INDUCTION OF HOST SPECIFIC TOLERANCE IN ALLOGENEIC BMT

潜在接受者和捐赠者之间的遗传差异限制了 对供者产生不利影响的异基因骨髓移植的利用和结局 可用性、植入物、移植物抗宿主病和免疫重建。而当 非特异性免疫抑制和T细胞耗尽都可以 减少GVHD的频率和严重程度，没有成功的计划 单倍体相同或严重不匹配的无血缘供者骨髓移植 出现了。此外，非特异性免疫操作和 积极的骨髓移植围手术期准备方案包括Present 用于改善GVHD的方法充满了毒副作用 包括终末性器官衰竭，机会性感染增加，B细胞 淋巴增生性疾病和移植物抗肿瘤作用丧失。 因此，试图在离开时特定地抑制异体识别 完整的剩余免疫谱系将减少非特异性 毒性，同时保留或改进现行标准 GVHD控制。该项目的中心目标是尝试 选择性灭活少量同种异体T细胞 转移到负责GVHD的捐赠者骨髓中。 同种异体反应性T细胞需要两种信号才能激活。一个信号是 由AlalAg通过TCR传递，另一种通过共刺激传递 分子。阻断B7家族介导的共刺激可诱导 体外对完全不相合的同种异基因供者T细胞无能。基于 这些发现，我们已经开始了体外耐受性的临床试验 供者T细胞对同种异体抗原的诱导。如果是持久的和不可逆转的 可以诱导对allAg的无反应，相关的随从 GVHD的临床毒性将得到改善，而符合条件的 将在不牺牲免疫力的情况下增加捐赠者池 感染剂和肿瘤。为了实现这些目标，有四个目标 建议。首先，继续我们正在进行的体外临床试验 供者T细胞对同种异体抗原的无能。第二，阻止其他 优化同种异体抗原特异性无能的途径。第三，比较资料来源 研究原始T细胞与先前激活的T细胞 确定它们被活化为同种银的能力。第四，确定 同种异体激发是否导致保留正常的T细胞功能 对抗病原体和肿瘤细胞。该项目依赖于并正在 与第二个项目高度相互依赖(用于选择 可能阻断CD4和CD8 T细胞无能的共刺激通路) 第三个项目(用于临床前动物模型确定 幼稚T细胞与活化T细胞的共刺激途径及研究 单元格)。

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).