INDUCTION OF HOST-SPECIFIC TOLERANCE IN ALLOGENIC BMT

我们研究的中心目标是尝试有选择地 只耐受少量的同种异体特异性T细胞转移到 供者骨髓（BM）导致GVHD。 通过离开 超过99%的供体T细胞过继转移到 BM功能完整，我们希望尽量减少移植物失败，同时保留 对病原体和肿瘤细胞的免疫。 此外，我们希望， 这种方法可以减少非特异性免疫抑制， 这降低了主机响应机会主义的能力， 感染. 为了实现这些目标，我们计划专门从体外 使供体BM中的同种异体反应性T细胞对宿主同种异体抗原无反应。 我们 已经表明阻断B7家族介导的共刺激是 是诱导同种异体抗原特异性T细胞克隆无反应性所必需的， 供体宿主特异性同种异体反应前体辅助性T细胞频率 细胞（pHTL）可以减少到低于认为是相关的 移植物抗宿主病的发病率很高 我们在诊所里 方法和初步证据表明， pHTL频率可以降低到低于预测的水平， GVHD。 第一个项目将在临床上开发和评估 抑制同种异体识别的实验治疗方式 特别是在保留完整的剩余免疫库的情况下。 这 可以让我们减少非特异性毒性，同时保持或 改善目前的GVHD控制标准。 在第二 项目，使用我们的人类T细胞克隆系统，我们计划定义 确切地说，哪些额外的分子可能会阻止诱导 无反应性，研究CD8 + T细胞是否可以无反应性， 最后，我们继续努力破译生物化学基础， 无反应性缺陷第三个项目的主要目标是 研究在幼稚和记忆中对共刺激的体内需求 T细胞对同种异体抗原的反应。 这些研究将提供新的 与考虑GVHD风险高度相关的见解 脐带血与成人骨髓造血来源的比较。 这个程序 从一开始就是高度互动的 为了确保成功，我们 组建了一个高度多样化但互动的合作团队， 分子生物学家、免疫学家、移植生物学家和临床医生 拥有长期成功合作的记录， 转化经验，推动我们的基础科学发现， 临床实验

The central goal of our PROGRAM is to attempt to selectively tolerize only the small numbers of allospecific T cells transferred in the donor marrow (BM) that are responsible for GVHD. By leaving greater than 99 percent of donor T cells adoptively transferred in the BM functionally intact, we hope to minimize graft failure yet retain immunity to pathogens and tumor cells. Moreover, we hope that this approach will permit us to decrease non-specific immunosuppression that decreases the host's capacity to respond to opportunistic infections. To achieve these objectives, we plan to specifically ex vivo anergize alloreactive T cells in the donor BM to host alloantigen. We have shown that blockade of B7 family mediated costimulation is necessary to induce alloantigen specific T cell clonal anergy and that the frequency of donor host specific alloractive precursor helper T cells (pHTL) can be reduced to below that thought to be associated with a significant incidence of GVHD. We are in the clinic with this methodology and preliminary evidence shows that the donor host pHTL frequency can be reduced to levels below that predictive for GVHD. The first project will develop and evaluate in clinical experimentation therapeutic modalities to inhibit allorecognition specifically while leaving intact the remaining immune repertoire. This may allow us to decrease non-specific toxicity while preserving or improving upon current standards of GVHD control. In the second project, using our human T cell clonal system, we plan to define precisely which additional molecules might prevent the induction of anergy, investigate whether CD8plus T cells can be anergized, and finally, to continue our efforts to decipher the biochemical basis for the anergic defect. The primary goal of the third project will be to study the in vivo requirements for costimulation in naive and memory T cell responses to alloantigen. These studies should provide new insights that are highly relevant to the consideration of the GVHD risk of cord blood versus adult BM hematopoietic sources. This Program has been highly interactive since its genesis. To ensure its success, we have assembled a highly diverse yet interactive collaborative team of molecular biologist, immunologists, transplant biologists, and clinicians with a long track record of successful collaboration and with extensive translational experience to drive our basic science discoveries to clinical experimentation.