Elucidating the Function of PKC-theta in Alloreactivity and GVHD

阐明 PKC-theta 在同种异体反应性和 GVHD 中的功能

• 批准号: 8073564
• 负责人: Amer Aziz Beg
• 金额: $ 41.33万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8073564
• 关键词: Affinity; Alloantigen; Allogeneic Bone Marrow Transplantation; Allogenic; Bone Marrow Transplantation; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Survival; Cell physiology; Defect; Development; Disease; Exhibits; Goals; Hematopoietic; Immunologics; Immunosuppressive Agents; Immunotherapy; In Vitro; Infection; Infectious Agent; Lead; Life; Liver; Lung; Malignant - descriptor; Mediating; Minor Histocompatibility Antigens; Molecular; Non-Malignant; Prevention; Proliferating; Protein Isoforms; Proteins; Regimen; Regulatory T-Lymphocyte; Residual Tumors; Role; Skin; T-Cell Activation; T-Lymphocyte; Therapeutic; Virus Diseases; cell motility; cell type; graft versus host disease induction; graft vs host disease; in vivo; inhibitor/antagonist; leukemia; neoplastic cell; novel strategies; prevent; protective effect; public health relevance; response; small molecule; therapeutic target; tumor

DESCRIPTION (provided by applicant): Alloreactivity is initiated by T cells that specifically recognize mismatched major (MHC) and/or minor histocompatibility antigens (MiHA). Graft-versus-host-disease (GVHD) is a potentially lethal consequence of bone marrow transplantation (BMT) in which alloreactive donor T cells undergo robust expansion and functional differentiation within recipients and can cause severe damage to the gut, liver, lung and skin. Therapeutic immunosuppressive regimens that prevent T cell activation can limit the deleterious effects of GVHD. However, because commonly used agents are broadly immunosuppressive, they also render recipients susceptible to life threatening infections. When used as immunotherapy for hematopoietic malignances (e.g. leukemia), the therapeutic potential of allogeneic BMT relies on the graft-versus-leukemia (GVL) effect to eradicate residual tumor cells through immunologic mechanisms. Thus, identification of targets important for alloreactivity but not GVL or responses against infectious agents may lead to development of novel approaches for preventing GVHD, and also allow more widespread use of BMT in a variety of malignant or non-malignant hematopoietic disorders. We have found an essential requirement for PKC?, a key T cell-specific PKC isoform, in alloreactivity and GVHD induction. Importantly, PKC?-/- T cells retain both the ability to respond to virus infection and induce GVL post-BMT. These findings indicate that PKC? is a potentially unique therapeutic target for the prevention of GVHD while preserving GVL effect and protective responses against infectious agents. The goal of studies proposed here is to define key aspects of the molecular and cellular function of PKC? in T cell alloreactivity, and determine whether PKC? is a viable therapeutic target for inhibition of alloreactivity and GVHD. We will accomplish this with the following three specific aims: Aim 1: Defining PKC?-dependent and independent mechanisms in alloreactivity. Aim 2: The role of PKC? in CD4 effector and regulatory T cells, and in T cell migration and survival. Aim 3: The role of PKC? in the beneficial effects of donor T cells after BMT. PUBLIC HEALTH RELEVANCE: Bone marrow transplantation (BMT) is a common strategy in the treatment of leukemia. However, Graft-versus-host-disease (GVHD) is a potentially lethal consequence of BMT, which can limit the therapeutic potential of BMT. The studies proposed in this application will determine whether specific inhibition of a protein called PKC8 can prevent detrimental consequences of BMT (i.e., GVHD) but preserve its beneficial effects (i.e., anti-tumor).

描述（由申请人提供）：同种异体反应性由特异性识别不匹配的主要（MHC）和/或次要组织相容性抗原（MiHA）的T细胞引发。移植物抗宿主病 (GVHD) 是骨髓移植 (BMT) 的一种潜在致命后果，其中同种异体反应性供体 T 细胞在受者体内经历强烈扩增和功能分化，并对肠道、肝脏、肺和皮肤造成严重损害。防止 T 细胞激活的治疗性免疫抑制方案可以限制 GVHD 的有害影响。然而，由于常用药物具有广泛的免疫抑制作用，因此它们也使接受者容易受到危及生命的感染。当用作造血系统恶性肿瘤（例如白血病）的免疫疗法时，同种异体 BMT 的治疗潜力依赖于移植物抗白血病 (GVL) 效应，通过免疫机制根除残留的肿瘤细胞。因此，鉴定对同种异体反应性而非 GVL 或针对感染因子的反应重要的靶点可能会导致预防 GVHD 的新方法的开发，并且还允许 BMT 在各种恶性或非恶性造血疾病中更广泛地使用。我们发现 PKC?（一种关键的 T 细胞特异性 PKC 同工型）在同种异体反应性和 GVHD 诱导中的基本要求。重要的是，PKC?-/- T 细胞保留了对病毒感染做出反应并在 BMT 后诱导 GVL 的能力。这些发现表明 PKC？是预防 GVHD 的潜在独特治疗靶点，同时保留 GVL 效应和针对感染因子的保护性反应。这里提出的研究目标是确定 PKC 分子和细胞功能的关键方面？进行T细胞同种异体反应，并判断是否有PKC？是抑制同种异体反应性和 GVHD 的可行治疗靶点。我们将通过以下三个具体目标来实现这一目标： 目标 1：定义同种异体反应性中 PKC？依赖性和独立机制。目标 2：PKC 的作用？ CD4 效应细胞和调节性 T 细胞，以及 T 细胞迁移和存活。目标 3：PKC 的作用？ BMT 后供体 T 细胞的有益作用。 公共卫生相关性：骨髓移植 (BMT) 是治疗白血病的常见策略。然而，移植物抗宿主病 (GVHD) 是 BMT 的潜在致命后果，这可能限制 BMT 的治疗潜力。本申请中提出的研究将确定对一种名为 PKC8 的蛋白质进行特异性抑制是否可以预防 BMT（即 GVHD）的有害后果，但保留其有益作用（即抗肿瘤）。