INDUCTION OF HOST-SPECIFIC TOLERANCE IN ALLOGENIC BMT

我们计划的中心目标是试图有选择地 仅耐受少量同种异体T细胞在 供者骨髓(BM)，负责GVHD。通过离开 超过99%的供者T细胞在体内过继转移 BM功能完好无损，我们希望将移植失败降至最低 对病原体和肿瘤细胞免疫。此外，我们希望这一点 这种方法将允许我们减少非特异性免疫抑制 这会降低主机对机会主义的响应能力 感染。为了实现这些目标，我们计划专门在体内进行 使供体骨髓中的同种异体反应性T细胞对抗宿主同种异体抗原。我们 已经表明，阻断B7家族介导的共刺激是 诱导同种异体抗原特异性T细胞克隆性无能所必需的 供体宿主特异性异构性前体辅助体T的频率 细胞(PHTL)可以减少到低于认为相关联的值 移植物抗宿主病的发病率很高。我们在诊所里带着这个 方法学和初步证据表明，捐赠者宿主 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 特别是在保持剩余免疫系统完好无损的情况下。这 可能允许我们减少非特异性毒性，同时保存或 改进GVHD控制的现行标准。在第二个 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，哪些额外的分子可以防止诱导 无能，研究CD8plus T细胞是否可以被无能，以及 最后，为了继续努力破译生物化学基础 无能缺陷。第三个项目的主要目标是 幼稚和记忆中共刺激作用的体内条件研究 T细胞对同种异体抗原的反应。这些研究应该提供新的 与考虑GVHD风险高度相关的见解 脐带血与成人骨髓造血源的对比。本计划 从一开始就具有很强的互动性。为了确保它的成功，我们 已经组建了一个高度多样化但具有互动性的协作团队 分子生物学家、免疫学家、移植生物学家和临床医生 拥有长期的成功协作记录，并拥有广泛的 将我们的基础科学发现推向 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.