tacrolimus and Immune-System-Diseases

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a severe autoimmune disease that is caused by regulatory T cell deficiency due to FOXP3 gene mutations. The long-term outcome can be variable depending on the extent of tissue damage caused by autoimmunity and infections, the use of immunosuppressive treatment or sequela of bone marrow transplantation.. We used immunohistochemical staining to analyze cell types infiltrating the tissue of affected organs from a classic IPEX patient with a splicing mutation (c.736-2A>C) in the FOXP3 gene. Expression of transcription factors that are critical for immune responses including T-bet, GATA-3, RORγt, and FOXP3 were evaluated in various tissue samples. For objective analysis of the distribution of different cell types in tissues, we used an automated microscope-based image acquiring system to assess quantitatively the different cell types by investigating the histopathological changes in the patient's biopsy samples obtained from the intestine and the kidneys before and after treatment.. The percentages of cells expressing the T. This study provides quantitative evidence that the inflamed intestinal and renal tissues of the IPEX patient contain T

Topics: Child; Diabetes Mellitus, Type 1; Diarrhea; Forkhead Transcription Factors; Gastrointestinal Tract; GATA3 Transcription Factor; Genetic Diseases, X-Linked; Humans; Immune System Diseases; Immunohistochemistry; Immunosuppression Therapy; Immunosuppressive Agents; Intestinal Mucosa; Kidney; Male; Nuclear Receptor Subfamily 1, Group F, Member 3; Rituximab; T-Box Domain Proteins; T-Lymphocytes, Regulatory; Tacrolimus; Th1 Cells; Th17 Cells; Th2 Cells

In this review, we propose that TRESK background K(+) channel could serve as a potential therapeutic target for T-cell mediated immune dysfunction. TRESK has many immune function-related properties. TRESK is abundantly expressed in the thymus, the spleen, and human leukemic T-lymphocytes. TRESK is highly activated by Ca(2+), calcineurin, acetylcholine, and histamine which induce hypertrophy, whereas TRESK is inhibited by immunosuppressants, such as cyclosporin A and FK506. Cyclosporine A and FK506 target the binding site of nuclear factor of activated T-cells (NFAT) to inhibit calcineurin. Interestingly, TRESK possesses an NFAT-like docking site that is present at its intracellular loop. Calcineurin has been found to interact with TRESK via specific NFAT-like docking site. When the T-cell is activated, calcineurin can bind to the NFAT-docking site of TRESK. The activation of both TRESK and NFAT via Ca(2+)-calcineurin-NFAT/TRESK pathway could modulate the transcription of new genes in addition to regulating several aspects of T-cell function.

Topics: Calcineurin; Calcium; Cyclosporine; Humans; Immune System Diseases; Immunosuppressive Agents; NFATC Transcription Factors; Potassium Channels; Protein Structure, Tertiary; T-Lymphocytes; Tacrolimus

Structurally-unrelated immunosuppressive drugs, cyclosporin A and FK506 (tacrolimus), that share a common intracellular target protein, calcineurin, display strong and similar efficacy in the cases of organ transplantation and other immunological diseases. However, prolonged use of these drugs in many chronic diseases is restricted due, at least in part, to their side effects. The pharmacological effects of cyclosporin A and FK506, represented by the suppression of T cell activation and proliferation, are exhibited via inhibiting the activity of a transcription factor, nuclear factors of activated T cells (NFAT). The NFAT family members are involved in inducible expression of numerous genes concerned with immune responses as well as other biological events. Studies using gene-targeted mice have suggested that each NFAT family member plays a differential role in the synthesis of multiple cytokines. The diversity of the NFAT family is one of the reasons for the potent and wide-variety of side effects induced by cyclosporin A and FK506. However, molecular mechanisms underlying the functional differences among the NFAT family have not been fully elucidated. We have been investigating the comparative roles of NFAT members in regulating T cell cytokine synthesis. In addition, in order to identify the essential region in NFAT responsible for the specificity of individual NFAT members, we have applied a novel assay technique to accurate assessment of interacting properties between NFAT and its binding partners. This article summarizes the potential and possibility of selective NFAT inhibitors in the treatment of immunological and inflammatory diseases with introducing our recently elucidated findings.

Topics: Animals; Calcineurin; Cyclosporine; Humans; Immune System Diseases; Immunosuppressive Agents; Inflammation; Lymphocyte Activation; NFATC Transcription Factors; Tacrolimus

Calcineurin inhibitors (CNI), including oral cyclosporin A and tacrolimus, are intensive immunosuppressants that are extensively used in the treatment of rheumatic and immunologic diseases in China. CNI selectively inhibit the activation and proliferation of T lymphocytes and the transcription of cytokines [such as tumor necrosis factor-α, interleukin (IL)-6, and IL-17] through inhibiting the activation of calcineurin in cells and reducing the release of IL-2. To standardize the use of CNI in the field of rheumatic and immunologic diseases, this consensus statement was developed by the National Clinical Research Center for Dermatologic and Immunologic Diseases (Peking Union Medical College Hospital), in conjunction with the Chinese Association of Rheumatology and Immunology Physicians, the Chinese Research Hospital Association, the Rheumatology and Immunology Professional Committee, and the Chinese Association of Rehabilitation Medicine. The 2011 Oxford Centre for Evidence-Based Medicine Levels of Evidence was used to rate the quality of the evidence and the strength of the recommendations, and the RIGHT (Reporting Items for practice Guidelines in HealThcare) checklist was followed to report the consensus. The consensus offers recommendations addressing nine clinical challenges to Chinese clinicians. The primary objective of this consensus is to deliver scientific and detailed guidance on CNI for Chinese clinicians, and to improve the quality of patient-centered medical services.. 钙调磷酸酶抑制剂（CNI）类药物属强效免疫抑制剂，我国风湿免疫性疾病领域主要应用的该类药物为口服环孢素A和他克莫司，其可通过抑制细胞内钙调磷酸酶活性，减少白细胞介素（IL）-2释放，从而选择性抑制T淋巴细胞活化增殖及肿瘤坏死因子-α、IL-6、IL-17等细胞因子转录。为规范口服CNI类药物在风湿免疫性疾病领域的应用，由国家皮肤与免疫疾病临床医学研究中心（北京协和医院）发起，中国医师协会风湿免疫科医师分会、中国研究型医院学会风湿免疫专业委员会、中国康复医学会风湿免疫康复专业委员会参与制订，采用2011年牛津循证医学中心分级系统和国际实践指南报告标准（RIGHT），对我国临床医生关注的9个临床问题，给出了较为详细的循证推荐意见，旨在为相关医疗卫生人员提供科学、具体的CNI类药物用药参考和指导，提高以患者为中心的医疗服务质量。.

Topics: Calcineurin Inhibitors; Humans; Immune System Diseases; Immunosuppressive Agents; Rheumatic Diseases; T-Lymphocytes; Tacrolimus

We describe an immune reconstitution syndrome (IRS)-like entity in the course of evolution of Cryptococcus neoformans infection in organ transplant recipients.. The study population comprised a cohort of 83 consecutive organ transplant recipients with cryptococcosis who were observed for a median of 2 years in an international, multicenter study.. In 4 (4.8%) of the 83 patients, an IRS-like entity was observed a median of 5.5 weeks after the initiation of appropriate antifungal therapy. Worsening of clinical manifestations was documented, despite cultures being negative for C. neoformans. These patients were significantly more likely to have received tacrolimus, mycophenolate mofetil, and prednisone as the regimen of immunosuppressive therapy than were all other patients (P = .007). The proposed basis of this phenomenon is reversal of a predominantly Th2 response at the onset of infection to a Th1 proinflammatory response as a result of receipt of effective antifungal therapy and a reduction in or cessation of immunosuppressive therapy.. This study demonstrated that an IRS-like entity occurs in organ transplant recipients with C. neoformans infection. Furthermore, this entity may be misconstrued as a failure of therapy. Immunomodulatory agents may have a role as adjunctive therapy in such cases.

Topics: Adult; Aged; Antifungal Agents; Cohort Studies; Cryptococcosis; Female; Humans; Immune System Diseases; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Organ Transplantation; Prednisone; Tacrolimus