Graft Versus Host Disease and Autoimmunity

描述(申请人提供)：移植物抗宿主病(GVHD)是一个复杂的病理生理过程，分为急性期和慢性期，在时间和临床上都是不同的。由于在大多数患者中，慢性GVHD是在既往存在的急性GVHD的背景下发展起来的，一个长期悬而未决的问题是，由同种异体反应性供者T细胞引发的急性GVHD如何演变为慢性GVHD，其中自身反应性供者T细胞被推测在该综合征的病理生理学中发挥了作用。在初步研究中，我们已经证明，在GVHD过程中，对自身抗原的耐受性被打破，这发生在正在进行的同种异体反应的背景下，并且这一过程严重依赖于供者APC的抗原提呈。这些初步数据使我们假设，自身反应性是移植物抗宿主病的一个组成部分，从强烈的先天同种异体反应演变而来，并有助于移植受者的病理损害。然而，仍然有许多悬而未决的问题。这些包括T细胞参与自身反应和异体反应之间的关系，移植受者自身反应的时间动力学，T细胞调节受损或缺失在自身反应的病理生理学中所起的作用，以及供体APC在传播自身反应和异体反应中的作用。为了解决这些问题，已设计了实验以解决以下特定目标：(1)确定不同的供体T细胞群体是否负责调节同种异体反应和自身反应，(2)确定来自GVHD小鼠的供体T细胞获得对自身抗原的反应能力的时间动力学，(3)确定自身免疫是由于调节反应缺失还是受损，以及(4)确定供体APC在诱导二次受体自身免疫和同种异体免疫中的作用。这项建议的总体目标是为GVHD的病理生理学提供新的见解，并解决GVHD受者的同种异体反应如何演变为自身反应的悖论。该项目与公共卫生的相关性源于GVHD是干细胞移植的主要并发症这一事实。我们希望通过这些拟议的研究更好地理解这一复杂的过程，从而产生更好的治疗方法，从而提高总体存活率，并扩大可能从干细胞移植中受益的患者数量。

DESCRIPTION (provided by applicant): Graft versus host disease (GVHD) is a complex pathophysiological process that has been divided into acute and chronic phases that are both temporally and clinically distinct. Since in most patients, chronic GVHD develops in the setting of preexisting acute GVHD, a longstanding unresolved issue has been how acute GVHD which is initiated by alloreactive donor T cells evolves into chronic GVHD where autoreactive donor T cells have been speculated to play a role in the pathophysiology of this syndrome. In preliminary studies, we have shown that, during the course of GVHD, there is breaking of tolerance to self antigens, that this occurs in the setting of ongoing alloreactivity, and that this process is critically dependent upon antigen presentation by donor APCs. These preliminary data lead us to hypothesize that autoreactivity is an integral component of GVHD, evolves from a strong antecedent alloresponse, and contributes to pathological damage in transplant recipients. However, there remain many unresolved questions. These include the relationship between T cells involved in autoreactivity versus alloreactivity, the temporal kinetics of autoreactivity in transplant recipients, the role that impaired or absent T cell regulation plays in the pathophysiology of autoreactivity, and the role of donor APCs in propagating both autoreactive and alloreactive responses. To address these issues, experiments have been designed to address the following specific aims: (1) to determine whether distinct donor T cell populations are responsible for mediating alloreactivity and autoreactivity, (2) to define the temporal kinetics whereby donor T cells from GVHD mice acquire the ability to respond to self antigens, (3) to determine whether autoimmunity is attributable to an absent or impaired regulatory response, and (4) to define the role of donor APCs in the induction of autoimmunity and alloimmunity in secondary recipients. The overall goal of this proposal is to provide new insights into the pathophysiology of GVHD and to resolve the paradox for how alloreactivity evolves into autoreactivity in GVHD recipients. The relevance of this project to public health derives from the fact that GVHD is the major complication of stem cell transplantation. Greater understanding of this complex process which we hope will come from these proposed studies will result in better therapies which will improve overall survival and expand the number of patients that might benefit from stem cell transplants.