Graft Versus Host Disease and Autoimmunity

描述（由申请人提供）：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是在先前存在的急性GVHD的情况下发展起来的，一个长期未解决的问题是，由同种异体供体T细胞引发的急性GVHD是如何演变成慢性GVHD的，在慢性GVHD中，自身反应性供体T细胞被推测在该综合征的病理生理中发挥作用。在初步研究中，我们已经表明，在GVHD的过程中，对自身抗原的耐受性被打破，这发生在持续的同种异体反应的环境中，并且这一过程严重依赖于供体apc的抗原呈递。这些初步数据使我们假设自身反应性是GVHD的一个组成部分，从强烈的先前同种异体反应演变而来，并有助于移植受体的病理损伤。然而，仍有许多未解决的问题。这些包括参与自身反应性和同种异体反应性的T细胞之间的关系，移植受者自身反应性的时间动力学，受损或缺失的T细胞调节在自身反应性病理生理学中的作用，以及供体APCs在传播自身反应性和同种异体反应中的作用。为了解决这些问题，设计了一些实验，以实现以下具体目标：(1)确定不同的供体T细胞群是否负责介导同种异体反应性和自身反应性，(2)确定GVHD小鼠供体T细胞获得对自身抗原反应能力的时间动力学，(3)确定自身免疫是否归因于缺乏或受损的调节反应，(4)确定供体apc在诱导继发受体自身免疫和同种异体免疫中的作用。本提案的总体目标是为GVHD的病理生理学提供新的见解，并解决GVHD受体中异源性如何演变为自身反应性的悖论。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。我们希望能从这些研究中更好地了解这个复杂的过程，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.