INDUCTION OF TOLERANCE TO ELIMINATE GVHD

虽然体外T细胞去除（TCD）是一种非常有效的方法， 预防致命的移植物--宿主病（GVHD），其临床 由于供体T细胞的有效去除可能 损害同种异体移植和抗白血病作用。 我们重点 不是关于TCD，而是关于操纵T细胞功能作为一种手段 防止GVHD。 功能操作的优点包括： 诱导宿主抗原（Ag）/肽特异性 无反应性，同时保留其他供体细胞功能。 为 在体内策略中，有可能残留的宿主T细胞， 排斥供体移植物可能会受到与供体GVHD类似的影响- 导致细胞。 由于所有的T细胞都会受到影响， 选择性而非泛性T细胞亚群操作所固有， 避免了 我们选择干扰T细胞的能力， 传递增殖所必需的细胞内信号 遇到宿主alloAg。 有两个主要的信号通路， T细胞 经典途径（信号1）是通过连接 使用抗TCR mAb或通过肽/MHC（主要 组织相容性复合物）分子。 CD3 β链的连接是 诱导TCR信号和T细胞增殖的有效手段， 还提供了共刺激分子。 为了干扰信号1， 我们注入了抗CD3 β单克隆抗体（mAb）， 通过去除FcR而非促有丝分裂。 我们已经证明，反- 不能与辅助细胞（AC）结合的CD3 ε F（ab '）2片段（AC 提供信号2）在预防GVHD中是高度有效的。 幸存 接受者经历了明显的非破坏性淋巴炎性反应， 在组织移植部位的过程Ags。 我们现在要问： 将在体内靶向或阻断CD28/CTLA4信号通路 是否能有效预防GVHD？ Will Ag特异性无反应性 发展？ 如果不是，什么细胞或可溶性介质参与 克服无反应诱导？对于发展成浸润性非- 当我们看到破坏性的细胞时，我们会问， 淋巴组织的浸润 有哪些 诱导这些细胞群的要求？ 我们将应用 体外无反应性原理（Ag特异性无反应性） 诱导体内GVHD系统，并询问：能否（宿主）Ag特异性非- 在体外诱导反应性作为保护鼠的手段 致命GVHD的同种异体移植物接受者 这是移植物抗宿主病吗 保护作用仅限于某些GVHD类型（例如，T辅助细胞1）？ 这项建议将提供重要的信息， 体内Ag特异性无反应性。

While ex vivo T-cell depletion (TCD) is a highly effective methodology for prevention of lethal graft-vs.-host disease (GVHD), its clinical application is limited since the efficient removal of donor T-cells may compromise alloengraftment and an anti-leukemic effect. We have focused not on TCD but on the manipulation of T-cell function as a means of preventing GVHD. Advantages of functional manipulations include the possibility of inducing host antigen (Ag)/peptide-specific nonresponsiveness while preserving other donor cellular functions. For in vivo strategies, it is possible that residual host T-cells which can reject the donor graft may be affected similarly to the donor GVHD- causing cells. Since all T-cells would be affected, difficulties inherent to selective rather than pan T-cell subset manipulation can be avoided. We have chosen to interfere with the ability of T-cells to deliver the necessary intracellular signals for proliferation following encountering of host alloAgs. There are 2 main signalling pathways in T-cells. The classical pathway (signal 1) is triggered by ligation of the T-cell receptor (TCR) using anti-TCR mAbs or by peptide/MHC (major histocompatibility complex) molecules. Ligation of CD3epsilon chain is potent means of inducing TCR signals and T-cell proliferation if costimulatory molecules are also provided. To interfere with signal 1, we have infused an anti-CD3epsilon monoclonal antibody (mab) rendered non-mitogenic through removal of FcR. We have shown that anti- CD3epsilonF(ab')2 fragments which cannot bind to accessory cells (AC) (AC provide signal 2) are highly efficacious in preventing GVHD. Surviving recipients experience a pronounced non-destructive lymphoid inflammatory process at the site of tissue transplantation Ags. We will now ask: Will in vivo targeting or blockage of the CD28/CTLA4 signalling pathway be effective in preventing GVHD? Will Ag-specific non-responsiveness develop? If not, what cellular or soluble mediators are involved in overcoming anergy induction? For mice that develop infiltrating non- destructive cells, we will ask what is the nature and cause of the lymphoid tissue infiltrate in these recipients? What are the requirements for the induction of these cell populations? We will apply the principles of in vitro anergy (Ag-specific nonresponsiveness) induction to an in vivo GVHD system and ask: can (host) Ag-specific non- responsiveness be induced in vitro as a means of protecting murine recipients of allogeneic grafts from lethal GVHD? Is this GVHD protective effect restricted to certain GVHD types (eg. T-helper 1)? This proposal will provide important information on strategies to induce Ag-specific non-responsiveness in vivo.