T cell repertoire of graft-versus-host disease and graft-versus-tumor effects

移植物抗宿主病和移植物抗肿瘤效应的 T 细胞库

• 批准号: 8242809
• 负责人: Robert Korngold
• 金额: $ 38.86万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242809
• 关键词: Address; Alloantigen; Allogenic; Blood; Blood specimen; Bone Marrow Transplantation; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Clinical; Complication; Data; Development; Disease; Donor person; Elements; Engraftment; Extracellular Matrix; Family; Foundations; Future; Gastrointestinal tract structure; Goals; Graft-Versus-Tumor Induction; Hematologic Neoplasms; Hematopoietic; Hematopoietic stem cells; Human; Immune; Immune response; Immunobiology; Immunotherapeutic agent; Immunotherapy; In Vitro; Incidence; Indium; Infusion procedures; Investigation; Lead; Lymphocyte; Malignant Neoplasms; Mature T-Lymphocyte; Mediating; Messenger RNA; Minor Histocompatibility Antigens; Mixed Lymphocyte Culture Test; Modality; Modeling; Mus; Myeloid Leukemia; Myeloproliferative disease; Opportunistic Infections; Organ; Outcome; Pathogenesis; Patients; Play; Predictive Value; Process; Proteins; Recombinant Inbred Strain; Relative (related person); Risk; Role; Sampling; Severities; Siblings; Solid; Specificity; Stromelysin 1; System; T cell response; T cell therapy; T-Cell Immunologic Specificity; T-Lymphocyte; Tenascin; Testing; Time; Tissue Grafts; Tissues; Translating; Transplantation; Tumor Antigens; Work; base; cancer therapy; design; gastrointestinal epithelium; graft vs host disease; in vivo; neoplastic cell; peripheral blood; pre-clinical; public health relevance; research study; response; tool; tumor

DESCRIPTION (provided by applicant): Following allogeneic blood and marrow transplantation (BMT), mature donor T cells can enhance engraftment, counteract opportunistic infections, and mount graft-versus-tumor (GVT) responses, but at the risk of developing graft-versus-host disease (GVHD). The key to the future of allogeneic BMT as immunotherapy for the treatment of cancer lies in the ability to enhance the beneficial effects of the donor T cells in mediating GVT while minimizing their capacity to cause GVHD. One approach to accomplish this goal would be to selectively deplete subsets of alloreactive T cells in the hematopoietic stem cell inoculum. In this regard, TCR V¿ repertoire analysis by CDR3-size spectratyping can be a powerful tool for the characterization of alloreactive T cell responses. The general aim of this proposal is the investigation of the immunobiology of lethal GVHD and GVT effects by concentrating on how the donor anti-host minor histocompatibility antigen (miHA) T cell repertoire develops and the broad definition of the TCR specificities involved in disease pathogenesis of the target tissues and GVT responses. To accomplish this, the B10.BR->CBA and the C57BL/6 (B6)->CXB-2, B6->BALB.B, B6->CXB-3 and B6->CXB-7 miHA-mismatched strain combination transplantation models will be utilized. Varying levels of GVHD pathogenesis are mediated by CD8+ and/or CD4+ T cells in each of these transplantation models. In addition, the role of host elements outside the hematopoietic compartment, as immune modulators for GVHD will be examined. The T cell repertoires involved in GVHD and GVT responses will be analyzed by TCR V¿ spectratyping. These latter studies will be accomplished by challenging the CBA or CXB-2 mice with host-derived murine myeloid leukemia cells (MMC6 and MME4). The spectratype analysis will be used to guide manipulation of donor T cell inocula in an effort to diminish GVHD and boost the GVT activity. These preclinical murine studies will establish the foundation for the human studies in which TCR V¿ spectratype analysis will be used to examine the predictive value for the in vivo GVT and GVHD responses from patients by analysis of in vitro mixed lymphocyte culture responses, generated between donor T cells and host tumor samples, as well as alloreactivity between donor and host peripheral blood samples (PBL). These in vitro analyses will be compared with TCR V¿ spectratyping of PBL obtained from the patient post-transplantation. Comparing V¿ spectratypes between the in-vitro tumor- and host- reactive responses with those of the in vivo analysis will allow determination of which T cell specificities are most likely to be GVH or GVT reactive-specific. PUBLIC HEALTH RELEVANCE: The widespread use of allogeneic blood and marrow transplantation as an immunotherapeutic approach for the treatment of malignancy has been hampered by the deleterious effects of T cell mediated graft-versus-host disease. T cell spectratype analysis can be used to distinguish tumor-reactive from host-alloreactive T cells, which can then be used to direct specific manipulation of the donor inoculum to promote engraftment and favor graft-versus-tumor responses for more successful outcomes in BMT.

描述（由申请人提供）：同种异体血液和骨髓移植（BMT）后，成熟供体T细胞可增强植入，抵抗机会性感染，并产生移植物抗肿瘤（GVT）反应，但有发生移植物抗宿主病（GVHD）的风险。同种异体BMT作为免疫疗法用于治疗癌症的未来的关键在于增强供体T细胞在介导GVT中的有益作用的能力，同时使其引起GVHD的能力最小化。实现该目标的一种方法是选择性地耗尽造血干细胞接种物中的同种异体反应性T细胞亚群。在这方面，TCR V通过CDR 3大小谱分析的库分析可以是表征同种异体反应性T细胞应答的有力工具。该提案的总体目的是通过集中于供体抗宿主次要组织相容性抗原（miHA）T细胞库如何发展以及靶组织和GVT应答的疾病发病机制中涉及的TCR特异性的广泛定义来调查致死性GVHD和GVT效应的免疫生物学。为了实现这一点，将利用B10. BR->CBA和C57 BL/6（B6）-> CX B-2、B6->BALB.B、B6-> CX B-3和B6-> CX B-7 miHA错配品系组合移植模型。在这些移植模型中的每一个中，不同水平的GVHD发病机制由CD 8+和/或CD 4 + T细胞介导。此外，造血区室外的宿主元素作为GVHD的免疫调节剂的作用将被检查。将通过TCR V谱分析参与GVHD和GVT应答的T细胞库。后一项研究将通过用宿主来源的鼠骨髓性白血病细胞（MMC 6和MME 4）攻击CBA或CXB-2小鼠来完成。谱型分析将用于指导供体T细胞接种物的操作，以努力减少GVHD并提高GVT活性。这些临床前小鼠研究将为人体研究奠定基础，其中TCR V？谱型分析将用于通过分析供体T细胞和宿主肿瘤样本之间产生的体外混合淋巴细胞培养应答以及供体和宿主外周血样本（PBL）之间的同种异体反应性来检查患者体内GVT和GVHD应答的预测值。这些体外分析将与从移植后患者获得的PBL的TCR V谱进行比较。比较V？体外肿瘤和宿主反应性应答与体内分析的那些之间的谱图将允许确定哪些T细胞特异性最可能是GVH或GVT反应性特异性的。 公共卫生相关性：广泛使用同种异体血液和骨髓移植作为治疗恶性肿瘤的免疫方法受到T细胞介导的移植物抗宿主病的有害影响的阻碍。T细胞谱型分析可用于区分肿瘤反应性T细胞和宿主同种异体反应性T细胞，然后可用于指导供体接种物的特异性操作，以促进植入并有利于移植物抗肿瘤反应，从而在BMT中获得更成功的结果。