IMMUNOGENOMICS OF GRAFT VS HOST DISEASE

移植物抗宿主疾病的免疫基因组学

• 批准号: 6195635
• 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/6195635
• 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) 清髓术后是多种形式的首选治疗方法 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) 抗原相匹配， 成功的重建通常会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 MHC 之外的部分充当 GVH 反应的目标。然而，研究在 人类和小鼠研究表明，少数占主导地位的 miHA 可能发挥作用 在严重的 GVHD 中发挥着不成比例的重要作用。因此，一个未解决的关键问题是 在同种异体 BMT 过程中，有多少 miHA 具有重要功能？ MHC匹配的条件？申请人的总体目标是定义 miHA 在小鼠中主导GVHD，然后确定他是否可以使用这个 有关风险评估和/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 中发挥着关键作用，他 已经鉴定出一种小鼠 miHA，H60，它是 CTL 的主要靶标 严重 GVHD 期间。他将确定是否还有其他 miHA GVH 期间占主导地位，这将构成第一个彻底的分析 人类或小鼠的 GVHD 相关 miHA。信息非常少 关于 GVH 反应中 CTL 的动态。申请人将使用 可用 miHA/MHC 四聚体在 GVHD 期间追踪特定 CTL。这应该 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。如果他发现功能上重要的数量 miHA 较低，这些占主导地位的 miHA 应该具有不成比例的巨大影响 引起GVHD。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 只能通过这些 miHA 的错配来重建；和（2） 捐赠者和接受者是否匹配（或容忍）有限数量的 与 GVH 相关但与所有其他不匹配的 miHA 可以免受严重影响 移植物抗宿主病。总之，GVHD 是一种复杂的遗传性疾病，由潜在的潜在致病因素引起。 大量 miHA。然而，研究表明某些 miHA 发挥作用 在严重的 GVHD 中发挥着不成比例的重要作用。申请人提出的 研究应该解决这个谜团，并且在这样做的过程中，研究应该澄清 GVHD 的免疫遗传学，并提供基因组数据如何发挥作用的可行性研究 可能被用来改善同种异体 BMT。