PANCREATIC TRANSPLANTATION AND DIABETES MELLITUS

胰腺移植和糖尿病

• 批准号: 2414772
• 负责人: DANIEL H MINTZ
• 金额: $ 48.7万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2414772
• 关键词: CD28 molecule; CD44 molecule; T lymphocyte; bone marrow transplantation; cell adhesion molecules; clinical research; clinical trials; diabetes mellitus therapy; disease /disorder model; dogs; homologous transplantation; human subject; human therapy evaluation; immune tolerance /unresponsiveness; immunoregulation; immunosuppression; insulin dependent diabetes mellitus; intravenous administration; isoantigen; laboratory mouse; laboratory rat; pancreatic islet function; pancreatic islet transplantation; tissue donors; transplantation immunology

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.

我们目前提案的总体主题是为下列方面制定议定书： 受体中供体特异性耐受的诱导和维持 胰岛移植，我们的最终目标是逆转胰岛素 依赖性糖尿病我们计划彻底调查三个 这些方法在动物模型中产生了有希望的结果： l）胸腺内接种供体细胞和/或抗原，主要用于 介导抗供体特异性T细胞的克隆缺失，和2）静脉内 给予供体骨髓细胞，目的是诱导 微嵌合状态和/或中央和外周招募 耐受机制，3）抑制共刺激（B7/CD 28/CTLA-4） 以及受体白细胞和供体细胞之间的粘附相互作用， 组织中我们将通过以下方式定义供体特异性耐受的机制： 评价体外和体内对供体和第3代的免疫反应性 党的细胞和组织，此外，将寻找的存在， 骨髓/胰岛受体中的嵌合体。我们亦会探讨 每个协议中固有的变量，通过分析 相对于胸腺内接种或静脉内骨髓的免疫抑制 输液这些途径中的干扰，即，捐赠者的认可 在缺乏适当共刺激信号的情况下，同种异体抗原可以 导致克隆无反应性。这些研究的结果有可能 指导我们采取多方面的办法， 人类的耐受性。此外，诱导耐受性 移植的胰岛可以提供耐受糖尿病的额外益处， 患者移植的胰岛，从而防止复发的 自身免疫过程这些研究结果的可用性 将提供关键的见解，将适用于完善 正在进行的人类胰岛同种异体移植的临床试验。的 这些信息的应用也应该普遍适用 器官移植领域。