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: 7986776
• 负责人: Amer Aziz Beg
• 金额: $ 41.75万
• 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/7986776
• 关键词: Affinity; Alloantigen; Allogeneic Bone Marrow Transplantation; Allogenic; Bone Marrow Transplantation; CD4 Positive T Lymphocytes; CD8B1 gene; 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）：特异性识别不匹配的主要（MHC）和/或较小的组织相容性抗原（MIHA）的T细胞引发了同种异体反应性。移植物与宿主 - 疾病（GVHD）是骨髓移植（BMT）的潜在致命后果，其中同种反应性的供体T细胞经历了受体内部强大的扩张和功能分化，并且可能对肠道，肝，肺和皮肤造成严重损害。预防T细胞激活的治疗性免疫抑制方案可能会限制GVHD的有害作用。但是，由于常用的药物是广泛的免疫抑制作用，因此他们也使受到威胁生命感染的受体。当用作造血恶性肿瘤（例如白血病）的免疫疗法时，同种异体BMT的治疗潜力取决于移植物 - 抗血清血症（GVL）的作用，可以通过免疫学机制消除残留的肿瘤细胞。因此，确定对同种反应性而不是GVL重要的目标的鉴定或对感染剂的反应可能会导致预防GVHD的新方法的发展，并且还可以在多种恶性或非恶性或非恶性或非恶性血肿中更广泛地使用BMT。我们发现了PKC？是一个关键T细胞特异性PKC同工型，在同种异体和GVHD诱导中。重要的是，PKC？ - / - T细胞既保留了对病毒感染反应的能力，又保留了BMT后GVL。这些发现表明PKC？是预防GVHD的潜在独特的治疗靶标，同时保留GVL效应和针对感染剂的保护反应。这里提出的研究的目的是定义PKC分子和细胞功能的关键方面？在T细胞中，同质性，并确定PKC是否？是抑制同种异体和GVHD的可行治疗靶标。我们将以以下三个特定目标来实现这一目标：目标1：定义PKC？ - 依赖性和独立的同种异体作用力。目标2：PKC的作用？在CD4效应子和调节性T细胞中，以及T细胞迁移和存活中。目标3：PKC的作用？在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。但是，移植物与宿主 - 疾病（GVHD）是BMT的潜在致命后果，它可能会限制BMT的治疗潜力。本应用中提出的研究将确定对称为PKC8的蛋白质的特定抑制是否可以防止BMT的不利后果（即GVHD），但保留其有益作用（即抗肿瘤）。