TOLERANCE TO BONE MARROW TRANSPLANTS

这个项目有两个总体目标：1)了解(S) 亲本系骨髓细胞移植耐受的实验研究 不相容的移植物，当消除供体的主要效应细胞 干细胞是一种自然杀伤细胞；2]发展中的“临床应用” 诱导不相容骨髓细胞移植耐受的方法(S)。这项研究 临床上的目标是实现成功的骨髓移植 没有移植物抗宿主病(GVHD)，即使门是不匹配的 在人类白细胞抗原(小鼠体内为H2)处表现完美。摘除捐献者的骨髓T细胞有助于 改善GVHD，但它增加了BMC被排斥的可能性 嫁接。为了实现这些目标，我们制定了两个具体目标， 第一个目标是目标1]，第二个目标是目标2]。在目标1中，我们 将分析小鼠NK细胞耐受诱导的机制 (BALB/c X C57BL/6)F1(CB6F1)-至BALB/c(C)辐射BMC嵌合体。在 CB6F1转C模型，效应细胞为5E6+NK细胞。这个模型可以是 用来确定耐受性的机制，如果‘缺失自我’假说 对于NK细胞介导的BMC移植排斥反应是正确的，即NK细胞 受体接收来自某些I类AGS的负面信号。一次失败 检测那些允许NK细胞杀伤的I类抗原。相比之下，“HH” 假设NK细胞使用NK受体识别AGS 以一种积极的方式培养干细胞。AGS本身也处于一种特殊的 表达需要纯合子的调节。在目标2中， 我们将尝试三种方法来诱导对BMC移植物的耐受性 “临床适用”。第一种是口服耐受性，由进食引起 骨髓移植挑战前的供体型BMC；第二个是 阿司匹林诱导前房相关免疫偏离(ACAID) 激发前眼前房内注射BMC 第三种是紫外线B(UVB)照射 抗原提呈细胞，如皮肤的朗格汉斯细胞(LC)。UVB 经治疗的LC不仅不能刺激免疫反应)，而且实际上 为了“宽容”。这一目标的成功可以使接受骨科手术的患者受益。 骨髓移植。

This project has two overall goals: 1] understanding the mechanism(s) of transplantation tolerance to parental strain bone marrow cell (BMC) incompatible grafts, when the major effector cell that eliminates donor stem cells is an NK cell; and 2] Developing 'clinically applicable' method(s) of inducing tolerance to incompatible BMC grafts. The research is aimed clinically at accomplishing successful bone marrow transplants without graft-versus-host disease (GVHD) even when the door is not matched perfectly at HLA (H2 in the mouse). Removal of donor marrow T cells helps ameliorates GVHD, but it increases the likelihood of rejection of the BMC graft. To accomplish these goals, we have created two specific aims, the first one aimed at goal 1] and the second aimed at goal 2]. In aim 1, we will analyze the mechanisms of tolerance induction in NK cells in murine (BALB/c X C57BL/6)F1 (cB6F1)-to BALB/c (C) radiation BMC chimeras. In the CB6F1-to-C model, the effector cells are 5E6+ NK cells. This model can be used to determine the mechanism of tolerance if 'missing self' hypothesis for NK cell mediated BMC graft rejection is correct, i.e., NK cell receptors receive negative signals from certain class I Ags. A failure to detect those class I Ags allows NK cells to kill. In contrast, the 'Hh" hypothesis suggests that NK cells use NK receptors to recognize Ags on stem cells in a positive fashion. The Ags themselves are under a peculiar regulation such that homozygosity is required for expression. In aim 2, we will try three approaches to induce tolerance to BMC grafts that are 'clinically applicable'. The first is oral tolerance, induced by feeding donor-type BMC prior to challenge with marrow grafts; the second is induction of anterior chamber-associated immune deviation (ACAID) by injection of BMC into the anterior chamber of the eye prior to challenge with BMC; the third is us of ultraviolet light B (UVB) irradiation of antigen-presenting cells, e.g. Langerhans cells (LC) of the skin. UVB treated LC not only fail to stimulate immune responses) but actually lead to 'tolerance'. Success in this aim could benefit patients undergoing bone marrow transplants.