PATHOGENESIS OF CHRONIC GRAFT-VS-HOST DISEASE

这项工作将探讨慢性移植物抗宿主病（GVHD）的发病机制 在老鼠。 近交系AUG.2b（PVG）间骨髓移植 而AUG菌株与慢性、长期 移植后4-6个月GVHD。 这两个菌株是同源的 对于血型抗原RT 2， 与RT 2相同或紧密连锁的组织相容性位点。 的 实验旨在实现三个具体目标。 一是 表征细胞和体液免疫病理学变化， 这些动物正在经历慢性GVHD。 临床疾病的发作 随后是一段稳定的嵌合体时期，我们特别感兴趣的是， 在GVHD发作期间发生的免疫学事件。 第二、 我们打算研究的发病机制的细胞介导的病变的 过继转移慢性GVHD，体外修饰 移植的骨髓，以及同种异体反应性T细胞克隆的产生。 的 T细胞克隆将特别适用于重建实验， 建立所需的细胞亚群和靶特异性， 产生GVHD。 第三，同源供体-受体菌株的使用 组合提供了表征抗原的机会 导致慢性移植物抗宿主病 我们打算用捐赠者 抗宿主抗体和T细胞克隆以建立组织分布， 多态性程度和靶抗原的结构特征。 拟议工作的重要性是有机会研究一个 慢性移植物抗宿主病的实验模型， 骨髓移植后出现的疾病 HLA相同的兄弟姐妹 在人类和我们的研究中发现的慢性GVHD 实验模型具有重要的临床和病理特征， 允许在其他实验中不可能进行的实验研究 动物 RT 2同源模型的独特特征是在小鼠中的慢性GVHD。 针对单个非MHC背景基因的MHC匹配动物。 的 从这些研究中获得的结果将大大提高我们的认识 慢性GVHD的发病机制，并应直接应用于 骨髓的供-受者选择和治疗应用 人体移植（TT）

This work will examine the pathogenesis of chronic graft-versus-host (GVHD) in the rat. Bone marrow transplantation between the inbred AUG.2b (PVG) and AUG strains is associated with the appearance of a chronic, prolonged GVHD 4-6 months following transplantation. These two strains are congenic for a blood group antigen, RT2, and apparently differ for a histocompatibility locus identical to or closely linked to RT2. The experiments are designed to achieve three specific aims. The first is to characterize the cellular and humoral immunopathological changes present in the animals undergoing a chronic GVHD. The onset of clinical disease follows a period of stable chimerism and we are particularly interested in the immunological events that occur during the onset of the GVHD. Second, we intend to examine the pathogenesis of the cell-mediated lesions of the chronic GVHD by adoptive transfer, in vitro modification of the transplanted marrow, and the generation of alloreactive T-cell clones. The T-cell clones will be particularly useful for reconstitution experiments to establish the cell subpopulations and target specificity required to produce the GVHD. Third, the use of the congenic donor-recipient strain combination provides the opportunity to characterize the antigen(s) responsible for stimulating a chronic GVHD. We intend to use donor antihost antibody and T-cell clones to establish the tissue distribution, degree of polymorphism and structural characteristics of the target antigen. The importance of the proposed work is the opportunity to study an experimental model of chronic graft-versus-host disease that closely mimics the disease seen following bone marrow transplantation between HLA-identical siblings. The chronic GVHD seen in man and in our experimental model share important clinical and pathological features that allow for experimental investigation not possible in other experimental animals. The unique feature of the RT2 congenic model is a chronic GVHD in MHC matched animals directed against a single non-MHC background gene. The results obtained from these studies will greatly improve our understanding of the pathogenesis of chronic GVHD and should have direct application for donor-recipient selections and therapeutic applications of bone marrow transplantation in man. (TT)