Genome-wide Identification of Minor Histocompatibility Antigens

次要组织相容性抗原的全基因组鉴定

• 批准号: 7384634
• 负责人: SHOUDAN LIANG
• 金额: $ 14.69万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-07 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7384634
• 关键词: Adjuvant Therapy; Adoptive Transfer; Adverse effects; Allogeneic Bone Marrow Transplantation; Allogenic; Antigens; Binding; Biological Assay; Blood; Blood specimen; Bone Marrow; Bone Marrow Transplantation; Cancer Center; Cancer Immunology Science; Caring; Cell-Mediated Cytolysis; Cells; Characteristics; Clinical; Clinical Research; Clinical Trials; Code; Collection; Complement; Complication; Cytolysis; Cytotoxic T-Lymphocytes; Data; Databases; Disease; Disease remission; Effectiveness; Environment; Epitopes; Gene Frequency; General Population; Genes; Genetic; Genetic Polymorphism; Genome; Genotype; HLA Antigens; Hematopoietic; Immune response; Immune system; Immunotherapy; Investigation; Knowledge; Laboratories; Lead; Legal; Link; Lymphocyte; Malignant Neoplasms; Measures; Mediating; Methods; Minor Histocompatibility Antigens; Mission; Numbers; Outcome; Patient Care; Patients; Pattern; Peptides; Personal Satisfaction; Physicians; Population; Proteins; Radiation therapy; Rate; Reaction; Recurrent disease; Relapse; Research; Research Personnel; Sampling; Screening procedure; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism in Coding Sequence; Specificity; Statistically Significant; Stem cells; T-Lymphocyte; Techniques; Testing; Therapeutic; Tissue Banks; Translating; Transplantation; Transplanted tissue; Vaccinated; Vaccination; Vaccine Therapy; Vaccines; Work; antigen binding; cancer immunology function; cancer therapy; chemotherapy; clinical effect; clinically relevant; cohort; cytotoxic; graft vs host disease; immunogenic; improved; leukemia; prevent; programs; sample collection

DESCRIPTION (provided by applicant): Allogeneic bone marrow transplantation (BMT) conveys a potent graft-versus-leukemia effect (GVL) that contributes to long-term remission for patients with leukemia. GVL is mediated by cytotoxic T lymphocytes (CTLs) that recognize the minor histocompatibility antigens (mHAs) derived from the genetic differences in the donor and recipient, particularly single nucleotide polymorphisms in the coding regions (cSNPs). Finding more mHAs can help improve BMT and can also be used to develop new adoptive T cell therapies. We propose to identify leukemia mHAs by searching for a statistically significant association between donor-recipient genotyping differences and the reduced rate of leukemia relapse following BMT. This project is made possible by the recently developed large-scale genotyping assays that measure thousands of common cSNPs simultaneously, and will use data from a large transplant tissue bank at MD Anderson Cancer Center. In this project, we will (1) genotype several hundred human leukocyte antigen (HLA)-matched BMT donor-recipient pairs for 13,900 cSNPs; (2) find cSNPs that are donor-negative and recipient-positive that best correlate with long-term remission, using existing and newly developed methods; and (3) experimentally verify mHA-HLA binding by tetramer technique, and verify leukemia-specific lysis by CTL cytotoxicity assay. A potentially legal complication in BMT is graft-versus-host disease (GVHD) which is also caused by recognition of mHAs. To separate mHA that might be targets for GVL from those that are targets for GVHD, we will use a cohort of patients with no GVHD. Using the same data, but by comparing instead with expected SNP distribution in general population (obtained from HapMap), we also identify the mHAs that are GVHD-linked antigens. Our large-scale screening approach will discover immunogenic peptides that are directly applicable to patient care, either to select and expand T cells for adoptive T cell transfer or to vaccinate donors before transplantation to increase the T cells specific for leukemia. These manipulations bring two benefits. First, the immune system being transplanted can be selected for preferential T cell activity against leukemia because the T cells against leukemia-specific antigens could be pre-expanded. Second, the graft-versus-host disease (GVHD) associated with bone marrow transplantation is reduced because the enrichment of leukemia-specific T cells dilutes the T cells with specificities to all other epitopes, including those that cause GVHD. The mHAs are HLA restricted, therefore any additional antigens that we discover will bring the benefit to a wider patient population. We also expect our research to discover more candidates for leukemia vaccines. Because vaccination has few side effects, we can test the effectiveness of potential vaccines by administering them alongside existing therapies.

描述（由申请人提供）：同种异体骨髓移植（BMT）具有有效的移植物抗白血病效应（GVL），有助于白血病患者的长期缓解。 GVL 由细胞毒性 T 淋巴细胞 (CTL) 介导，CTL 识别源自供体和受体遗传差异的次要组织相容性抗原 (mHA)，特别是编码区 (cSNP) 中的单核苷酸多态性。寻找更多 mHA 有助于改善 BMT，也可用于开发新的过继性 T 细胞疗法。我们建议通过寻找供体-受体基因分型差异与 BMT 后白血病复发率降低之间的统计显着关联来识别白血病 mHA。该项目是通过最近开发的大规模基因分型测定法实现的，该测定法可同时测量数千个常见的 cSNP，并将使用来自 MD 安德森癌症中心大型移植组织库的数据。在这个项目中，我们将 (1) 对数百个人类白细胞抗原 (HLA) 匹配的 BMT 供体-受体对进行 13,900 个 cSNP 的基因分型； (2) 使用现有和新开发的方法，找到与长期缓解最相关的供体阴性和受体阳性的 cSNP； (3)通过四聚体技术实验验证mHA-HLA结合，并通过CTL细胞毒性测定验证白血病特异性裂解。 BMT 的一个潜在合法并发症是移植物抗宿主病 (GVHD)，这也是由 mHA 识别引起的。为了将可能是 GVL 目标的 mHA 与 GVHD 目标的 mHA 区分开来，我们将使用一组没有 GVHD 的患者。使用相同的数据，但通过与一般人群中预期的 SNP 分布（从 HapMap 获得）进行比较，我们还鉴定了与 GVHD 相关的抗原的 mHA。我们的大规模筛选方法将发现直接适用于患者护理的免疫原性肽，用于选择和扩增用于过继性 T 细胞移植的 T 细胞，或在移植前对捐赠者进行疫苗接种，以增加白血病特异性 T 细胞。这些操纵带来两个好处。首先，可以选择要移植的免疫系统，使其具有针对白血病的优先 T 细胞活性，因为针对白血病特异性抗原的 T 细胞可以预先扩增。其次，与骨髓移植相关的移植物抗宿主病 (GVHD) 减少，因为白血病特异性 T 细胞的富集稀释了对所有其他表位（包括引起 GVHD 的表位）具有特异性的 T 细胞。 mHA 受到 HLA 限制，因此我们发现的任何其他抗原都将为更广泛的患者群体带来益处。我们还期望我们的研究能够发现更多的白血病疫苗候选药物。由于疫苗接种几乎没有副作用，因此我们可以通过将潜在疫苗与现有疗法一起使用来测试其有效性。