IMMUNOGENOMICS OF GRAFT VS HOST DISEASE

移植物抗宿主疾病的免疫基因组学

• 批准号: 6390901
• 负责人: Derry Charles Roopenian
• 金额: $ 33万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390901
• 关键词: bone marrow transplantation; cytotoxic T lymphocyte; disease /disorder model; disease /disorder proneness /risk; graft versus host disease; histocompatibility antigens; homologous transplantation; immunogenetics; laboratory mouse

DESCRIPTION: (Applicant's Abstract) Allogeneic bone marrow transplantation (BMT) following myeloablation is the treatment of choice for many forms of neoplasm, including leukemia and lymphoma. However, even when donor and recipient are matched for Major Histocompatibility Complex (MHC) antigens, successful reconstitution often results in serious graft vs. host disease (GVHD) because so-called minor histocompatibility antigens (miHA) encoded outside of the MHC act as targets of the GVH response. However, studies in humans and in mice have suggested that a small number of dominant miHA may play a disproportionately major role in serious GVHD. Thus, a key unsolved issue is how many miHA are functionally significant during allogeneic BMT under conditions of MHC matching? The applicant's overall goal is to define the miHAs that dominate GVHD in mice, and to then determine whether he can use this information toward risk assessment and/or therapeutic regimes. Cytotoxic T lymphocytes (CTLs) are thought to play a pivotal role in serious GVHD and he has already identified one mouse miHA, H60, which is the major target of CTLs during serious GVHD. He will determine whether additional miHAs that also dominate during GVH, which will constitute the first thorough analysis in humans or mice of GVHD-associated miHAs. There is remarkably little information regarding the dynamics of CTLs in the GVH response. The applicant will use available miHA/MHC tetramers to track specific CTLs during GVHD. This should provide new insights into the dynamics and fate of CTLs engaging in systemic immune responses in vivo. If he finds that the number of functionally important miHA is low, these dominant miHAs should have a disproportionately large effect in causing GVHD. He will test this possibility by determining: (1) whether severe GVHD can be reconstructed by mismatching only at these miHAs; and (2) whether donors and recipients matched for (or tolerized to) a limited number of GVH-associated miHAs but mismatched for all others are protected from serious GVHD. In summary, GVHD is a complex genetic disease caused by a potentially large number of miHAs. However, studies have suggested that certain miHAs play a disproportionately major role in serious GVHD. The applicant's proposed studies should resolve this enigma, and in doing so, the studies should clarify the immunogenetics of GVHD and provide a feasibility study of how genomic data might be exploited to improve allogeneic BMT.

描述：(申请人摘要)异基因骨髓移植 (BMT)是许多形式的骨髓瘤的首选治疗方法。 肿瘤，包括白血病和淋巴瘤。然而，即使捐赠者和 受体与主要组织相容性复合体(MHC)抗原匹配， 成功的重建往往会导致严重的移植物抗宿主疾病 (GVHD)，因为所谓的次要组织相容性抗原(MIHA)编码 MHC以外的区域作为GVH反应的靶点。然而，中国的研究 人类和小鼠的研究表明，少数占优势的miha可能会发挥作用 在严重的GVHD中扮演着不成比例的主要角色。因此，一个尚未解决的关键问题是 在同种异体骨髓移植期间，有多少MIHA在功能上有意义 MHC匹配的条件？申请者的总体目标是定义MIHAS 在小鼠体内主导GVHD的基因，然后确定他是否可以使用这种 关于风险评估和/或治疗方案的信息。细胞毒T细胞 淋巴细胞(CTL)被认为在严重的GVHD和HE中起着关键作用。 已经确定了一只小鼠Miha，H60，它是CTL的主要目标 在严重的GVHD期间。他将确定是否还有更多的MIHAS 在GVH期间占主导地位，这将构成 与GVHD相关的MIHAS的人或小鼠。有关这方面的信息非常少 关于GVH反应中CTL的动态。申请者将使用 提供MIHA/MHC四聚体，用于在GVHD期间追踪特定的CTL。这应该是 为参与系统性研究的CTL的动态和命运提供新的见解 体内的免疫反应。如果他发现功能上很重要的数量 Miha是低的，这些占主导地位的MIHa应该会产生不成比例的大影响 导致移植物抗宿主病。他将通过以下方式测试这种可能性：(1)是否 严重的GVHD只能通过这些MIHA的不匹配来重建；以及(2) 捐赠者和接受者是否匹配(或容忍)有限数量的 与GVH相关但与所有其他MIHA不匹配的MIHA受到保护，不会受到严重 GVHD。总而言之，移植物抗宿主病是一种复杂的遗传性疾病，可能由 大量的MIHA。然而，研究表明，某些MIHA发挥了作用 在严重的GVHD中扮演着不成比例的主要角色。申请人的建议 研究应该解开这个谜团，在这样做的过程中，研究应该澄清 GVHD的免疫遗传学，并提供了基因组数据如何 可能被利用来改善异基因骨髓移植。