PATHOLOGY UTSWMC

病理学 UTSWMC

• 批准号: 6340695
• 负责人: Michael Bennett
• 金额: $ 12.43万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6340695
• 关键词: CD2 molecule; CD28 molecule; CD40 molecule; T lymphocyte; artificial immunosuppression; biological signal transduction; bone marrow transplantation; dendritic cells; immune tolerance /unresponsiveness; laboratory mouse; natural killer cells; receptor; receptor expression; tissue mosaicism

Bone marrow transplantation is used to treat neoplastic, certain genetic, and even autoimmune diseases. The need to transplant across MHC barriers due to the lack of MHC-identical siblings for patients. It is important to devise approaches to prevent rejection, and induction of tolerance is a logical strategy. Because NK cells are major effectors that reject BMC grafts by recognizing class I Ag by positive signaling Ly49 receptors, but that ability is regulated by negative signaling Ly49 receptors. The mechanism requires co-existence of donor and host type NK cells to allow such 'alteration' of the NK cell repertoire. Moreover, T cells are not required. To test these notions marrow chimeras will be generated, e.g., F1 hybrid to parent strain, and NK cells will be examined for expression of positive and negative expression of receptors for class I Ag, such as D4. Marrow grafts will validate tolerance induction, and use of T cell deficient marrow donors and hosts will critically test the importance of T cells to induction of NK cell tolerance. In Aim 2, experiments are designed to develop clinically applicable approaches to inducing tolerance to marrow grafts that involve T cells and/or NK cells. These approaches include 1] infusion of marrow derived dendritic cells in immunosuppressed mice (low dose irradiation, antibodies to CD4 and CD8 T cells and to NK cells, 2] blockade of CD4 and CD8 cells with non-depleting antibodies to induce a tolerance that is maintained by T suppressor cells, 3] interference with co-stimulatory signals between CD28 or CD40L, on T cells with B7 or CD40 on dendritic cells, 4] interruption of CD2 or 2B4-CD48 interactions that regulate alloreactivity, 5] polarization of effector cells to a 'Th2-like' phenotype with anti-IL-12 and IL-4, or combinations of these. These approaches will be tried in sequence from minor H antigen mismatches, F1 to parent mismatches, HS mismatches that do or do not involve host NK cells, and parent to F1 hybrid grafts (hybrid resistance). The results of these studies will hopefully lead to clinical marrow engraftment.

骨髓移植用于治疗肿瘤、某些遗传性疾病，甚至自身免疫性疾病。由于患者缺乏 MHC 相同的兄弟姐妹，因此需要跨越 MHC 障碍进行移植。设计防止排斥的方法很重要，而诱导耐受是一种合乎逻辑的策略。因为 NK 细胞是通过正信号 Ly49 受体识别 I 类 Ag 来排斥 BMC 移植物的主要效应细胞，但这种能力受到负信号 Ly49 受体的调节。该机制需要供体和宿主型 NK 细胞共存，以允许 NK 细胞库的这种“改变”。此外，不需要T细胞。为了测试这些概念，将产生骨髓嵌合体，例如与亲本菌株杂交的F1，并且将检查NK细胞的I类Ag受体（例如D4）的阳性和阴性表达。骨髓移植将验证耐受性诱导，使用 T 细胞缺陷的骨髓供体和宿主将严格测试 T 细胞对诱导 NK 细胞耐受性的重要性。在目标 2 中，实验旨在开发临床适用的方法来诱导对涉及 T 细胞和/或 NK 细胞的骨髓移植物的耐受性。这些方法包括 1] 在免疫抑制小鼠中输注骨髓来源的树突状细胞（低剂量照射、针对 CD4 和 CD8 T 细胞以及 NK 细胞的抗体，2] 用非耗竭抗体阻断 CD4 和 CD8 细胞以诱导耐受性由 T 抑制细胞维持，3] 干扰 T 细胞上 CD28 或 CD40L 之间的共刺激信号，与树突状细胞上的 B7 或 CD40，4] 中断调节同种异体反应性的 CD2 或 2B4-CD48 相互作用，5] 使用抗 IL-12 和 IL-4 或这些方法的组合将效应细胞极化为“Th2 样”表型，将从次要 H 开始按顺序尝试这些方法。抗原错配、F1 与亲本错配、涉及或不涉及宿主 NK 细胞的 HS 错配以及 F1 杂交移植物的亲本（杂交抗性）。这些研究的结果有望带来结果。临床骨髓移植。