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.

 描述（由申请人提供）：同种异体造血干细胞移植（HSCT）是血液系统恶性肿瘤和其他疾病的潜在治愈方法。供体来源的 T 细胞能够识别和攻击宿主肿瘤细胞，产生有益的移植物抗白血病/淋巴瘤 (GVL) 效应，这对于癌症患者 HSCT 的有效性至关重要。然而，当供体 T 细胞损伤遗传上不同的正常宿主组织时，可能会发生移植物抗宿主病 (GVHD)，这仍然是同种异体 HSCT 更成功应用的主要障碍。这项工作的目标是检查同种异体 HSCT 后颗粒酶 B (GzmB) 功能的新范例。该提议是基于我们对 GzmB 在 GVH 和 GVL 反应中反直觉作用的新发现。通过使用小鼠模型，我们了解到虽然 CD8+ 细胞毒性 T 细胞 (CTL) 需要 GzmB 才能引起 GVHD，但它却意外地减弱了 GVL 效应。值得注意的是，这种双重有害作用可能表明 GzmB 是一个长期期望的靶标，从而可以分离 GVH 和 GVL 反应。值得注意的是，造血抗原呈递细胞 (APC) 可启动 GVH 和 GVL 反应。然而，专业的 APC（例如 CD8a+ 树突状细胞）对于 GVL 反应可能比 GVH 反应更重要。也就是说，GVL反应可能需要APC的交叉呈递，因为肿瘤细胞经常通过有缺陷的抗原呈递来逃避免疫监视，而在没有专业APC的情况下，非造血组织细胞可能足以诱导GVHD。在此背景下，我们自己的初步数据和其他人的研究结果表明，CTL可以利用GzmB杀死宿主专业APC，这可以作为病毒感染模型中控制CTL扩增的负反馈机制。总之，这些发现促使我们假设 GzmB 介导的专业 APC（或特定亚群）的损伤可能会减弱 GVL 反应而不影响 GVH 反应，而 GzmB 也会损害其他宿主组织，从而引起 GVHD。为了检验这一假设，我们将使用过度表达或缺乏 Spi6（非冗余 GzmB 抑制剂）的转基因小鼠来制造嵌合体，其中对 GzmB 的“抵抗”或“敏感性”仅限于造血组织和非造血组织。这个独特的系统将使我们能够确定供体 T 细胞使用 GzmB 损害造血 APC 和其他正常宿主组织从而扭曲 GVL 和 GVH 反应的机制。此外，我们将进行全面但分区的分析，以检查 HSCT 患者各种淋巴细胞亚群中粒酶 A 和 B 激活的临床相关性。总之，本研究深入研究了基本 T 细胞途径的新机制，旨在构建新的干预策略，将 GVHD 与有益的 GVL 效应区分开来。这些新概念和干预策略可能有可能为 HSCT 患者带来更好的生存率和生活质量。