Elucidating the Function of PKC-theta in Alloreactivity and GVHD

描述（由申请人提供）：同种异体反应性是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细胞发起的。移植物抗宿主病（GVHD）是骨髓移植（BMT）的潜在致命后果，同种异体反应性供体T细胞在受者体内经历强劲的扩张和功能分化，并可能对肠道、肝脏、肺和皮肤造成严重损害。预防T细胞活化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危及生命的感染。当用作造血恶性肿瘤（如白血病）的免疫治疗时，异基因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或对感染因子的反应重要的靶标可能会导致预防GVHD的新方法的发展，并且也允许BMT在各种恶性或非恶性造血疾病中更广泛地使用。我们已经找到了PKC的基本要求？它是一种关键的T细胞特异性PKC异构体，在同种异体反应性和GVHD诱导中起作用。重要的是,PKC ?-/- T细胞保留了对病毒感染的反应能力和诱导bmt后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的效果和对感染因子的保护反应。这里提出的研究目标是定义PKC的分子和细胞功能的关键方面？并确定PKC？是抑制同种异体反应性和GVHD的可行治疗靶点。我们将透过以下三个具体目标：目标一：界定PKC？异源性的依赖和独立机制。目标2:PKC的作用？CD4效应T细胞和调节性T细胞，以及T细胞的迁移和存活。目标3:PKC的作用？移植后供体T细胞的有益作用。

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.