach.

Topics: Aged; Biopsy; Canada; Composite Tissue Allografts; Dose-Response Relationship, Drug; Facial Transplantation; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Male; Retrospective Studies; Severity of Illness Index; Skin; Tacrolimus; Transplantation, Homologous; Treatment Outcome; Vasculitis

An infant boy with steroid-resistant nephrotic syndrome (idiopathic membranous glomerulonephropathy) achieved remission with ciclosporin but developed eosinophilia and high IgE levels (max 19 000  iU/mL). Conversion to tacrolimus resulted in chronic diarrhoea (eosinophilic gastroenteritis), muscle weakness, polyserositis and failure-to-thrive. In contrast, a trial without tacrolimus resulted in a ciclosporin-responsive relapse, therapy-resistant focal seizures with generalised spikes, worsening muscle weakness and diarrhoea. The patient was weaned off of ciclosporin and completely normalised. In vitro testing demonstrated decreased viability of the patient's cells when incubated with calcineurin inhibitors (ciclosporin, 70%; tacrolimus, 80% compared to control cells), supporting their role in this adverse drug reaction.

Topics: Cell Survival; Cyclosporine; Deprescriptions; Drug Substitution; Enteritis; Eosinophilia; Failure to Thrive; Gastritis; Gingival Hyperplasia; Glomerulonephritis, Membranous; Humans; Hypertrichosis; Immunosuppressive Agents; In Vitro Techniques; Infant; Kidney Glomerulus; Male; Microscopy, Electron; Muscle Weakness; Seizures; Serositis; Tacrolimus; Vasculitis

Immunosuppressive drugs are an integral part of therapy in organ transplantation. However, they are not without side effects, and although rare, these agents should be considered in the differential diagnosis of pulmonary complications in patients receiving transplants. We present a case of a patient who developed acute respiratory failure 7 days after orthotopic heart transplantation and who had been on both mycophenolate mofetil (MMF) and tacrolimus agents. Lung biopsy revealed features of pulmonary hemorrhage with capillaritis. Considered as a possible etiology, MMF was withdrawn. There was immediate improvement of the patient's symptoms. The temporal relationship between MMF exposure and onset of pulmonary symptoms in the absence of other possible etiologies strongly suggests a causal relationship. Previously published reports of pulmonary toxicity from MMF included interstitial fibrosis. To the best of our knowledge, this is the first reported case of pulmonary hemorrhage with capillaritis because of administration of MMF.

Topics: Heart Transplantation; Hemorrhage; Humans; Immunosuppressive Agents; Lung Diseases; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Vasculitis

Hemophagocytic syndrome (HPS) is an unusual disorder associated with systemic lupus erythematosus (SLE). A 64-year-old woman was admitted because of fever and urticarial vasculitis. Laboratory data revealed pancytopenia and immunological abnormalities, suggesting elevated disease activity. Prednisolone monotherapy failed to improve the pancytopenia despite the amelioration of other clinical findings. Because her condition was suggestive of HPS, tacrolimus at 2-3 mg/day was added to the prednisolone regimen. Eventually, the pancytopenia improved and prednisolone could be effectively tapered. Tacrolimus could be an additional or alternative modality for treating refractory HPS.

Topics: Bone Marrow; Dose-Response Relationship, Drug; Female; Fever; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lymphohistiocytosis, Hemophagocytic; Middle Aged; Pancytopenia; Prednisolone; Remission Induction; Tacrolimus; Treatment Failure; Treatment Outcome; Urticaria; Vasculitis

Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease that affects multiple organs. Neuropsychiatric SLE develops during the course of the disease in 50% to 74% of SLE patients. The pathogenesis of CNS manifestations is multifactorial. The most common neuropathological finding has, in various studies, been multifocal infarcts. The cerebral vascular lesions in SLE that can cause cerebral infarction can be categorized into thromboembolism and vasculitis. On the other hand, tacrolimus is an immunosuppressive drug used for several autoimmune diseases, which inhibits the calcineurin pathway in T cells and reduces accompanying inflammatory cytokine production. We experienced that treatment of a patient with SLE with tacrolimus and steroid pulse therapy yielded improvement of vasculitis of brain vessels on magnetic resonance angiography. We suggest that tacrolimus may play an important role in the treatment of vasculitis of SLE.

Topics: Adult; Brain; Calcineurin; Cerebrovascular Circulation; Female; Fever; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Magnetic Resonance Angiography; Magnetic Resonance Imaging; T-Lymphocytes; Tacrolimus; Treatment Outcome; Vasculitis

A 60-year-old man who had been diagnosed as rheumatoid arthritis admitted to our hospital by dysesthesia on his legs with edema. Nerve conduction velocity test led to diagnosis of mononeuritis multiplex. Magnetic resonance imaging (MRI) of lower legs showed high intensity in slow tau inversion recovery. Typical vasculitis with neutrophil-dominant cell infiltration was observed by muscle biopsy without inflammatory myopathy or fascitis. Diagnosis was made by rheumatoid vasculitis found in crural muscles. Intravenous cyclophosphamide with oral tacrolimus effectively improved dysesthesia with reduction of inflammatory response.

Topics: Administration, Oral; Antirheumatic Agents; Arthritis, Rheumatoid; Biopsy; Cyclophosphamide; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Injections, Intravenous; Magnetic Resonance Imaging; Male; Middle Aged; Muscle, Skeletal; Muscular Diseases; Neural Conduction; Neutrophils; Paresthesia; Tacrolimus; Treatment Outcome; Vasculitis

An unusual case of inter-haemispheric disconnection syndrome occurring in a patient who had undergone hepatic transplantation is presented. The underlying disorder, at first wrongly interpreted as encephalitis, was found to be severe, diffuse cerebral vasculitis. The hypothesis that treatment with tacrolimus might have caused, or at least favoured the vascular damage is discussed.

Topics: Brain Damage, Chronic; Cerebral Angiography; Cerebral Infarction; Corpus Callosum; Disability Evaluation; Disease Progression; Fatal Outcome; Humans; Liver Transplantation; Magnetic Resonance Imaging; Male; Middle Aged; Split-Brain Procedure; Tacrolimus; Vasculitis

The histone deacetylase (HDAC) inhibitor FR276457, a hydroxamic derivative, was identified during chemical library screening and was found to exhibit potent inhibitory effects on the activity of mammalian HDACs. It has been shown that FR276457 exhibited marked immunosuppressive effects in a rat heterotopic cardiac transplant model. To predict clinical efficacy of FR276457, we investigated the inhibitory effect of the proliferation of Jurkat cells in vitro and immunosuppressive effect of orally administered FR276457 on allograft rejection as a monotherapy or in combination with tacrolimus (0.04 mg/kg) injected intramuscularly (i.m.) in a canine renal transplant model. Animal survival, the plasma creatinine level, and histopathology were evaluated. FR276457 inhibited the proliferation of Jurkat cells probably by targeting activity of NF-kappaB. FR276457 prolonged the median survival time (MST) of transplanted grafts from 11.5 days (untreated group) to 29.0 days (FR276457-treated group). FR276457 administered 1 mg/kg twice a day in combination with tacrolimus prevented allograft rejection. In addition, a dose of 1.5 mg/kg twice a day or 5.0 mg/kg once a day prolonged the MST from 18 days (control group) to >73 or >90 days, respectively. Histopathological analysis showed that FR276457 suppressed the score for mononuclear cell infiltration and vasculitis. In conclusion, the HDAC inhibitor FR276457 inhibited the proliferation of T cell line established from human in vitro. And more, FR276457 clinically prolonged allograft survival when administered as a monotherapy, and had additive or synergistic effects when combined with tacrolimus with the canine renal transplant model. These results showed HDAC inhibitor is a promising biological target for treatment in transplant field.

Topics: Administration, Oral; Animals; Dogs; Drug Therapy, Combination; Graft Rejection; Histone Deacetylases; Humans; Hydroxamic Acids; Immunosuppression Therapy; Immunosuppressive Agents; Jurkat Cells; Kidney Transplantation; T-Lymphocytes; Tacrolimus; Vasculitis

To study how the balance between tacrolimus elution and polymer degradation from drug-eluting stents (DES) affects neointimal thickening (NIT) in swine coronary arteries.. We assessed a fast-degrading high dose (2 microg/mm2), a slow degrading low dose (1 microg/mm2) or polymer-only coated DES (Pol) versus bare metal stent (BMS). Coronary segments were pre-injured with a balloon/artery ratio of 1.1 to 1.3. Then stents were implanted at that site with a stent/artery ratio of 1.1, with a follow-up period of 5 to 180 days. Histology showed a well endothelialised neointima (82 +/- 1% in high dose DES vs. 93 +/- 8% in BMS) already at five days, without differences in eNOS expression. Morphometry indicated that neointimal thickness in DES was significantly reduced as compared to BMS and Pol at 28 and 90 days. Polymer degradation products induced a distinct inflammatory response which was effectively suppressed in DES. Between 90 and 180 days, however, the slow degrading low-dose stent showed catch-up of NIT.. Tacrolimus eluted from a biodegradable stent coating can suppress the inflammatory effect of the coating degradation products if the balance between the drug levels and the degradation products is favorable.

Topics: Angioplasty, Balloon, Coronary; Animals; Coated Materials, Biocompatible; Coronary Vessels; Disease Models, Animal; Drug-Eluting Stents; Elastin; Endothelium, Vascular; Immunohistochemistry; Immunosuppressive Agents; Lactic Acid; Metals; Nitric Oxide Synthase Type III; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Sus scrofa; Swine; Swine, Miniature; Tacrolimus; Tunica Intima; Tunica Media; Vasculitis

Successful immunosuppressive therapy is critical for the treatment of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and nephrosis. However, a considerable number of patients have shown clinical resistance to therapy. Bacterial infection might influence the clinical response of patients to immunosuppressive drugs, but few studies have been carried out to investigate the effect of bacterial superantigens on the efficacy of the drugs in these patients. We evaluated the suppressive efficacy of prednisolone, methylprednisolone, cyclosporine, and tacrolimus on the blastogenesis of PBMCs obtained from 12 ANCA-associated vasculitis patients (ANCA patients), eight patients with nephrotic syndrome, and eight healthy subjects. PBMC-stimulation index was calculated from the formula: [3H]thymidine incorporated in the presence of stimulant (dpm)/[3H]thymidine incorporated in the absence of stimulant (dpm). In vitro drug concentrations giving 50% inhibition (IC50s) of PBMC blastogenesis stimulated with concanavalin A (con A) or toxic shock syndrome toxin 1 (TSST-1) derived from Staphylococcus aureus (S. aureus) were calculated. The IC50 values for the four drugs evaluated in TSST-1-stimulated PBMCs were significantly higher than those evaluated in con A-stimulated PBMCs in both ANCA patients and nephrosis patients (p<0.012-0.044). Whereas, the IC50 values for these immunosuppressive drugs, except methylprednisolone, were not significantly different between con A- and TSST-1-stimulated PBMCs in healthy subjects. The stimulation index was not significantly different between the con A- and TSST-1-stimulated PBMCs in either of the subject groups. These observations raise the possibility that TSST-1 induced by S. aureus infection attenuates the clinical efficacy of glucocorticoids and calcineurin inhibitors in ANCA patients and nephrosis patients.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Bacterial Toxins; Calcineurin Inhibitors; Cell Proliferation; Concanavalin A; Cyclosporine; Enterotoxins; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Inhibitory Concentration 50; Leukocytes, Mononuclear; Lymphocyte Activation; Male; Methylprednisolone; Middle Aged; Nephrosis; Prednisolone; Superantigens; Tacrolimus; Vasculitis

Standard treatment for autoimmune hemolytic anemia (AIHA) due to warm antibodies includes combinations of glucocorticoids, immunosuppressive drugs (mainly azathioprine) and splenectomy. Patients who are refractory or intolerant to these therapies constitute an important therapeutic challenge. Rituximab, an anti-CD20 chimeric monoclonal antibody, can effectively deplete B-cells and is commonly used in B-cell non-Hodgkin lymphoma. In addition, it is being increasingly used in autoimmune disorders, such as idiopathic thrombocytopenic purpura, AIHA, systemic lupus erythematosus or vasculitis. We report a case of warm AIHA associated to primary antiphospholipid syndrome (APS). The patient was refractory to high-dose corticosteroids. Splenectomy was discarded in view of the high risk of thrombotic and/or hemorrhagic perioperative complications, due to the presence of APS. After treatment with four weekly doses of rituximab the patients had a rapid and sustained response which allowed progressive tapering of prednisone dose to 5 mg/d. In addition, IgM anticardiolipin titres decreased from > 600 MPL to < 100 MPL. Thirteen further cases of warm AIHA in adults treated with rituximab have been reviewed, showing excellent tolerance and high response rates. Rituximab may be considered prior to splenectomy in patients with refractory AIHA and high risk of complications following splenectomy.

Topics: Anemia, Hemolytic, Autoimmune; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antiphospholipid Syndrome; Contraindications; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Methylprednisolone; Middle Aged; Postoperative Complications; Prednisone; Remission Induction; Rituximab; Splenectomy; Stroke; Tacrolimus; Vasculitis

The immunosuppressive agent FK 506 is widely used in liver transplant patients. Neurotoxicity is a major complication of its use. We report progressive and irreversible neurologic complications occurring in a 39-year-old woman who underwent liver transplantation and was treated with FK 506. Neuropathologic examination revealed multiple vasculitic lesions. The possibility of an FK 506-mediated toxic effect on the cerebral vessels is suggested.

Topics: Adult; Cerebral Arteries; Cerebrovascular Circulation; Fatal Outcome; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Magnetic Resonance Imaging; Neurotoxins; Tacrolimus; Vasculitis

Central venulitis denotes a histologic lesion of the allograft liver characterized by perivenular and subendothelial mononuclear inflammation of the terminal hepatic venules associated with varying degrees of perivenular hepatocyte dropout. Although this lesion has generally been considered a manifestation of acute rejection, some have suggested that it instead represents tacrolimus hepatotoxicity.. We therefore compared the clinicopathologic features of 30 episodes of isolated central venulitis with 22 episodes of combined central venulitis and typical portal acute rejection occurring in 27 patients. Nineteen of the patients received tacrolimus and eight received cyclosporine as primary immunosuppression.. No significant differences were found between the two groups, except that isolated central venulitis more often displayed a mild inflammatory component (P=0.007) with small lymphocytes as the predominant cell type (P=0.002). None of the patients had tacrolimus or cyclosporine levels that exceeded the therapeutic range, and none had other clinical evidence of drug toxicity. Usual antirejection therapy was instituted in all but two episodes; response was evident in 93% (28 of 30) of the isolated central venulitis and 86% (19 of 22) of the central venulitis-portal acute rejection group, with histologic regression documented in all follow-up specimens (four and five, respectively). Due to persistent central venulitis, two cyclosporine patients were switched to tacrolimus, with prompt resolution.. These findings are inconsistent with the concept that central venulitis represents drug toxicity and indicate instead that it is a form of acute allograft rejection.

Topics: Adult; Chemical and Drug Induced Liver Injury; Cyclosporine; Female; Graft Rejection; Hepatic Veins; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Tacrolimus; Time Factors; Transplantation, Homologous; Treatment Outcome; Vasculitis; Venules

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

Behçet's disease (BD) affects the lung as well as the intestine, central nervous system, kidney, and other organs. Pulmonary vasculitis is one of the most severe complications in BD because it can cause fatal bleeding. Corticosteroids and other immunosuppressive drugs have been used to treat pulmonary vasculitis, but the efficacy of these agents has not yet been established. We administered FK506, a novel immunosuppressive agent, as a treatment for BD. A 21-year-old woman presented definitive symptoms of BD, ie, repeated oral and genital ulcers, folliculitis, and panuveitis. The patient showed localized pulmonary infiltrates on her chest x-ray film that were histologically proved to be venulitis consistent with BD. These pulmonary infiltrates evanesced after the oral administration of FK506 for 8 weeks; in addition, the skin lesions and uveitis improved. This clinical observation indicates that FK506 is an effective agent in the treatment of pulmonary vasculitis associated with BD.

Topics: Adult; Behcet Syndrome; Female; Humans; Lung; Lung Diseases; Tacrolimus; Vasculitis; Venules

Topics: Female; Humans; Inflammation; Keratitis; Middle Aged; Syndrome; Tacrolimus; Vasculitis; Vestibular Diseases

In our previous experiments studying the effects of FK506 on renal allografting in the dog, we encountered two major problems. One problem was anorexia and the other problem was vascular changes mainly in the recipient heart. Anorexia was generally dose dependent, but the vascular changes were seen to be more prominent at lower doses rather than at higher immunosuppressive doses. The present study was undertaken to study these two problems. A nonanorexic, vascular change-related, nonimmunosuppressive dose of FK506 was combined with a low dose of cyclosporine or prednisolone in beagle dogs after renal allografting. Treatment with either FK506 alone at a dose of 0.32 mg/kg or cyclosporine alone at 2.5 mg/kg was not effective in prolonging renal recipient survival. The recipient dogs died of rejection, and a variety of vascular changes were observed in the hearts of both groups. Combined treatment with FK506 and cyclosporine at these same doses resulted in statistically significant prolongation of the survival time of the renal recipient (P less than 0.01), and histologic studies showed that the frequency and severity of the vascular changes were suppressed in the recipient receiving the combined treatment. The combination of FK506 and prednisolone at 0.5 mg/kg was not effective in prolonging survival. Furthermore, the extent of vascular changes was similar to those found in recipients receiving FK506 alone. The data suggest that combined treatment with low doses of both FK506 and cyclosporine acted synergistically in prolonging canine renal allografts and that the vascular changes frequently seen at low doses of FK506 were reduced by additional immunosuppression with a low dose of cyclosporine.

Topics: Animals; Blood Vessels; Cyclosporins; Dogs; Drug Synergism; Drug Therapy, Combination; Female; Graft Survival; Immunosuppressive Agents; Kidney Transplantation; Prednisolone; Pyridines; Tacrolimus; Vasculitis

Topics: Animals; Diabetes Mellitus, Experimental; Dogs; Graft Survival; Immunosuppressive Agents; Kidney Transplantation; Papio; Pyridines; Tacrolimus; Vasculitis

Topics: Animals; Dogs; Drug Evaluation, Preclinical; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Pyridines; Tacrolimus; Vasculitis; Vomiting

Topics: Administration, Oral; Animals; Dogs; Drug Evaluation, Preclinical; Female; Graft Rejection; Heart; Immunosuppressive Agents; Injections, Intramuscular; Intestines; Kidney; Kidney Transplantation; Liver; Myocardium; Postoperative Complications; Pyridines; Tacrolimus; Vasculitis

Topics: Animals; Dogs; Drug Evaluation, Preclinical; Hyperglycemia; Immunosuppressive Agents; Kidney; Kidney Transplantation; Papio; Postoperative Complications; Pyridines; Tacrolimus; Vasculitis