PANCREATIC TRANSPLANTATION AND DIABETES MELLITUS

我们当前提案的总体主题是为 供体特异性耐受的诱导和维持 同种异体胰岛移植，我们的最终目标是逆转胰岛素 依赖型糖尿病。我们计划彻查三个 在动物模型中产生了有希望的结果的方法： L)胸腺内接种供体细胞和/或抗原，主要用于 介导抗供者特异性T细胞的克隆性删除，以及2)静脉注射 给供者骨髓细胞，目的是诱导 微嵌合体状态和/或招募中枢和外周两者 耐受机制，3)抑制共刺激作用(B7/CD28/CTLA-4) 受者白细胞与供者细胞之间的黏附相互作用或 纸巾。我们将通过以下方式定义供者特异性耐受的机制(S) 对供体和3号供体的体内外免疫反应性评价 政党细胞和组织，此外，还将搜索是否存在 骨髓/胰岛受体中的嵌合体。我们还将探索 通过分析每个协议的类型和时间 免疫抑制相对于胸腺接种或静脉注射。骨髓 输液。对这种途径的干扰，即对捐赠者的认识 同种异体抗原在缺乏适当的共刺激信号的情况下，可以 导致克隆性无能。这些研究的发现有可能 引导我们采用多方面的方法来诱导供者 人类特有的耐受性。此外，诱导对 移植的胰岛可以提供额外的好处，可以耐受糖尿病 患者移植的胰岛，从而防止胰岛复发 自身免疫过程。这些研究结果的可得性 将提供关键的见解，这些见解将应用于改进 正在进行的人类同种异体胰岛移植的临床试验。这个 这一信息的应用也应普遍适用。 涉及到器官移植领域。

The overall theme of our current proposal is to delineate protocols for the induction and maintenance of donor specific tolerance in recipients of islet allografts, with our ultimate goal being the reversal of insulin dependent diabetes mellitus. We plan to thoroughly investigate three approaches which have yielded promising results in animal models: l)intrathymic inoculation of donor cells and/or antigen, primarily to mediate clonal deletion of anti-donor specific T cells, and 2) intravenous administration of donor bone marrow cells, with the aim of inducing a state of microchimerism and/or recruiting both central and peripheral mechanisms of tolerance, 3) inhibition of costimulatory (B7/CD28/CTLA-4) and adhesive interactions between recipient leukocytes and donor cells or tissues. We will define the mechanism(s) of donor specific tolerance by evaluating in vitro and in vivo immunoreactivity to both donor and 3rd party cells and tissues, and in addition, will search for the presence of chimerism in bone marrow/islet recipients. We will also explore the variables inherent in each protocol by analyzing the type and timing of immunosuppression relative to intrathymic inoculation or i.v. bone marrow infusion. Interference in such pathways, i.e., recognition of donor alloantigen in the absence of the appropriate costimulatory signals, can lead to clonal anergy. Findings from these studies have the potential of directing us towards a multifaceted approach to the induction of donor specific tolerance in humans. In addition, the induction of tolerance to transplanted islets may provide the added benefit of tolerizing a diabetic patient to the grafted islets, thus preventing recurrence of the autoimmune process. The availability of the findings from these studies will provide key insights that will be applied to the refinement of ongoing clinical trials of islet allotransplantation in humans. The application of this information should, as well, be generally applicable to the field of organ transplantation.