tacrolimus and Hypersensitivity

Atopic dermatitis is a prevalent condition in children and can be effectively managed with medications such as topical calcineurin inhibitors (pimecrolimus or tacrolimus). A key unresolved safety concern is whether use of topical calcineurin inhibitors is associated with cancer. We systematically reviewed the risk of cancer in patients with atopic dermatitis exposed to topical calcineurin inhibitors.. As part of the 2022 American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters atopic dermatitis guidelines, we searched MEDLINE, Embase, the Latin American and Caribbean Health Sciences Literature database, the Índice Bibliográfico Espanhol de Ciências da Saúde database, the Global Resource of Eczema Trials database, WHO's International Clinical Trials Registry Platform, the US Food and Drug Administration database, the European Medicines Agency database, company registers, and relevant citations from inception to June 6, 2022. We included randomised controlled trials and comparative and non-comparative non-randomised studies in any language addressing cancer risk in patients with atopic dermatitis using topical calcineurin inhibitors. We excluded split-body studies and studies with less than 3 weeks of follow-up. Paired reviewers independently screened records, extracted data, and assessed risk of bias in duplicate. We used Bayesian models to estimate the probability for cancer due to topical calcineurin inhibitor exposure and the GRADE approach to determine the certainty of the evidence. Patients, advocacy groups, and care providers set a priori thresholds of important effects. This study is registered with Open Science Framework, https://osf.io/v4bfc.. We identified and analysed 110 unique studies (52 randomised controlled trials and 69 non-randomised studies [11 were non-randomised study extensions of randomised controlled trials]) including 3·4 million patients followed up for a mean of 11 months (range 0·7-120). The absolute risk of any cancer with topical calcineurin inhibitor exposure was not different from controls (absolute risk 4·70 per 1000 with topical calcineurin inhibitors vs 4·56 per 1000 without; odds ratio 1·03 [95% credible interval 0·94-1·11]; moderate certainty). For all age groups and using data from observational studies and randomised controlled trials, the use of pimecrolimus (OR 1·05 [95% credible interval 0·94-1·15]) or tacrolimus (0·99 [0·89-1·09]) is likely to have had little to no association with cancer compared with no topical calcineurin inhibitor exposure. For pimecrolimus versus tacrolimus, the finding was similar (0·95 [95% credible interval 0·83-1·07]). Findings were similar in infants, children, and adults, and robust to trial sequential, subgroup, and sensitivity analyses.. Among individuals with atopic dermatitis, moderate-certainty evidence shows that topical calcineurin inhibitors do not increase the risk of cancer. These findings support the safe use of topical calcineurin inhibitors in the optimal treatment of patients with atopic dermatitis.. American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology via the Joint Task Force on Practice Parameters.

Topics: Adult; Asthma; Bayes Theorem; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Humans; Hypersensitivity; Infant; Neoplasms; Randomized Controlled Trials as Topic; Tacrolimus

Drug delivery systems (DDS) are based on the concept of providing the optimal amount of a drug to a specific area requiring treatment. Liposomes are lipid-based nanoparticles capable of encapsulating any drug into both their membrane and aqueous phases. They have the potential to be targeted when their surfaces are modified with functional molecules such as antibodies and peptides. Thus, liposomes have strong potential as drug carriers if designed for active targeting. Our research group has recently developed a new concept for liposome targeting called "reverse targeting DDS (RT-DDS)". RT-DDS differs from conventional active targeting in that the surface of the liposomes is modified with an antigenic molecule that is specifically recognized by antigen-specific immune cells. This review describes in detail the differences between these two DDS targeting concepts and proposes the application of RT-DDS to the treatment of allergies based on research using ovalbumin as a model allergy antigen.

Topics: Animals; B-Lymphocytes; Disease Models, Animal; Drug Delivery Systems; Humans; Hypersensitivity; Immunosuppressive Agents; Liposomes; Mice; Ovalbumin; Spleen; Tacrolimus

The purpose of this study was to review currently available literature data concerning pathomechanisms of action, indications, treatment efficacy, as well as side effects of nonsteroidal immunomodulators used in dermatology, primarily for the treatment of allergic dermatoses. MEDLINE search was undertaken using the key words "Topical Immunomodulators, Dermatology and Allergy". Full articles, and nothing but full articles, were used.

Topics: Administration, Topical; Anti-Inflammatory Agents, Non-Steroidal; Humans; Hypersensitivity; Immunologic Factors; Skin Diseases; Tacrolimus

Contact lens-induced papillary conjunctivitis (CLPC) is a common ocular allergic disease in contact lens wearers. In its more severe form, it can cause giant papillary conjunctivitis, resulting in contact lens intolerance and the need to discontinue the use of contact lenses. This review presents the pathogenesis, clinical manifestations and management guidelines of this common disorder.. Different types of contact lenses are associated with differences in the severity of CLPC. Refitting patients with silicone hydrogel contact lenses or with daily disposable contact lenses may improve the signs and symptoms of CLPC. The recent introduction of the topical immunomodulatory agent tacrolimus in other severe allergic eye diseases may apply in suppressing the allergic inflammation in CLPC as well.. CLPC is a common ocular disorder in contact lens wearers, with a significant impact on the quality of vision. It should be promptly recognized by healthcare practitioners and managed by modifications of the types and wearing schedules of contact lenses, as well as novel treatment options with topical immunomodulators.

Topics: Animals; Conjunctivitis, Allergic; Contact Lenses; Eye; Humans; Hypersensitivity; Immunomodulation; Tacrolimus

The clinical symptoms of allergy are caused by cellular (IgE-triggered) responses to an allergen. Effector cells of allergy include eosinophil and basophil granulocytes, as well as tissue mast cells. Growth and accumulation, as well as IgE-dependent and independent functions of these cells are regulated by distinct proteohormones and peptides. The hemopoietic cytokines IL-3 (interleukin-3), IL-5 and GM-CSF (granulocyte-macrophage colony-stimulating factor) are involved in the regulation of basophils (and eosinophils), whereas the ligand for c-kit, SCF (stem cell factor) is a mast cell-specific agonist. Basophils and mast cells express high-affinity IgE-binding sites. Allergen binding to IgE on mast cells and basophils, and consecutive cross-linking of IgE receptors is followed by production and/or secretion of inflammatory mediator substances. Specific activation and deactivation of mast cells/basophils in vitro has been demonstrated by use of recombinant cytokines and allergens, and specific haptens or by use of novel drugs, and should lead to epitope-specific diagnosis and better management of allergic diseases in the future.

Topics: Allergens; Basophils; Cyclosporine; Desensitization, Immunologic; Eosinophils; Humans; Hypersensitivity; Immunoglobulin E; Mast Cells; Tacrolimus

Atopic dermatitis is a prevalent condition in children and can be effectively managed with medications such as topical calcineurin inhibitors (pimecrolimus or tacrolimus). A key unresolved safety concern is whether use of topical calcineurin inhibitors is associated with cancer. We systematically reviewed the risk of cancer in patients with atopic dermatitis exposed to topical calcineurin inhibitors.. As part of the 2022 American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters atopic dermatitis guidelines, we searched MEDLINE, Embase, the Latin American and Caribbean Health Sciences Literature database, the Índice Bibliográfico Espanhol de Ciências da Saúde database, the Global Resource of Eczema Trials database, WHO's International Clinical Trials Registry Platform, the US Food and Drug Administration database, the European Medicines Agency database, company registers, and relevant citations from inception to June 6, 2022. We included randomised controlled trials and comparative and non-comparative non-randomised studies in any language addressing cancer risk in patients with atopic dermatitis using topical calcineurin inhibitors. We excluded split-body studies and studies with less than 3 weeks of follow-up. Paired reviewers independently screened records, extracted data, and assessed risk of bias in duplicate. We used Bayesian models to estimate the probability for cancer due to topical calcineurin inhibitor exposure and the GRADE approach to determine the certainty of the evidence. Patients, advocacy groups, and care providers set a priori thresholds of important effects. This study is registered with Open Science Framework, https://osf.io/v4bfc.. We identified and analysed 110 unique studies (52 randomised controlled trials and 69 non-randomised studies [11 were non-randomised study extensions of randomised controlled trials]) including 3·4 million patients followed up for a mean of 11 months (range 0·7-120). The absolute risk of any cancer with topical calcineurin inhibitor exposure was not different from controls (absolute risk 4·70 per 1000 with topical calcineurin inhibitors vs 4·56 per 1000 without; odds ratio 1·03 [95% credible interval 0·94-1·11]; moderate certainty). For all age groups and using data from observational studies and randomised controlled trials, the use of pimecrolimus (OR 1·05 [95% credible interval 0·94-1·15]) or tacrolimus (0·99 [0·89-1·09]) is likely to have had little to no association with cancer compared with no topical calcineurin inhibitor exposure. For pimecrolimus versus tacrolimus, the finding was similar (0·95 [95% credible interval 0·83-1·07]). Findings were similar in infants, children, and adults, and robust to trial sequential, subgroup, and sensitivity analyses.. Among individuals with atopic dermatitis, moderate-certainty evidence shows that topical calcineurin inhibitors do not increase the risk of cancer. These findings support the safe use of topical calcineurin inhibitors in the optimal treatment of patients with atopic dermatitis.. American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology via the Joint Task Force on Practice Parameters.

Topics: Adult; Asthma; Bayes Theorem; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Humans; Hypersensitivity; Infant; Neoplasms; Randomized Controlled Trials as Topic; Tacrolimus

Topics: Anti-Bacterial Agents; Female; Follow-Up Studies; Humans; Hypersensitivity; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Macrolides; Male; Middle Aged; Prognosis; Retrospective Studies; Risk Factors; Tacrolimus

Type I allergies have repeatedly been reported after solid organ transplantation despite T cell-targeted immunosuppressive therapy. A causal relationship with tacrolimus has been proposed.. The present study directly compared the occurrence of allergic sensitization and disease under tacrolimus- vs. cyclosporin A-based immunosuppressive therapy.. The prevalences of IgE-mediated sensitization and allergy were assessed in a cross-sectional study of kidney-transplanted adults receiving tacrolimus (n = 100) or cyclosporin A (n = 100).. included a standardized questionnaire, skin prick test and measurement of total and specific IgE against common nutritive and inhalant allergens. Results The prevalence of sensitization was significantly higher in the tacrolimus- than in the cyclosporin A-treated group (34%, n = 34, vs. 20%, n = 20; P = 0.026). The rate of clinically relevant allergy in patients receiving tacrolimus was twice that in patients receiving cyclosporin A (15%, n = 15, vs. 8%, n = 8; P = 0.12). No other factor (age, serum drug level, concomitant immunosuppressive medication, time since transplantation, underlying disease) was found to have an influence on sensitization or allergy prevalence (logistic regression).. Our results suggest that post-transplant immunosuppression with tacrolimus is associated with an increased occurrence of IgE-mediated sensitization and probably manifestation of allergic disease, which has to be treated specifically despite immunosuppressive therapy.

Topics: Adolescent; Adult; Cross-Sectional Studies; Cyclosporine; Eosinophilia; Humans; Hypersensitivity; Immunoglobulin E; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Sensitivity and Specificity; Skin Tests; Tacrolimus; Young Adult

Topics: Administration, Cutaneous; Administration, Topical; Adult; Allergens; Animals; Cats; Dermatitis, Atopic; Dogs; Double-Blind Method; False Negative Reactions; Humans; Hypersensitivity; Immunosuppressive Agents; Skin Tests; Tacrolimus

To describe the clinical and laboratory profile, natural course, treatment outcome, and risk factors of posttransplant esophageal and nonesophageal eosinophilic gastrointestinal disorders (EGIDs).. All children (aged <18 years) who underwent liver transplantation, between 2011 and 2019, in a single transplant center with a follow-up period of 1 year or more posttransplant and with a history of posttransplant endoscopic evaluation were included in this study.. During the study period, 89 children met the inclusion criteria. Patients were followed for a median of 8.0 years. A total of 39 (44%) patients were diagnosed with EGID after transplantation. Of these, 29 (33%) had eosinophilic esophagitis (EoE), and 10 (11%) had eosinophilic gastritis, gastroenteritis or enterocolitis. In comparison with the non-EGID group, patients with EGID were younger at transplant (P ≤ 0.0001), transplanted more frequently due to biliary atresia (P ≤ 0.0001), and had higher rates of pretransplant allergy (P = 0.019). In the posttransplant period, they had higher rates of mammalian Target of Rapamycin inhibitor use (P = 0.006), Epstein-Barr virus viremia (P = 0.03), post-transplant lymphoproliferative disease (P = 0.005), and allergen sensitization (P ≤ 0.0001). In regression analysis, young age at transplant, age at diagnosis, pretransplant atopic dermatitis, and post-transplant lymphoproliferative disease were associated with an increased risk of EGID or EoE. Laboratory abnormalities such as anemia (P = 0.007), thrombocytosis (P = 0.012), and hypoalbuminemia (P = 0.031) were more commonly observed in the eosinophilic gastritis, gastroenteritis or enterocolitis group than in the EoE group. Following treatment, most patients had symptomatic resolution at 3 months and histologic resolution at 6 months postdiagnosis. Among the patients who had 5 years of follow-up, none recurred.. EGID is a common posttransplant diagnosis, which seems to affect patients who are transplanted earlier and who have pretransplant atopy. Posttransplant EGID is responsive to treatment, but as histologic remission occurs after symptomatic resolution, the decision to perform control endoscopy should be delayed.

Topics: Age Factors; Anti-Allergic Agents; Biliary Atresia; Budesonide; Child; Child, Preschool; Cholestasis, Intrahepatic; Dermatitis, Atopic; Disease Progression; Drug Tapering; Enteritis; Enterocolitis; Eosinophilia; Eosinophilic Esophagitis; Epstein-Barr Virus Infections; Female; Follow-Up Studies; Gastritis; Glucocorticoids; Graft Rejection; Humans; Hypersensitivity; Immunosuppressive Agents; Infant; Ketotifen; Liver Failure, Acute; Liver Transplantation; Lymphoproliferative Disorders; Male; Postoperative Complications; Prevalence; Retrospective Studies; Risk Factors; Tacrolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Viremia

Eosinophils are a common clinical feature associated with chronic allergic diseases, and elemental diets, systemic steroids, anti-IL-5 and anti-IL-13 treatment have shown some therapeutic promise. Herein, we present evidence that pre- and post-intraperitoneal administration of tacrolimus (FK506) is very effective in reducing CCR3/Siglec-F

Topics: Allergens; Animals; Apoptosis; Aspergillosis; Aspergillus; Asthma; Calcium-Binding Proteins; Enteritis; Eosinophilia; Eosinophils; Fibrosis; Gastritis; Humans; Hypersensitivity; Immunosuppressive Agents; Interleukin-13; Interleukin-5; Lung; Mice; Mice, Inbred BALB C; Mice, Transgenic; Muscle Proteins; Respiratory Mucosa; Tacrolimus

Severe dermatitis, multiple allergies and metabolic wasting (SAM) syndrome is a recently recognized syndrome caused by mutations in the desmoglein 1 (DSG1) and desmoplakin (DSP) genes. Only two cases of SAM-DSP have been reported. We report on a 2-year-old girl presenting with pustular lakes within areas of erythema and large accumulations of intraepidermal neutrophils, which initially led to our misdiagnosis of generalized pustular psoriasis. No mutation was found in either the IL36RN or CARD14 genes by Sanger sequencing. The distinctive manifestations of erythroderma with severe itching, hypotrichosis, enamel defects, onychodystrophy, palmoplantar keratoderma and the crucial result of de novo missense mutation in exon 14 of the DSP gene (c.1828T>C, p.S610P) discovered by next-generation sequencing finally confirmed the diagnosis of SAM syndrome. The eruptions significantly improved after a 4-week treatment with oral acitretin and topical pimecrolimus. Oral gabapentin was prescribed simultaneously for 4 months, relieving her skin pruritus and suggesting that early treatment with pimecrolimus, acitretin and gabapentin for SAM-DSP syndrome is effective. It may even inhibit multiple allergies induced by skin barrier injury. In this work we also review the clinical features, differential diagnoses and pathological manifestations of SAM-DSP syndrome.

Topics: Acitretin; Administration, Cutaneous; Administration, Oral; Child, Preschool; Dermatitis, Exfoliative; Desmoplakins; Diagnosis, Differential; Diagnostic Errors; DNA Mutational Analysis; Female; Gabapentin; Humans; Hypersensitivity; Mutation, Missense; Psoriasis; Severity of Illness Index; Skin; Syndrome; Tacrolimus; Treatment Outcome; Wasting Syndrome

Use of the reverse targeting drug delivery system (RT-DDS) is a new targeting strategy based on the specific delivery of drugs to immune cells in antigen-sensitized animals by using antigen-modified liposomes, and it is expected to be a curative treatment for allergic diseases.. Herein, we prepared ovalbumin (OVA)-modified liposomes encapsulating the immunosuppressive drug FK506 (OVA-LipFK) and aimed to demonstrate the delivery selectivity of the liposomes to splenic B cells, and its antiallergic effect in an OVA-sensitized allergic model mouse.. Fluorescently labeled OVA-LipFK was intravenously injected into OVA-sensitized mice, and the intrasplenic localization of liposomes was observed. The antiallergic effect of OVA-LipFK in OVA-sensitized mice was examined by measuring the blood levels of OVA-specific IgE and IgG antibodies.. OVA-LipFK was co-localized to not only B cells but also germinal centers, in the spleen of OVA-sensitized mice. However, there was no accumulation of unmodified liposomes encapsulating FK506 (LipFK) in the splenic B-cell area. In a therapeutic study, OVA-LipFK significantly suppressed the production of both OVA-specific IgE and IgG antibodies in OVA-sensitized mice after the animals had been boosted with OVA, whereas LipFK showed little antiallergic effect.. The present study suggested that the introduction of RT-DDS for use with immunosuppressive drugs could be useful for the treatment of allergic diseases.

Topics: Animals; B-Lymphocytes; Hypersensitivity; Immunosuppressive Agents; Liposomes; Mice; Ovalbumin; Spleen; Tacrolimus; Tissue Distribution

The pathogenesis of pain in irritable bowel syndrome (IBS) is poorly understood and treatment remains difficult. The present study was designed to investigate roles of adrenergic signaling and the endogenous hydrogen sulfide producing enzyme cystathionine β-synthetase (CBS) in a previously validated rat model of IBS induced by neonatal colonic inflammation (NCI). Here we showed that NCI-induced visceral hypersensitivity (VH) was significantly attenuated by β2 subunit inhibitor but not by β1 or β3 or α subunit inhibitor. NCI markedly elevated plasma norepinephrine (NE) concentration without alteration in expression of β2 subunit receptors in dorsal root ganglion (DRGs) innervating the colon. In addition, NCI markedly enhanced TRPV1 and CBS expression in the colon DRGs. CBS inhibitor AOAA reversed the upregulation of TRPV1 in NCI rats. In vitro experiments showed that incubation of DRG cells with NE markedly enhanced expression of TRPV1, which was reversed by application of AOAA. Incubation of DRG cells with the H2S donor NaHS greatly enhanced TRPV1 expression. Collectively, these data suggest that activation of adrenergic signaling by NCI sensitizes TRPV1 channel activity, which is likely mediated by upregulation of CBS expression in peripheral sensory neurons, thus contributing to chronic visceral hypersensitivity.

Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Animals; Behavior, Animal; Cystathionine beta-Synthase; Disease Models, Animal; Ganglia, Spinal; Hypersensitivity; Irritable Bowel Syndrome; Male; Norepinephrine; Patch-Clamp Techniques; Propranolol; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta-2; Signal Transduction; Sulfites; Tacrolimus; TRPV Cation Channels; Up-Regulation

Pimecrolimus (Elidel, SDZ ASM 981) is an anti-inflammatory and immunomodulatory 33-epichloro-derivative of macrolactam ascomycin, with low potential for affecting systemic immune responses compared with other calcineurin inhibitors, cyclosporin A and tacrolimus. Despite numerous studies focused on the mechanism of pimecrolimus action on mast cells, only the single report has addressed pimecrolimus effects on other typical FcεRI-expressing cells, the basophils. Patients allergic to birch pollen (n = 20), hymenopteran venoms (n = 23) and 10 non-allergic volunteers were examined. Primary human basophils pre-treated or not with 0.5-50 μMol pimecrolimus were exposed to various concentrations of recombinant Bet v 1a allergen, bee or wasp venom extracts and anti-IgE for 20 min, and then examined for the expression of CD45, CD193, CD203c, CD63 and CD164 using flow cytometry. The externalization of basophil activation markers (CD63 and CD164) was equally inhibited through pimecrolimus in cells activated by recombinant pollen allergen, hymenopteran venom extracts and anti-IgE. Although the individual response rate was subject to strong variation, importantly, pre-treatment with pimecrolimus lowered the number of activated basophils in response to any of the stimuli in the basophils from all patients. The inhibition was concentration-dependent; approximately half of the basophils were inhibited in the presence of 2.5 mMol pimecrolimus. Pimecrolimus is a valuable new tool for the inhibition of hyper-reactive basophils in patients with pollen allergy and a history of anaphylactic reactions to bee or wasp venoms. Further research should address short-term use of pimecrolimus in vivo in a wide spectrum of allergic diseases.

Topics: Adult; Aged; Allergens; Animals; Anti-Allergic Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Anti-Idiotypic; Basophils; Bees; Betula; Cells, Cultured; Humans; Hypersensitivity; Immunoglobulin E; Middle Aged; Receptors, IgE; Rhinitis, Allergic, Seasonal; Tacrolimus; Wasp Venoms; Wasps; Young Adult

We conducted a study to clarify the incidence, clinical course, and risk factors of de novo allergies after liver transplantation. Ninety-three patients who had been followed longer than one yr and who had no previous allergy history were included. Forty-two patients (45.2%) developed de novo allergy. Of them, food allergy developed in 35 (37.6%). Respiratory allergy was observed in three (3.2%), and a patient (1.1%) had drug allergy. Fifty-two (55.9%) of the 93 patients developed eosinophilia. The median age of patients with de novo allergy was 15 months (IR 11.3-20 months). De novo allergy developed five months after liver transplantation (IR 2.3-9.5 months) and lasted for 16 months (IR 8-34.5 months). Younger age at liver transplantation displayed statistically significant differences in development of allergy between allergy and non-allergy groups. Twenty-nine (69.0%) patients improved from allergy during the follow-up period. No patient with de novo gastrointestinal allergy progressed to any respiratory allergy such as asthma. Older age at transplantation, EBV non-risk, and CMV non-risk had statistical significance in allergy improvement. Younger age at transplant predisposes to the development of allergy, while improvement of allergy is achieved more in older age.

Topics: Age Factors; Child, Preschool; Drug Hypersensitivity; Eosinophilia; Follow-Up Studies; Food Hypersensitivity; Humans; Hypersensitivity; Immunosuppressive Agents; Incidence; Infant; Liver Failure; Liver Transplantation; Proportional Hazards Models; Respiratory Hypersensitivity; Tacrolimus; Time Factors

Using a class I-disparate swine lung transplant model, we examined whether an intensive course of tacrolimus could induce operational tolerance and whether preoperative allopeptide immunization would prevent the development of tolerance.. Left lung grafts were performed using class I-disparate (class II-matched) donors. Recipients were treated with 12 days of postoperative tacrolimus. Three recipients were immunized prior to transplantation with class I allopeptides. Three other recipients were not immunized.. The nonimmunized recipients maintained their grafts long term (>497, >451, and >432 days), without developing chronic rejection. The immunized swine also maintained their grafts long term (>417, >402, >401 days), despite developing a variety of in vitro and in vivo responses to the immunizing peptides, as well as having strong mixed lymphocyte reactions to donor cells prior to transplantation.. Using only a brief course of tacrolimus, we have been able to induce a state of operational tolerance in a class I-disparate preclinical lung transplant model. Moreover, preoperative alloimmunization did not block tolerance induction or induce chronic rejection. These data show that it is possible to create a state of operational tolerance to lung allografts even in the presence of donor-sensitized cells.

Topics: Animals; Graft Survival; Histocompatibility Antigens Class I; Hypersensitivity; Immune Tolerance; Lung Transplantation; Peptides; Skin Transplantation; Swine; Swine, Miniature; Tacrolimus; Time Factors; Transplantation, Homologous

We report on a 30-year-old man, with type 1 diabetes mellitus, who developed generalized allergy to insulin consisting of several bouts of tremor, tachycardia, breathlessness and syncope. Strong positive reactions to protamine and metacresol were demonstrated by skin-prick testing. Symptoms persisted despite the use of antihistamine therapy, Actrapid HM Paraben and Monotard (insulin without protamine and metacresol) and immunosuppression (tacrolimus). He underwent a cadaver pancreas transplantation with portal-enteric drainage in June 2003. Following the antithymocyte globulin induction, immunosuppression consisted in tacrolimus and sirolimus without steroids. The patient subsequently reported a complete resolution of his symptoms and excellent glycaemic control. Thirteen months after transplantation, the patient developed oral ulcerations and severe leucopoenia initially attributed to sirolimus, which was subsequently stopped. A hyperglycaemic episode following corticosteroid therapy for acute rejection therapy required the reintroduction of insulin. Allergic manifestations reappeared promptly. Currently, 2 years after transplantation, the patient is euglycaemic without insulin (glycated haemoglobin 5.8%) and he is free of allergic reactions.

Topics: Adult; Diabetes Mellitus, Type 1; Homeostasis; Humans; Hypersensitivity; Hypersensitivity, Immediate; Immunosuppressive Agents; Insulin; Insulin Resistance; Male; Pancreas Transplantation; Protamines; Sirolimus; Tacrolimus

4-tert-Octylphenol (OP) is a representative endocrine disruptor that may have adverse effects on human health. The influence of this compound on allergic immune responses remains unclear. In this study, we have examined the effects of OP on production of interleukin-4 (IL-4), a pro-inflammatory cytokine closely associated with allergic immune responses. OP significantly enhanced IL-4 production in antigen-primed T cells in a dose-dependent manner. Treatment with OP in vivo resulted in significant increase of IL-4 production in T cells and of IgE levels in sera of antigen-primed mice. Furthermore, OP enhanced the activation of IL-4 gene promoter in EL4 T cells transiently transfected with IL-4 promoter/reporter constructs, and the enhancing effect mapped to a region in the IL-4 promoter containing binding sites for nuclear factor of activated T cell (NF-AT). Activation of T cells by phorbol-12-myristate-13-acetate (PMA) resulted in markedly enhanced binding activities to the NF-AT site, which significantly increased upon addition of OP, indicating that the transcription factor NF-AT was involved in the enhancing effect of OP on IL-4 production. The enhancement of IL-4 production by OP was blocked by FK506, a calcineurin inhibitor, but not by the estrogen receptor (ER) antagonist ICI 182780. FK506 inhibited the NF-AT-DNA binding activity and IL-4 gene promoter activity enhanced by OP in a dose-dependent manner. These findings demonstrate that OP enhances IL-4 production in T cells via the stimulation of calcineurin-dependent NF-AT activation.

Topics: Animals; Calcineurin Inhibitors; Environmental Pollutants; Estradiol; Estrogen Antagonists; Female; Fulvestrant; Hemocyanins; Hypersensitivity; Immunoglobulin E; Immunosuppressive Agents; Interleukin-4; Luciferases; Lymph Nodes; Mice; Mice, Inbred BALB C; NF-kappa B; Phenols; Receptors, Estrogen; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocytes; Tacrolimus; Tetradecanoylphorbol Acetate; Transfection

The ascomycin macrolactam pimecrolimus (Elidel, SDZ ASM 981) has recently been developed as a novel and cell-selective inhibitor of inflammatory cytokine secretion; it has fewer adverse effects than currently available drugs.. In this study, we investigated the capacity of pimecrolimus to directly inhibit in vitro mediator release from human skin mast cells and basophils.. Purified cutaneous mast cells or basophil-containing peripheral blood leukocytes were obtained from healthy human donors and preincubated with pimecrolimus (0.1 nmol/L to 1 micromol/L) in the absence or presence of its specific antagonist (rapamycin), cyclosporin A (100 nmol/L to 1 micromol/L), or dexamethasone (1 micromol/L) and then stimulated with anti-IgE or with calcium ionophore A23187 plus phorbol myristate acetate. Cell supernatants were kept for analysis of histamine, tryptase, LTC4, and TNF-alpha.. Pimecrolimus caused a strong and dose-dependent inhibition of anti-IgE--induced release of histamine from mast cells and basophils (maximally 73% and 82%, respectively, at 500 nmol/L pimecrolimus) and of mast cell tryptase (maximally 75%) and a less pronounced inhibition of LTC4 (maximally 32%) and of calcium ionophore plus phorbol myristate acetate--induced mast cell TNF-alpha release (90% maximum at 100 nmol/L pimecrolimus). In contrast, inhibition achieved during mast cell histamine release was maximally 60% with cyclosporin A and only 28% with dexamethasone.. These data demonstrate a marked inhibitory capacity of pimecrolimus on mediator release from human mast cells and basophils with a potency exceeding that of cyclosporin A and dexamethasone. Pimecrolimus might thus be expected to be effective in the treatment of mast cell-- and basophil-dependent diseases.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Basophils; Calcimycin; Dose-Response Relationship, Drug; Histamine Release; Humans; Hypersensitivity; Immunoglobulin E; Inflammation Mediators; Mast Cells; Skin; Tacrolimus; Tetradecanoylphorbol Acetate

Because interferon-gamma, interleukin-4, and interleukin-5 have been identified at the mRNA and protein levels in the lesional skin of patients with atopic dermatitis, we investigated the roles played by granulocytes as effector cells in allergic inflammation by using two unique murine skin models. In vitro generated Th1 and Th2 cells from naïve splenocytes of antiovalbumin T cell receptor transgenic BALB/C mice were adoptively transferred with ovalbumin into the ear pinnae or air-pouches produced in the back skin of naïve, nontransgenic BALB/C mice. The injection of Th1 cells with ovalbumin induced delayed type ear swelling that peaked at 48 h, whereas that of Th2 resulted in ear swelling that peaked at a much earlier time, 24 h. Histologic study of the swollen ear skin and granulocytes recruited into the air-pouch demonstrated that, although the Th1-induced inflammation caused a neutrophil-predominant infiltrate with few eosinophils, larger numbers of eosinophils accumulated in the Th2-induced inflammation. Using these murine models, we further evaluated the effects of drugs used for the treatment of atopic diseases. The results showed that FK506 administration could effectively reduce skin inflammation induced by either Th cells. Interestingly, the neutrophil elastase inhibitor ONO-6818 efficiently inhibited Th1-induced inflammation. In contrast, a leukotriene receptor antagonist, ONO-1078, specifically suppressed Th2-induced inflammation. We also found that each ONO drug exerted direct influence on specified granulocytes, as neither affected in vitro production of relevant Th cytokines. Thus, we succeeded in developing animal skin inflammation models in which we can evaluate the contribution of protein antigen-specific Th1 or Th2 cells through the action of granulocytic effector cells.

Topics: Animals; Cells, Cultured; Chromones; Dermatitis, Atopic; Disease Models, Animal; Ear; Edema; Enzyme Inhibitors; Eosinophils; Hypersensitivity; Immunosuppressive Agents; Leukotriene Antagonists; Male; Mice; Mice, Inbred BALB C; Neutrophils; Ovalbumin; Oxadiazoles; Pyrimidinones; Skin; Tacrolimus; Th1 Cells; Th2 Cells

Topics: Administration, Topical; Animals; Cattle; Collagen; Humans; Hypersensitivity; Immunosuppressive Agents; Tacrolimus

Cyclosporin A (CS) and tacrolimus (FK506, FK) are calcineurin antagonists used widely as T-cell immunosuppressants; however, their relative efficacy on antigen-stimulated T-cell subsets remains undefined.. We have examined the effects of CS and FK on antigen-driven proliferation and cytokine generation from human PBMCs and T-cell clones.. Proliferation was assessed by tritiated thymidine incorporation. Cytokine generation was assessed by reverse transcription-PCR and ELISA.. Ragweed- and tetanus toxoid-driven proliferation of PBMCs was down-regulated equally by CS or FK. Gene expression for proinflammatory cytokines (IL-4, IL-5, IL-13, and IFN-gamma) assessed by reverse transcription-PCR was down-regulated in a concentration-dependent manner by either drug. Antigen-induced proliferation of ragweed-specific Th0, Th1, or Th2 clones was inhibited by either CS or FK. Cytokine gene expression and protein secretion into culture supernatants (IL-4, IL-5, IL-13, and IFN-gamma) were down-regulated in a concentration-dependent manner by either CS or FK in all relevant T-cell subsets. Interestingly, down-regulation of IL-5 protein generation from Th0 and Th2 clones was consistently less sensitive to either drug than was the effect on either IL-4 or IL-13 protein generation.. CS and FK promote equivalent down-regulation of Th0, Th1, and Th2 responses; however, IL-5 generation is relatively insensitive to the immunomodulatory effects of calcineurin antagonists.

Topics: Calcineurin Inhibitors; Cyclosporine; Dose-Response Relationship, Drug; Gene Expression Regulation; Humans; Hypersensitivity; Interferon-gamma; Interleukins; Lymphocyte Activation; Signal Transduction; T-Lymphocytes, Helper-Inducer; Tacrolimus

Topics: Anti-Bacterial Agents; Asthma; Clarithromycin; Eosinophils; Erythromycin; Fosfomycin; Humans; Hypersensitivity; Immunosuppressive Agents; In Vitro Techniques; Interleukin-8; Josamycin; Tacrolimus

The ability of cyclosporin-A (CSA) and four of its metabolites M1, M17, M18 and M21, to inhibit antigen-stimulated release of beta-hexoseaminidase from IgE-sensitized rat basophilic leukemia cells (RBL-2H3), as an in vitro correlate of anti-allergic effect, was studied Metabolites M17, M1 and M21 were effective in inhibiting enzyme release, though less potent than the parent compound. The concentrations achieving 50% inhibition (IC50 values) were 53.3, 315.5 and 875.7 ng/ml for CSA, M17 and M1, respectively. M21 had approximately same IC50 as M1 while M18 was essentially inactive. At the highest concentration tested (1000 ng/ml) the mean maximum percentage inhibitions were 98.6, 79.5, 53.9, 48.6 and 12.2 for CSA, M17, M1, M21 and M18, respectively. The relative anti-allergic potency of the metabolites was similar to their reported relative immunosuppressive potency. Combinations of low concentrations of CSA and its metabolites were synergistic in inhibiting enzyme release whereas at higher concentrations interactions were either additive or antagonistic. Even the concentrations of the metabolites that have little or no activity when used alone also potentiated the effect of CSA. The immunosuppressor FK 506 was found to be about three times more potent than CSA in this system and the interactions between FK 506 (3, 10 and 30 ng/ml) and CSA (10, 30 and 100 ng/ml) or M17 (20, 100 and 500 ng/ml) were synergistic at all combinations. Both CSA and M17 synergized more strongly with FK 506 than they did between themselves. These results show that some metabolites of CSA, like the parent compound, possess anti-allergic effects and that at concentrations that are obtainable in transplant patients, synergistic interaction occurs between CSA and its metabolites, and this may be of some therapeutic significance.

Topics: Animals; Anti-Allergic Agents; beta-N-Acetylhexosaminidases; Cyclosporine; Cyclosporins; Hypersensitivity; Immunoglobulin E; Leukemia, Mast-Cell; Rats; Tacrolimus; Tumor Cells, Cultured

The effects of two new immunosuppressors, FK-506 and mizoribine, on antigen-induced bronchial inflammation and reactivity to acetylcholine in mice were studied in comparison with those of cyclosporin A and cyclophosphamide. Three inhalations of an antigen by actively sensitized BALB/c mice resulted in an increase in airway reactivity to acetylcholine. Twenty-four hours after the final inhalation, the number of leukocytes (mononuclear cells and eosinophils) and the amount of interleukin 5 (IL-5) increased significantly. In BALB/c nu/nu mice (athymic mice), three inhalations of antigen caused no significant change in either airway inflammation or hyperresponsiveness. The administration of each of the four immunosuppressors clearly inhibited antigen-induced airway eosinophilia. Moreover, FK-506, mizoribine and cyclophosphamide clearly inhibited the antigen-induced IL-5 production and cyclosporin A showed the tendency to inhibit IL-5 production. Whereas FK-506, mizoribine and cyclosporin A clearly inhibited the antigen-induced airway hyperreactivity in BALB/c mice, cyclophosphamide did not show a significant effect on this airway hyperreactivity. These results indicate that FK-506, mizoribine and cyclosporin A, but not cyclophosphamide, inhibit antigen-induced airway hyperreactivity in mice. The mechanism which inhibits antigen-induced airway eosinophilia and IL-5 production is not involved in the inhibitory mechanism of airway hyperreactivity by FK-506 and mizoribine.

Topics: Aerosols; Animals; Bronchial Provocation Tests; Chemotaxis, Leukocyte; Cyclophosphamide; Cyclosporine; Hypersensitivity; Immunosuppressive Agents; Interleukin-5; Mice; Mice, Inbred BALB C; Mice, Nude; Ovalbumin; Respiratory System; Ribonucleosides; Tacrolimus

Topics: Animals; CD4-Positive T-Lymphocytes; Eosinophils; Hypersensitivity; Interferon-gamma; Lymphocyte Depletion; Male; Mice; Mice, Inbred BALB C; Neutrophils; Ovalbumin; Peritoneal Cavity; Peritonitis; Recombinant Proteins; Tacrolimus