CELLULAR PATHOLOGY OF GRAFT VERSUS HOST DISEASE

描述：（改编自申请人的摘要）- GVHD是一种主要疾病 同种异体骨髓移植成功的障碍 建立白血病和非霍奇金淋巴瘤的缓解。 这 竞争更新是1995年开始的研究的继续， 理解GVHD细胞病理学的基础机制。 在之前的周期中，已经建立了人GVHD的相关鼠模型。 发展和特点。 GVHD样细胞毒性的体内生物测定 在人体皮肤中也有描述。 调查人员了解到， 皮肤急性GVHD中的组织损伤具有至少三个阶段： 同种异体刺激，其中供体T细胞通过抗原结合被激活， 与T细胞受体-CD 3复合物相关的CD 4表面分子; ii） 作为表达的结果，激活的供体细胞归巢到特定器官 粘附分子的表达; 和iii）涉及特异性细胞的选择性凋亡的细胞毒性， 靶细胞的亚群。 同种异体刺激、归巢和细胞毒性 阶段，分别涉及T细胞之间的直接相互作用， 抗原呈递细胞、T细胞和内皮细胞，以及T细胞和 靶向角质形成细胞。 这种相互作用是潜在的目标， 治疗干预 调查人员成功地阻止了 通过使用特异性设计的合成肽的实验性小鼠GVHD 以模拟鼠的D1免疫球蛋白结构域的CDR 3区， 人CD 4分子。 他们假设这种方法的有效性 在于T细胞同种异体刺激和细胞毒性能力的钝化诱导 以及抑制T细胞归巢至特定靶组织。 他们现在 计划探索小鼠CD 4-CDR 3肽消除靶点的机制 GVHD中的细胞凋亡。 模拟FceRIa的新型合成肽 肥大细胞上的分子，似乎也能抑制这种疾病， 研究了 此外，他们将评估肽管理协议， 在实验GVHD，以评估这一新的实际效用 治疗方法 最后，他们将评估 免疫调节策略，包括CD 4-CDR 3肽，以抑制 在与人相关体内嵌合模型中的人皮肤细胞毒性 疾病 这些数据应该扩大目前对关键早期事件的理解 导致急性GVHD中潜在致命组织损伤，并有助于 评价合成肽作为人类疾病相关治疗策略 疾病

DESCRIPTION: (Adapted from the applicant's abstract) - GVHD is a major impediment to successful allogeneic bone marrow transplantation for establishing remission from leukemias and non-Hodgkin's lymphomas. This competing renewal is a continuation of research initiated in l995 devoted to understanding mechanisms that underlie the cellular pathology of GVHD. During previous cycles, a relevant murine model for human GVHD has been developed and characterized. An in vivo bioassay for GVHD-like cytotoxicity in human skin also has been described. The investigators have learned that tissue injury in cutaneous acute GVHD has at least three phases: i) Allostimulation whereby donor T cells are activated via antigen binding to CD4 surface molecules associated with the T-cell receptor-CD3 complex; ii) homing of activated donor cells to specific organs as a result of expression of adhesion molecules by cytokine-activated microvascular endothelial cells; and iii) cytotoxicity involving selective apoptosis of specific subpopulations of target cells. Allostimulation, homing, and cytotoxic phases, respectively, involve direct interactions between T cells and antigen presenting cells, T cells and endothelial cells, and T cells and target keratinocytes. Such interactions are potential targets for therapeutic intervention. The investigators have successfully inhibited experimental murine GVHD by use of synthetic peptides designed specifically to mimic the CDR3 region of the D1 immunoglobulin domain of the murine and human CD4 molecule. They hypothesize that the efficacy of this approach lies in blunted induction of T-cell allostimulation and cytotoxic capacity as well as inhibition of T-cell homing to specific target tissues. They now plan to explore mechanisms whereby murine CD4-CDR3 peptide abrogates target cell apoptosis in GVHD. A novel synthetic peptide that mimics the FceRIa molecule on mast cells and that appears also to inhibit this disease will be studied. In addition, they will evaluate peptide administration protocols in experimental GVHD to assess the practical utility of this novel therapeutic approach. Finally, they will evaluate mechanisms of immunomodulatory strategies, including the CD4-CDR3 peptide, to inhibit human cutaneous cytotoxicity in an in vivo chimeric model relevant to human disease. These data should expand present understanding of key early events that result in potentially lethal tissue damage in acute GVHD, and assist in evaluating synthetic peptides as relevant therapeutic strategies for human disease.