IMMUNOGENOMICS OF GRAFT VS HOST DISEASE

移植物抗宿主疾病的免疫基因组学

• 批准号: 6644813
• 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/6644813
• 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）同种异体骨髓移植 (BMT)骨髓消融术后是许多形式的 肿瘤，包括白血病和淋巴瘤。然而，即使捐助者和 受体的主要组织相容性复合物（MHC）抗原匹配， 成功的重建常常导致严重的移植物抗宿主病 （GVHD），因为所谓的次要组织相容性抗原（miHA）编码 在MHC之外的细胞充当GVH应答的靶标。然而，研究 人类和小鼠的研究表明，少数占优势的miHA可能在 在严重的GVHD中扮演了不成比例的重要角色。因此，一个关键的未解决的问题是 在同种异体BMT中，有多少miHA在功能上是重要的？ MHC匹配的条件？申请人的总体目标是定义miHA 在小鼠中控制GVHD，然后确定他是否可以使用这个 风险评估和/或治疗方案的信息。细胞毒性T 淋巴细胞（CTL）被认为在严重的GVHD中起关键作用， 已经确定了一种小鼠miHA，H60，它是CTL的主要靶点 严重的GVHD。他将决定是否有更多的miHA， 在GVH期间占主导地位，这将构成第一次彻底的分析， 人或小鼠的GVHD相关miHA。关于这方面的信息 关于GVH应答中CTL的动力学。申请人将使用 可用的miHA/MHC四聚体来追踪GVHD期间的特异性CTL。这应该 提供了新的见解的动态和命运的CTL参与系统性 体内免疫反应。如果他发现在功能上重要的 如果miHA水平较低，这些主要miHA应该会产生不成比例的巨大影响， 导致移植物抗宿主病他将通过确定以下内容来测试这种可能性：（1）是否 严重的GVHD可以通过仅在这些miHA处的错配来重建;以及（2） 捐赠者和接受者是否匹配（或容忍）有限数量的 GVH相关的miHA，但所有其他人都不匹配， GVHD。总之，GVHD是一种复杂的遗传性疾病， 大量的MiHA。然而，研究表明，某些miHA发挥 在严重的GVHD中扮演了不成比例的重要角色。申请人提出 研究应该解决这个谜，这样做，研究应该澄清 GVHD的免疫遗传学，并提供了一个可行性研究， 可能被用于改善同种异体骨髓移植。