Graft Versus Host Disease and Autoimmunity

描述（由申请方提供）：移植物抗宿主病（GVHD）是一种复杂的病理生理过程，分为急性期和慢性期，两者在时间和临床上均不同。由于在大多数患者中，慢性GVHD在预先存在的急性GVHD的情况下发展，因此长期未解决的问题是由同种异体反应性供体T细胞引发的急性GVHD如何演变成慢性GVHD，其中推测自身反应性供体T细胞在该综合征的病理生理学中起作用。在初步研究中，我们已经表明，在GVHD的过程中，有打破耐受性自身抗原，这发生在设置正在进行的同种异体反应性，这一过程是严重依赖于抗原呈递供体APC。这些初步的数据使我们假设，自体反应性是GVHD的一个组成部分，从一个强大的先行同种异体反应，并有助于移植受者的病理损伤。然而，仍有许多未解决的问题。这些包括参与自身反应性与同种异体反应性的T细胞之间的关系，在移植受者中的自身反应性的时间动力学，受损或缺乏T细胞调节在自身反应性的病理生理学中发挥的作用，以及供体APC在传播自身反应性和同种异体反应性反应中的作用。为解决这些问题，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）确定来自GVHD小鼠的供体T细胞获得应答自身抗原的能力的时间动力学，（3）确定自身免疫是否可归因于缺乏或受损的调节应答，（4）确定供者APC在诱导二次受者自身免疫和同种免疫中的作用。该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受体中同种异体反应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。我们希望通过这些拟议的研究对这一复杂过程有更好的理解，这将导致更好的治疗方法，从而提高总体生存率，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.