ICOS-B7h in Islet Transplant Rejection and Autoimmunity

ICOS-B7h 在胰岛移植排斥和自身免疫中的作用

基本信息

批准号：
6801482
负责人：
ANDREW M SHAPIRO
金额：
$ 24.3万
依托单位：
UNIVERSITY OF ALBERTA
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-30 至 2006-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6801482
关键词：
CD28 molecule CD40 molecule NOD mouse T cell receptor artificial immunosuppression autoimmunity clinical research human subject human therapy evaluation immune tolerance /unresponsiveness immunotherapy laboratory mouse liver transplantation pancreatic islet transplantation passive immunization transplant rejection

项目摘要

DESCRIPTION (provided by applicant): Recent progress in clinical islet transplantation with the introduction of the 'Edmonton Protocol' has created enthusiasm for this approach as an effective therapy for highly selected patients with unstable forms of Type I diabetes. The therapy, however, is not suitable for patients in the earliest stages of Type I diabetes because of potential risks associated with anti-rejection therapies. While the risk of malignancy and life-threatening infection has been very low in recent clinical series, complications of severe mouth ulceration, elevated cholesterol, hypertension and the need for two or more organ donors to secure insulin independence emphasize the need for further improvements in the safety and efficacy profile of islet transplantation if it is to be more broadly applied in diabetes. Our Laboratory has focused intense efforts in exploring ways to induce minimal immunosuppression or tolerance in mouse models of islet transplantation. Recently, we have found that an antibody directed against the surface inducible co-stimulatory molecule ICOS (12A8) is highly effective in prolonging islet allograft survival beyond 100 days in approximately half of treated mice. The current proposal is designed to further explore blockade of the ICOS-B7h pathway in control of allograft rejection and autoimmune recurrence after islet transplantation in mice. We believe that this promising finding could be further enhanced by rational combination of anti-ICOS therapy with complimentary approaches that have potential for rapid clinical translatability. More specifically, anti-ICOS will be combined with either donor specific transfusion, CTLA4-1g, CD40 blockade, or with the drug FTY720 to evaluate its effect in preventing islet allograft rejection. The most promising of these approaches will be further tested in the primary and secondary prevention of spontaneous diabetes in NOD mice. We will explore the immunological mechanisms associated with tolerance phenotypes [mice treated with anti-ICOS based therapies] by donor and third party islet and skin graft rechallenge, by thymectomy, or by following the fate of donor-specific T cells in TCR-transgenic models. Furthermore, in vitro co-culture assays and adoptive transfer studies, in addition to islet-kidney graft re-transplantation experiments will be conducted to search for regulatory T cell activity. We will also study our clinical islet transplant patients by flow cytometry and TaqMan quantitative PCR for ICOS expression in peripheral blood and in graft biopsies. We will correlate clinical outcomes with ICOS expression to determine if ICOS monitoring might be a useful tool for prediction of clinical course. If these initial studies show promise, we would plan to further explore anti-ICOS therapies in primate models of islet transplantation within the context of an extended future proposal, with a view to ultimate testing in clinical islet transplant recipients.

描述（由申请人提供）：随着“埃德蒙顿方案”的引入，临床胰岛移植方面的最新进展激起了人们对这种方法的热情，将其作为一种有效治疗精心挑选的不稳定型 I 型糖尿病患者的方法。然而，由于抗排斥疗法存在潜在风险，该疗法并不适合早期 I 型糖尿病患者。虽然在最近的临床系列中，恶性肿瘤和危及生命的感染的风险非常低，但严重口腔溃疡、胆固醇升高、高血压的并发症以及需要两个或更多器官捐献者确保胰岛素独立性强调需要进一步改善如果要更广泛地应用于糖尿病，胰岛移植的安全性和有效性概况。我们的实验室致力于探索在胰岛移植小鼠模型中诱导最小免疫抑制或耐受的方法。最近，我们发现针对表面诱导型共刺激分子 ICOS (12A8) 的抗体能够非常有效地将大约一半的治疗小鼠的胰岛同种异体移植物存活时间延长到 100 天以上。目前的提案旨在进一步探索阻断 ICOS-B7h 通路以控制小鼠胰岛移植后的同种异体移植排斥和自身免疫复发。我们相信，通过将抗 ICOS 疗法与具有快速临床转化潜力的互补方法合理结合，可以进一步增强这一有希望的发现。更具体地说，抗-ICOS将与供体特异性输血、CTLA4-1g、CD40阻断或药物FTY720相结合，以评估其预防胰岛同种异体移植排斥的效果。这些方法中最有希望的将在 NOD 小鼠自发性糖尿病的一级和二级预防中进行进一步测试。我们将通过供体和第三方胰岛和皮肤移植再激发、通过胸腺切除术或通过跟踪 TCR 转基因模型中供体特异性 T 细胞的命运，探索与耐受表型（接受抗 ICOS 治疗的小鼠）相关的免疫学机制。此外，除了胰岛-肾移植物再移植实验外，还将进行体外共培养测定和过继转移研究，以寻找调节性T细胞活性。我们还将通过流式细胞术和 TaqMan 定量 PCR 研究临床胰岛移植患者的外周血和移植物活检中的 ICOS 表达。我们将临床结果与 ICOS 表达相关联，以确定 ICOS 监测是否可能是预测临床病程的有用工具。如果这些初步研究显示出希望，我们将计划在未来扩展提案的背景下，在灵长类胰岛移植模型中进一步探索抗ICOS疗法，以期在临床胰岛移植受者中进行最终测试。