INDUCTION OF HOST SPECIFIC TOLERANCE IN ALLOGENEIC BMT

在同种异体 BMT 中诱导宿主特异性耐受

• 批准号: 6347233
• 负责人: JOHN G. GRIBBEN
• 金额: $ 27.64万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6347233
• 关键词: bone marrow transplantation; clinical research; clinical trials; cytotoxic T lymphocyte; graft versus host disease; homologous transplantation; human subject; human therapy evaluation; immune tolerance /unresponsiveness; immunotherapy; leukocyte activation /transformation; mixed lymphocyte reaction test

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).

潜在宿主和捐赠者之间的遗传差异限制了 对供体的不利影响对同种异体 BMT 的利用和结果 可用性、植入、GVHD 和免疫重建。 尽管 非特异性免疫抑制和 T 细胞耗竭都可以 降低 GVHD 的频率和严重程度，没有成功的计划 单倍体相同或显着不匹配的无关供体 BMT 出现了。 此外，非特异性免疫操作和 积极的围 BMT 准备方案包括目前 用于改善 GVHD 的方法充满毒性 包括终末器官衰竭、机会性感染增加、B 细胞 淋巴组织增生性疾病和移植物抗肿瘤效应丧失。 因此，尝试在离开时专门抑制同种异体识别 完整的剩余免疫库将减少非特异性 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 仅选择性地灭活少量同种异体特异性 T 细胞 转移到负责 GVHD 的供体 BM 中。 同种反应性 T 细胞需要两个信号才能激活。 一个信号是 由 alloAg 通过 TCR 传递，另一个通过共刺激传递 分子。 阻断 B7 家族介导的共刺激可诱导 对离体完全错配的同种异体供体 T 细胞无反应。 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 诱导供体 T 细胞产生同种异体抗原。 如果持久且不可逆转 可以诱导对同种异体抗原无反应，相关的伴随 GVHD 的临床毒性将得到改善，同时符合条件 捐助者库将在不牺牲免疫力的情况下增加 传染源和肿瘤。 为了实现这些目标，四个目标是 建议的。首先，继续我们正在进行的离体临床试验 供体 T 细胞对同种异体抗原 (alloAg) 进行无激活。 二、区块追加 优化同种异体抗原特异性无能的途径。 三、比较来源 同种异体 T 细胞来研究初始 T 细胞与先前激活的 T 细胞 确定他们被同种抗原激活的能力。 四、确定 同种异能是否会导致正常 T 细胞功能的保留 对抗病原体和肿瘤细胞。 该项目依赖于并且是 与第二个项目高度相互依赖（用于选择 可能阻断 CD4 和 CD8 T 细胞无反应性的共刺激途径） 以及第三个项目（用于临床前动物模型确定 共刺激途径以及初始 T 与先前激活 T 的研究 细胞）。