INDUCTION OF HOST-SPECIFIC TOLERANCE IN ALLOGENIC BMT

在同种异体 BMT 中诱导宿主特异性耐受

• 批准号: 6373663
• 负责人: Lee Marshall Nadler
• 金额: $ 90.65万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6373663
• 关键词: T lymphocyte; bone marrow transplantation; graft versus host disease; homologous transplantation; immune tolerance /unresponsiveness; immunotherapy

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.

我们计划的中心目标是尝试有选择地 仅耐受转移到细胞中的少量同种异体特异性 T 细胞 导致 GVHD 的供体骨髓 (BM)。 通过离开 超过 99% 的供体 T 细胞在体内过继转移 BM 功能完好，我们希望最大限度地减少移植失败并保留 对病原体和肿瘤细胞的免疫力。 此外，我们希望这 方法将使我们能够减少非特异性免疫抑制 这降低了宿主应对机会主义的能力 感染。 为了实现这些目标，我们计划专门离体 激活供体 BM 中同种异体反应性 T 细胞以宿主同种异体抗原。 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 细胞克隆无能所必需的 供体宿主特异性同种异体前体辅助因子 T 的频率 细胞 (pHTL) 可以降低至低于认为相关的值 GVHD 发生率显着。 我们在诊所里有这个 方法和初步证据表明，捐助东道国 pHTL 频率可以降低到低于预测值的水平 移植物抗宿主病。 第一个项目将在临床中进行开发和评估 抑制同种异体识别的实验治疗方式 特别是同时保留剩余的免疫库完整。 这 可以让我们减少非特异性毒性，同时保留或 改进现行的 GVHD 控制标准。 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能会阻止诱导 无能，研究 CD8+ T 细胞是否可以被激发，以及 最后，继续努力破译其生化基础 无能缺陷。第三个项目的主要目标是 研究幼稚和记忆中共刺激的体内要求 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来源的比较。 本计划 自诞生以来一直具有高度互动性。 为了确保其成功，我们 组建了一支高度多元化但互动的协作团队 分子生物学家、免疫学家、移植生物学家和临床医生 拥有长期的成功合作记录和广泛的 转化经验推动我们的基础科学发现 临床实验。

项目成果

Differential localization and function of ADP-ribosylation factor-6 in anergic human T cells: a potential marker for their identification.

无能人类 T 细胞中 ADP-核糖基化因子 6 的差异定位和功能：其鉴定的潜在标记。

• DOI: 10.4049/jimmunol.171.4.1691
• 发表时间: 2003
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Tzachanis,Dimitrios;Appleman,LeonardJ;VanPuijenbroek,AndreAFL;Berezovskaya,Alla;Nadler,LeeM;Boussiotis,VassilikiA
• 通讯作者: Boussiotis,VassilikiA