TOLERANCE TO BONE MARROW TRANSPLANTS

对骨髓移植的耐受性

• 批准号: 6235437
• 负责人: Michael Bennett
• 金额: $ 15.62万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6235437
• 关键词: bone marrow transplantation; immune tolerance /unresponsiveness; immunologic techniques; laboratory mouse; method development; natural killer cells; tissue /cell culture; tissue mosaicism; transplantation immunology

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.

该项目有两个总体目标：1）了解 亲本骨髓细胞移植耐受 不相容的移植物，当消除供体的主要效应细胞 干细胞是NK细胞; 2]开发“临床适用” 诱导对不相容BMC移植物耐受的方法。研究 旨在临床上完成成功的骨髓移植 没有移植物抗宿主病（GVHD），即使门不匹配 在HLA（小鼠中为H2）上完全相同。移除供体骨髓T细胞有助于 改善GVHD，但增加了BMC排斥的可能性 移植物为了实现这些目标，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细胞诱导耐受的机制， (BALB/c X C57 BL/6）F1（cB 6 F1）-至BALB/c（C）辐射BMC嵌合体。在 在CB 6 F1至C模型中，效应细胞是5E 6 + NK细胞。该模型可 用于确定“缺失自我”假设的耐受机制 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Ag的负信号。未能 检测到那些I类抗原允许NK细胞杀死。相反，“Hh” 一种假说认为，NK细胞使用NK受体识别 干细胞以积极的方式。阿格人自己也处于一种特殊的 调节，使得表达需要纯合性。 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，通过喂食诱导 供体型BMC，然后用骨髓移植物激发;第二种是 前房相关免疫偏离（ACAID）的诱导 在激发前将BMC注射到眼前房中 第三种是用紫外线B（UVB）照射， 抗原呈递细胞，例如皮肤的朗格汉斯细胞（LC）。UVB 治疗LC不仅不能刺激免疫反应），但实际上导致 “宽容”。这一目标的成功可以使接受骨移植的患者受益。 骨髓移植