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，需要跨越MHC障碍进行移植。重要的是要制定防止排斥的办法，而诱导容忍是一个合乎逻辑的战略。因为NK细胞是通过正信号Ly 49受体识别I类抗原来排斥BMC移植物的主要效应物，但这种能力受负信号Ly 49受体调节。该机制需要供体和宿主型NK细胞的共存以允许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，将检查F1与亲本菌株杂交，NK细胞的I类Ag受体（如D4）阳性和阴性表达。骨髓移植将验证耐受诱导，并且使用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细胞耐受的重要性。在目标2中，设计实验以开发临床上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。这些方法包括1]在免疫抑制小鼠中输注骨髓来源的树突细胞（低剂量照射，针对CD 4和CD 8 T细胞以及针对NK细胞的抗体，2]用非消耗性抗体阻断CD 4和CD 8细胞以诱导由T抑制细胞维持的耐受，3]干扰CD 28或CD 40 L之间的共刺激信号，4]调节同种异体反应性的CD 2或2B 4-CD 48相互作用的中断，5]用抗IL-12和IL-4将效应细胞极化为“Th 2样”表型，或这些的组合。这些方法将按顺序尝试，从次要H抗原错配，F1到亲本错配，涉及或不涉及宿主NK细胞的HS错配，以及亲本到F1杂交移植物（杂交抗性）。这些研究的结果将有望导致临床骨髓移植。