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: 7581063
• 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/7581063
• 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; Cell Therapy; 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; 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; Outcome; Patient Care; Patients; Pattern; Peptides; Physicians; Proteins; Radiation therapy; Reaction; Recurrent disease; Relapse; Research; Research Personnel; Sampling; Screening procedure; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism in Coding Sequence; Specificity; Stem cells; T-Lymphocyte; Techniques; Testing; Therapeutic; Tissue Banking; Tissue Banks; Translating; Transplantation; Transplanted tissue; Vaccinated; Vaccination; Vaccine Therapy; Vaccines; Work; antigen binding; cancer therapy; chemotherapy; clinical care; clinical effect; clinically relevant; cohort; genome wide association study; genome-wide; graft vs host disease; immunogenic; improved; leukemia; patient population; 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）传达了有效的移植物 - 抗链球菌效应（GVL），该效应有助于白血病患者长期缓解。 GVL是由细胞毒性T淋巴细胞（CTL）介导的，该细胞淋巴细胞（CTL）识别从供体和受体中遗传差异得出的较小的组织相容性抗原（MHA），尤其是编码区域（CSNPS）的单核苷酸多态性。寻找更多的MHA可以帮助改善BMT，也可以用于开发新的收养T细胞疗法。我们建议通过在BMT后寻找供体 - 重视基因分型差异与降低的白血病复发率之间的统计学意义相关性来鉴定白血病。最近开发的大型基因分型测定法使该项目成为可能，该测定法同时测量了数千个普通CSNP，并将使用MD Anderson癌症中心的大型移植组织库中的数据。在这个项目中，我们将（1）基因型数百个人类白细胞抗原（HLA）匹配的BMT供体 - 启用对，用于13,900 CSNP； （2）找到使用现有和新开发的方法最能与长期缓解相关的供体阴性和受体阳性的CSNP； （3）通过四聚体技术验证MHA-HLA结合，并通过CTL细胞毒性测定法验证白血病特异性裂解。 BMT的可能法律并发症是移植抗宿主病（GVHD），这也是由MHA识别引起的。为了将可能是GVL的靶标与GVHD靶标的目标分开，我们将使用一系列没有GVHD的患者。使用相同的数据，但通过将与普通人群中的预期SNP分布进行比较（从HAPMAP获得），我们还确定了与GVHD连接抗原的MHA。我们的大规模筛查方法将发现直接适用于患者护理的免疫原性肽，以选择和扩展T细胞以进行收养T细胞的转移或在移植之前接种供体接种供体，以增加特异性白血病的T细胞。这些操作带来了两个好处。首先，可以选择被移植的免疫系统针对白血病的优先T细胞活性，因为可以预先扩展针对白血病特异性抗原的T细胞。其次，由于白血病特异性T细胞的富集以特异性对所有其他表位（包括引起GVHD的表现）稀释T细胞，因此减少了与骨髓移植相关的移植物抗宿主病（GVHD），因为白血病特异性T细胞的富集稀释了T细胞。 MHA受到HLA的限制，因此我们发现的任何其他抗原都会为更广泛的患者人群带来好处。我们还希望我们的研究能够发现更多的白血病疫苗候选者。由于疫苗接种几乎没有副作用，因此我们可以通过与现有疗法一起对潜在疫苗进行测试。