Donor Cell Facilitation of Tolerance

供体细胞耐受性促进

• 批准号: 7806783
• 负责人: SAMUEL STROBER
• 金额: $ 4.8万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-25 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7806783
• 关键词: Alloantigen; Allogenic; Apoptosis; Back; Bone Marrow Transplantation; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Chimera organism; Dependence; Development; Heart; Immune Tolerance; Immunosuppressive Agents; Inbred BALB C Mice; Interleukin-10; Interleukin-4; Lymphatic Irradiation; Monitor; Mus; Organ; Organ Transplantation; Pharmaceutical Preparations; Phenotype; Prevention; Research; Residual state; Resistance; Serum; Specificity; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; TP53 gene; Testing; Transgenic Mice; Transgenic Organisms; Transplantation; Wild Type Mouse; conditioning; cytokine; disorder prevention; graft vs host disease; heart allograft; killer T cell; prevent; programs; thymocyte

DESCRIPTION (provided by applicant): The long-term objective of the research program is to induce immune tolerance to allogeneic organ transplants such that immunosuppressive drugs are not required to maintain permanent graft acceptance. Previous studies in the program have shown that tolerance to heart allografts can be achieved using combined heart and bone marrow transplantation in wild-type MHC-mismatched murine hosts that have been conditioned with total lymphoid irradiation (TLI) and anti-thymocyte serum (ATS). The hosts become stable mixed chimeras without the development of graft versus host disease (GVHD). Tolerance induction and prevention of GVHD is dependent on host regulatory natural killer (NK) T cells that become the predominant residual T cell subset after TLI and ATS conditioning. Our recent studies show that tolerance and GVHD prevention is also dependent on the development of donor Treg cells and host Treg cells that are not NK T cells. A hypothesis that explains the results is that host NK T cells interact with host and donor APC's, and then augment/activate the non-NK Treg cells that provide alloantigen specificity for tolerance induction. Whereas the regulatory activity of the NK T cells is IL-4 dependent, that of the non-NK Treg cells is IL-4 and IL-10 dependent. The hypothesis will be tested by adding back purified NK T cells and non-NK Treg cells from wild-type, Treg deficient, and cytokine deficient (i.e. IL-4"'", IL-10"'") host and donor type mice to appropriate TLI/ATS conditioned hosts. The conditioned hosts will receive combined MHC-mismatched organ and bone marrow transplants, and graft acceptance and GVHD will be monitored. The phenotype and cytokine dependence of the non-NK Treg cells will be determined as well as the dependence of NK T cell activation on interaction with APC's. Our recent studies show that the NK T cells in wild type mice are far more resistant to apoptosis induced by TLI/ATS conditioning than conventional T cells. However, the differential resistance is lost in p53"'" mice and in Bcl-2 transgenic mice. We will determine whether the ability to induce tolerance and prevent GVHD is also lost in the latter genetically altered mice.

描述（由申请人提供）：该研究计划的长期目标是诱导对同种异体器官移植的免疫耐受，从而不需要免疫抑制药物来维持永久的移植物接受。该项目之前的研究表明，在经过全淋巴照射 (TLI) 和抗胸腺细胞血清 (ATS) 调节的野生型 MHC 不匹配的小鼠宿主中，通过联合心脏和骨髓移植，可以实现对心脏同种异体移植的耐受性。宿主成为稳定的混合嵌合体，而不会发生移植物抗宿主病（GVHD）。 GVHD 的耐受诱导和预防依赖于宿主调节性自然杀伤 (NK) T 细胞，这些 T 细胞在 TLI 和 ATS 调理后成为主要的残留 T 细胞亚群。我们最近的研究表明，耐受性和 GVHD 预防还依赖于供体 Treg 细胞和非 NK T 细胞的宿主 Treg 细胞的发育。解释该结果的假设是宿主 NK T 细胞与宿主和供体 APC 相互作用，然后增强/激活非 NK Treg 细胞，为耐受诱导提供同种异体抗原特异性。 NK T 细胞的调节活性依赖于 IL-4，而非 NK Treg 细胞的调节活性则依赖于 IL-4 和 IL-10。通过将来自野生型、Treg 缺陷和细胞因子缺陷（即 IL-4"'"、IL-10"'"）宿主和供体型小鼠的纯化 NK T 细胞和非 NK Treg 细胞添加回适当的 TLI/ATS 条件宿主来测试该假设。条件化宿主将接受 MHC 不匹配的器官和骨髓联合移植，并监测移植物接受情况和 GVHD。将确定非 NK Treg 细胞的表型和细胞因子依赖性以及 NK T 细胞激活对与 APC 相互作用的依赖性。我们最近的研究表明，野生型小鼠的 NK T 细胞比传统 T 细胞对 TLI/ATS 条件诱导的细胞凋亡具有更强的抵抗力。然而，p53"'" 小鼠和 Bcl-2 转基因小鼠中，差异抗性消失。我们将确定后者的基因改造小鼠是否也丧失了诱导耐受和预防 GVHD 的能力。