PATHOLOGY UTSWMC

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。设计防止排斥的方法很重要，诱导容忍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而排斥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。该机制要求供体和宿主NK细胞共存，以允许NK细胞库的这种“改变”。此外，也不需要T细胞。为了验证这些概念，将产生骨髓嵌合体，例如与亲本株的F1杂交，并检查NK细胞是否表达I类Ag（如D4）受体的阳性和阴性表达。骨髓移植将验证耐受诱导，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细胞耐受的重要性。在Aim 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细胞的骨髓移植的耐受性。这些方法包括1]注入骨髓衍生在免疫抑制小鼠树突状细胞(低剂量照射,抗体CD4和CD8 T细胞和NK细胞,2]的封锁CD4和CD8细胞non-depleting抗体诱导的公差由T抑制细胞,3]干扰co-stimulatory CD28之间的信号或CD40L在T细胞B7或树突细胞CD40, 4]中断CD2或2调节alloreactivity b4-cd48交互,[5]效应细胞极化为具有抗il -12和IL-4的“th2样”表型，或它们的组合。这些方法将按照轻微H抗原错配、F1与亲本错配、HS错配是否涉及宿主NK细胞、亲本与F1杂交移植物（杂交抗性）的顺序进行试验。这些研究的结果有望引导临床骨髓移植。

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.