PATHOLOGY UTSWMC

骨髓移植被用于治疗肿瘤、某些遗传性疾病，甚至是自身免疫性疾病。由于患者缺乏MHC相合的同胞，需要跨越MHC障碍进行移植。重要的是制定防止排斥的方法，而诱导宽容是一种合乎逻辑的战略。因为NK细胞是排斥BMC移植物的主要效应者，通过正信号Ly49受体识别I类抗原，但这种能力受负信号Ly49受体的调节。这一机制需要供体和宿主类型的NK细胞共存，才能允许NK细胞谱系的这种“改变”。此外，T细胞也不是必需的。为了测试这些概念，将产生骨髓嵌合体，例如F1与亲本株杂交，并将检查NK细胞I类抗原受体的阳性和阴性表达，如D4。骨髓移植将验证耐受诱导，使用T细胞缺陷的骨髓供者和宿主将关键地测试T细胞在诱导NK细胞耐受中的重要性。在目标2中，实验旨在开发临床适用的方法，以诱导T细胞和/或NK细胞参与的骨髓移植耐受。这些方法包括：1)骨髓来源的树突状细胞在免疫抑制小鼠中输注(低剂量照射，抗CD4和CD8 T细胞和NK细胞的抗体)，2)用非耗竭抗体阻断CD4和CD8细胞，以诱导由T抑制细胞维持的耐受，3)干扰CD28或CD40L之间的共刺激信号，T细胞与树突状细胞上的B7或CD40，4)阻断CD2或2B4-CD48调节同种异体反应的相互作用，5)效应细胞极化为具有抗IL-12和IL-4的类Th2表型，或这些细胞的组合。这些方法将按从小的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、亲本到F1杂交移植物(杂交抗性)的顺序进行试验。这些研究的结果将有望导致临床骨髓移植。

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.