CELLULAR PATHOLOGY OF GRAFT VERSUS HOST DISEASE

描述：(改编自申请者的摘要)-GVHD是一个专业 异基因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机制。这 竞争更新是始于1995年的研究的继续，致力于 了解移植物抗宿主病细胞病理基础的机制。 在之前的周期中，一个相关的人类移植物抗宿主病小鼠模型 被开发和表征的。移植物抗宿主病样细胞毒性的体内生物测定 在人类皮肤上也有过描述。调查人员了解到， 皮肤急性移植物抗宿主病的组织损伤至少有三个阶段：i) 通过抗原结合激活供体T细胞的同种异体刺激 与T细胞受体-CD3复合体相关的表面分子；ii) 由于表达，激活的供体细胞归巢到特定的器官 细胞因子激活的微血管内皮细胞对黏附分子的作用； 和iii)细胞毒性，涉及特定的细胞选择性凋亡 目标细胞亚群。异体刺激、归巢和细胞毒性 各个阶段分别涉及T细胞和 抗原提呈细胞、T细胞和内皮细胞，以及T细胞和 靶向角质形成细胞。这样的互动是 治疗性干预。调查人员已经成功地阻止了 利用专门设计的合成肽进行小鼠GVHD的实验研究 为模拟小鼠免疫球蛋白D1区的CDR3区， 人类的CD4分子。他们假设这种方法的有效性 在于钝化诱导T细胞同种异体刺激和细胞毒能力 以及抑制T细胞归巢到特定的靶组织。他们现在 计划探索小鼠CD-4-CDR3多肽排斥靶标的机制 移植物抗宿主病中的细胞凋亡。一种新型的模拟FceRIa的合成肽 肥大细胞上的分子，似乎也能抑制这种疾病 学习。此外，他们还将评估多肽给药方案 在实验性GVHD中评估这部小说的实用价值 治疗方法。最后，他们将评估 免疫调节策略，包括CD4-CDR3肽，以抑制 与人类相关的体内嵌合模型中的人皮肤细胞毒性 疾病。这些数据应该会扩大目前对关键早期事件的理解 在急性移植物抗宿主病中导致潜在的致命组织损伤，并协助 评价合成肽作为人类相关治疗策略的价值 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.