Elucidating the Function of PKC-theta in Alloreactivity and GVHD

描述(由申请人提供)：同种异体反应是由特异性识别不匹配的主要组织相容性抗原(MHC)和/或次要组织相容性抗原(MIHA)的T细胞启动的。移植物抗宿主病(GVHD)是骨髓移植(BMT)的一种潜在致命性后果，在骨髓移植中，同种异体反应性供者T细胞在受体体内经历强劲的增殖和功能分化，可对肠道、肝脏、肺和皮肤造成严重损害。阻止T细胞激活的治疗性免疫抑制方案可以限制移植物抗宿主病的有害影响。然而，由于常用的药物具有广泛的免疫抑制作用，它们也使接受者容易受到威胁生命的感染。异基因骨髓移植用于血液系统恶性肿瘤(如白血病)的免疫治疗时，其治疗潜力依赖于移植物抗白血病(GVL)效应，通过免疫机制清除残留的肿瘤细胞。因此，识别同种异体反应的重要靶点，而不是GVL或对感染性物质的反应，可能会导致开发预防GVHD的新方法，并允许BMT在各种恶性或非恶性造血疾病中更广泛地使用。我们已经发现，在同种异体反应和GVHD诱导中，对关键的T细胞特异性PKC亚型PKC？有一个基本的要求。重要的是，在骨髓移植后，PKC？-/-T细胞既保留了对病毒感染的应答能力，又保持了诱导GVL的能力。这些发现表明，PKC？是预防移植物抗宿主病的潜在独特的治疗靶点，同时保留移植物抗宿主病的效应和对感染性病原体的保护性反应。本文提出的研究目标是明确PKC的分子和细胞功能的关键方面。在T细胞同种异体反应中，确定PKC？是抑制同种异体反应和移植物抗宿主病的有效治疗靶点。我们将通过以下三个具体目标来实现这一点：目标1：定义同种异体反应中PKC？依赖和独立的机制。目标2：PKC的作用？在CD4效应和调节性T细胞中，以及在T细胞的迁移和存活中。目标3：PKC的作用？在骨髓移植后供者T细胞的有益作用。 公共卫生相关性：骨髓移植(BMT)是治疗白血病的常用策略。然而，移植物抗宿主病(GVHD)是骨髓移植的一个潜在的致命性后果，这可能限制骨髓移植的治疗潜力。在这项申请中提出的研究将确定特定抑制一种名为PKC8的蛋白质是否可以防止骨髓移植(即GVHD)的有害后果，但保留其有益的效果(即抗肿瘤)。

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).