INDUCTION OF HOST SPECIFIC TOLERANCE IN ALLOGENEIC BMT

潜在宿主和供体之间的遗传差异限制了 对供者有不良影响的异基因骨髓移植的利用和结局 可用性、植入、GVHD和免疫重建。 而 非特异性免疫抑制和T细胞耗竭都可以 减少GVHD的频率和严重程度，没有成功的方案， 单倍相合或显著不匹配的无关供体BMT具有 涌现 此外，非特异性免疫操作和 包括本发明的侵袭性BMT周围制备方案 用于改善GVHD的方法充满了毒性 包括终末器官衰竭、机会性感染增加、B细胞 淋巴增生性疾病和移植物抗肿瘤效应的丧失。 因此，尝试在离开时特异性抑制别构化， 完整的剩余免疫库将减少非特异性 毒性，同时保持或改善现行标准， GVHD控制。 该项目的中心目标是试图 选择性地只接种少量的同种异体特异性T细胞 在供体骨髓中转移的负责GVHD的基因。 同种异体反应性T细胞需要两个信号激活。 一个信号是 一种是通过TCR由alloAg递送，另一种是通过共刺激 分子。 阻断B7家族介导的共刺激可以诱导 对完全错配的同种异体供体T细胞无反应性。 基于 根据这些发现，我们已经开始了体外耐受性的临床试验， 将供体T细胞诱导为alloAg。 如果是长期的不可逆的 可以诱导对alloAg的无反应性，相关的伴随物 GVHD的临床毒性将得到改善， 在不牺牲免疫力的情况下， 感染因子和肿瘤。 为了实现这些目标，四个目标是 提出了首先，继续我们正在进行的体外临床试验 供体T细胞对alloAg的无反应。 第二，阻止额外 途径来优化alloAg特异性无反应性。 第三，比较来源 同种异体T细胞来研究初始与先前活化的T细胞， 确定他们的能力，以被无反应，以alloAg。 第四，确定 异体无能化是否导致正常T细胞功能的保留 抵抗病原体和肿瘤细胞。 该项目依赖于并 与第二个项目高度依赖（供选择 可能阻断CD4和CD8 T细胞无反应性的共刺激途径） 第三个项目（用于临床前动物模型确定 共刺激通路和研究幼稚与先前激活的T细胞 细胞）。

Genetic disparity between potential hosts and donors limits the utilization and outcome allogeneic BMT by adversely affecting donor availability, engrafument, GVHD, and immune reconstitution. While both non-specific immunosuppression and T cell depletion can decrease frequency and severity of GVHD, no successful program of haploidentical or significantly mismatched unrelated donor BMT has emerged. Further, the non-specific immunologic manipulations and aggressive peri-BMT preparative regimens comprising present methodologies used to ameliorate GVHD are fraught with toxicities including end organ failure, increase in opportunistic infections, B-cell lymphoproliferative disease and loss of graft versus tumor effect. Therefore, attempts to inhibit allorecognitiion specifically while leaving intact the remaining immune repertoire would decrease non-specific toxicity while preserving or improving upon current standards of GVHD control. The central goal of this project is to attempt to selectively inactivate only the small numbers of allospecific T cells transferred in the donor BM that are responsible for GVHD. Alloreactive T cells require two signals for activation. One signal is delivered by alloAg via the TCR and the other by costimulatory molecules. Blockade of B7 family mediated costimulation can induce anergy to fully mismatched allogeneic donor T cells ex vivo. Based on these findings, we have commenced a clinical trial of ex vivo tolerance induction of donor T cells to alloAg. If long-lasting and irreversible unresponsiveness to alloAg can be induced, the associated attendant clinical toxicities of GVHD would be ameliorated while the eligible donor pool would be increased without sacrificing immunity to infectious agents and tumor. To achieve these goals, Four Aims are proposed. First, to continue our ongoing clinical trials of ex vivo anergization of donor T cells to alloAg. Second, block additional pathways to optimize alloAg specific anergy. Third, compare sources of allogeneic T cells to study naive vs previously activated T cells and determine their capacity to be anergized to alloAg. Fourth, determine whether alloanergization results in retention of normal T cell function against pathogens and tumor cells. This Project relies upon and is highly interdependent with the second project (for selection of costimulatory pathways that might block CD4 and CD8 T cell anergy) and with the third project (for preclinical animal models determining costimulatory pathways and study of naive vs previously activated T cells).