Targeting Granzyme B to Separate GVH from GVL Responses

靶向颗粒酶 B 将 GVH 与 GVL 反应分开

• 批准号: 8888555
• 负责人: Xuefang Cao
• 金额: $ 40.15万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8888555
• 关键词: Affect; Allogeneic Bone Marrow Transplantation; Allogenic; Antigen Presentation; Antigen-Presenting Cells; Biopsy; Blood specimen; CD8B1 gene; Cancer Patient; Cancer Relapse; Cells; Chimera organism; Clinic; Clinical Trials; Cross Presentation; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Disease; Effectiveness; Feedback; Goals; Granzyme; Hematologic Neoplasms; Hematopoietic; Hematopoietic Stem Cell Transplantation; Human; Immune; Immunologic Monitoring; Immunosuppressive Agents; Infection; Intervention; Intestines; Lead; Learning; Liver; Lymphocyte; Lymphocyte Function; Lymphocyte Subset; Lymphoid; Malignant Neoplasms; Mediating; Medical; Modeling; Mus; Natural Killer Cells; Organ; Pathogenesis; Pathway interactions; Patients; Publications; Quality of life; Resistance; Role; Skin; Speed; Sum; System; T-Lymphocyte; T-Lymphocyte Subsets; TLR5 gene; Testing; Tissues; Transgenic Mice; Translations; Transplantation; Up-Regulation; Virus Diseases; Work; Xenograft procedure; cell injury; clinically relevant; design; disorder prevention; graft vs host disease; hematopoietic tissue; improved; inhibitor/antagonist; killings; leukemia/lymphoma; neoplastic cell; novel; novel therapeutic intervention; outcome forecast; overexpression; perforin; public health relevance; reconstitution; response; small hairpin RNA

 DESCRIPTION (provided by applicant): Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for hematologic malignancies and other diseases. Donor-derived T cells are capable of identifying and attacking host tumor cells, producing the beneficial graft-versus-leukemia/lymphoma (GVL) effect that is crucial for the effectiveness of HSCT for cancer patients. However, graft-versus-host disease (GVHD) may develop when donor T cells damage the genetically distinct normal host tissues, and remains a major obstacle for more successful applications of allogeneic HSCT. The goal of this work is to examine a new paradigm regarding Granzyme B (GzmB) function after allogeneic HSCT. This proposal is built on our novel discovery of the counter-intuitive role of GzmB in GVH and GVL responses. Using murine models, we have learned that while GzmB is required for CD8+ cytotoxic T cells (CTLs) to cause GVHD, it unexpectedly diminishes the GVL effect. Remarkably, this dual detrimental role may reveal GzmB as a long-desired target, allowing separation between GVH and GVL responses. Notably, hematopoietic antigen-presenting cells (APCs) were shown to initiate both GVH and GVL responses. However, professional APCs (e.g., CD8a+ dendritic cells) may be more important for GVL than GVH responses. That is, GVL response may require cross-presentation by APCs because tumor cells often escape immunosurveillance via defective antigen presentation, while non-hematopoietic tissue cells may be sufficient to induce GVHD in the absence of professional APCs. In this context, our own preliminary data and the findings of others show that CTLs can use GzmB to kill host professional APCs, which serves as a negative feedback mechanism for the control of CTL expansion in viral infection models. Together, these findings prompt us to hypothesize that GzmB-mediated damage of professional APCs (or specific subsets) may diminish GVL response without affecting GVH response, while GzmB also damages other host tissues thereby causing GVHD. To test this hypothesis, we will use transgenic mice that overexpress or are deficient for Spi6 (the non-redundant GzmB inhibitor) to make chimeras in which either "resistance" or "sensitivity" to GzmB is confined to hematopoietic vs. non-hematopoietic tissues. This unique system will allow us to determine the mechanisms by which donor T cells use GzmB to damage hematopoietic APCs and other normal host tissues thereby skewing GVL and GVH responses. In addition, we will perform comprehensive but compartmentalized analyses to examine the clinical relevance of Granzymes A and B activation in various lymphocyte subsets in HSCT patients. In summary, this study delves into novel mechanisms of a fundamental T cell pathway, and aims to construct new intervention strategies that can separate GVHD from the beneficial GVL effect. These new concepts and intervention strategies may have the potential to lead to better survival and improved quality of life for HSCT patients.