CELLULAR PATHOLOGY OF CUTANEOUS GRAFT VS HOST DISEASE

这项提案代表了修订后的竞争性续签，涉及到 随着急性移植物抗宿主病(GVHD)的细胞病理学， 人类异基因骨髓移植的主要并发症。 皮肤移植物抗宿主病是这种情况在靶器官的一种表现。 便于研究的：皮肤。尽管蜂窝 皮肤移植物抗宿主病的发病机制仍不清楚，皮损 被认为是同种异体反应性供体效应细胞相互作用的结果 皮肤靶细胞。因此，GVHD是一个潜在的家庭范例 一系列细胞毒性皮肤反应，从多形性红斑到 红斑狼疮对艾滋病的细胞毒性作用。 H-2配型小鼠GVHD的实验研究 组织相容性抗原提供了重要的见解 皮肤中效应器与靶细胞的相互作用。取决于捐赠者和接受者 使用的菌株，供体T细胞具有成熟的CD4或CD8表型 可能会引起皮肤和内脏的损害。尽管这些效应器T 细胞能够启动疾病的早期事件 进展，最终渗透到靶组织的细胞有一种新的 CD4+CD3-CD8-表型，似乎优先损伤上皮干细胞 细胞。在他们进入目标地点之前，先要脱颗粒 我们和其他人最近发现的血管周围肥大细胞是一种 肿瘤坏死因子-α(TNF)的有效来源。反过来，肿瘤坏死因子可能会， 促进白细胞与微血管内皮细胞的黏附，并与 肥大细胞蛋白水解酶，促进靶细胞损伤。这些 观察结果表明，急性移植物抗宿主病涉及 成熟供者T细胞同种异体激活和增殖的起始期； 血管诱导期，非常规的效应性T细胞 肥大细胞联合表型对靶组织的侵袭 脱颗粒/释放肿瘤坏死因子；以及上皮干 细胞优先受到损伤。 在本系列中，我们将使用实验验证这一假设 专门解决这些问题的模型。肥大细胞的贡献 分泌产物和CD4+8-3单核效应细胞产物 角质形成细胞的毒性将在相关的体外和体内得到解决 系统。最近鉴定上皮干细胞的方法应该是清楚的 它们作为这些效应器通路的细胞靶标。的作用 皮肤黏附分子在效应细胞归巢中的表达 首次在实验性移植物抗宿主病中进行了研究。

This proposal, representing a revised competing renewal, is concerned with the cellular pathology of acute graft-versus-host disease (GVHD), a major complication of human allogeneic bone marrow transplantation. Cutaneous GVHD is a manifestation of this condition in a target organ readily accessible for study: the skin. Although the cellular pathogenesis of cutaneous GVHD remains poorly understood, lesions are believed to result from interaction of alloreactive donor effector cells with skin target cells. thus, GVHD is a potential paradigm for a family of cytotoxic cutaneous reactions, ranging from erythema multiforme to lupus erythematosus to cytotoxicity in AIDS. Experimental GVHD using H-2 matched mice differing only at minor histocompatibility antigens has provided important insights into effector-target cell interactions in skin. Depending on donor-recipient strains employed, donor T cells of either a mature CD4 or CD8 phenotype may initiate cutaneous and visceral lesions. Although these effector T cells are capable of setting into motion early events in disease progression, cells that eventually infiltrate target tissue have a novel CD4+CD3-CD8-phenotype and appear to preferentially damage epithelial stem cells. Their entry into target sites is preceded by degranulation of perivascular mast cells which we and others have recently shown to be a potent source of tumor necrosis factor-alpha (TNF). TNF may, in turn, promote leukocyte adhesion to microvascular endothelium, and long with mast cell proteinases, contribute to target cell injury. These observations have resulted in the hypothesis that acute GVHD involves an initiation phase of mature donor T cell alloactivation and proliferation; a vasoinductive phase whereby effector T cells of unconventional phenotype infiltrate target tissue in concert with mast cell degranulation/TNF release; and a target phase in which epithelial stem cells are preferentially injured. In this continuation, we will test this hypothesis using experimental models that specifically address these issues. Contribution of mast cell secretory products and CD4+8-3-mononuclear effector cell products to keratinocyte toxicity will be addressed in relevant in vitro and in vivo systems. Recent methods to identify epithelial stem cells should clarify their role as cellular targets of these effector pathways. The role of skin adhesion molecule expression in effector cell homing will be investigated for the first time in experimental GVHD.