INDUCTION OF IMMUNOLOGICAL TOLERANCE TO ISLET ALLOGRAFTS

本项目的目的是诱导胰岛移植耐受， 无全身免疫抑制。我们认为， 目前胰岛移植策略的替代方案是诱导 免疫耐受性。耐受性诱导目前还不是一种 临床现实，因为它的机制是不完全理解，但 新的发现大大增加了我们的理解。这 计划项目是基于这些新发现之一，并将重点放在 两个关键激活分子，CD 40和CD 40配体（CD 4 OL）。这些 分子在T细胞活化和耐受中起着重要作用 诱导了解蜂窝（项目$2，$3，和这个 项目）、分子（项目$4）和生物化学（项目$3和$4） CD 40和CD 40 L的活性应使我们能够实现胰岛移植 耐受性，无全身免疫抑制。在这个项目中，我们将 在两种化学性糖尿病接受者中诱导免疫耐受， 胰岛同种异体移植物，以及糖尿病是由于 自身免疫即使是同基因移植也会被后者排斥。我们将 基于我们发表的关于CD 40-CD 40 L共激活系统的研究， 观察到它可以被操纵以诱导对胰岛的耐受， 在没有免疫抑制的情况下进行同种异体移植。我们已经证明 由同种异体脾细胞和短期 用抗CD 40 L mAb治疗使动物对胰岛和皮肤耐受 从脾细胞供体获得的同种异体移植物。初步收养 转移研究，我们已经证明了耐受的同种特异性 由两个元素程序引起的状态。数据有力地表明， 该方案诱导抗原特异性耐受状态， 全身免疫抑制 我们将首先确定诱导耐受性的最佳参数， 正常小鼠和新型T细胞受体（TcR）转基因小鼠 （具体目标#1）。一旦优化，这些模型系统将用于 旨在确定同种异体移植物存活机制的研究 在耐受化小鼠中（具体目标#2）。在最后一系列实验中，我们 将测试优化的两元素协议将 在自发性糖尿病NOD小鼠中诱导胰岛移植耐受（特异性 目标3）。我们的近期目标是开发临床上可应用的胰岛 移植手术最终将被证明适合治愈 自身免疫性和非自身免疫性糖尿病。这是我们更长的 任期内，希望这些程序将普遍适用于所有 目前需要终身全身性移植的移植受者 免疫抑制

The goal of this Project is to induce islet allograft tolerance in the absence of generalized immunosuppression. We believe that the optimal alternative to current islet transplantation strategies is the induction of immunological tolerance. Tolerance induction is not currently a clinical reality because its mechanisms are incompletely understood, but new discoveries have increased our understanding substantially. This Program Project is based on one of these new discoveries and will focus on two key activation molecules, CD40 and CD40 ligand (CD4OL). These molecules play a central role in T cell activation and tolerance induction. Understanding of the cellular (Projects $2, $3, and this Project), molecular (Project $4), and biochemical (Projects $3 and $4) activities of CD40 and CD40L should enable us to achieve islet graft tolerance without generalized immunosuppression. In this Project, we will induce immunological tolerance in both chemically diabetic recipients of islet allografts, and in allograft recipients whose diabetes is due to autoimmunity. Even syngeneic grafts are rejected by the latter. We will focus on the CD40-CD40L co-activation system based on our published observation that it Can be manipulated to induce tolerance to islet allografts in the absence of immunosuppression. We have demonstrated that a two element therapy comprised of allogeneic splcen cells and short term treatment with anti-CD40L mAb renders animals tolerant to islet and skin allografts obtained from the splcen cell donors. In preliminary adoptive transfer studies, we have demonstrated the allospecificity of the tolerant state induced by the two element procedure. The data strongly suggest that the protocol induces a state of antigen specific tolerance rather than systemic immunosuppression. We will first identify the optimal parameters for tolerance induction in both normal mice and in a novel T cell receptor (TcR) transgenic mouse (Specific Aim #1). Once optimized, these model systems will be used in studies intended to identify the mechanisms that permit allograft survival in tolerized mice (Specific Aim #2). In a final series of experiments, we will test the hypothesis that an optimized two element protocol will induce islet graft tolerance in spontaneously diabetic NOD mice (Specific Aim #3). Our immediate goal is to develop clinically applicable islet transplantation procedures that will eventually prove suitable for curing both auto-immune and non-autoimmune diabetes mellitus. It is our longer term hope that these procedures will be generally applicable to all transplant recipients who currently require lifelong generalized immunosuppression.