Role of Autoreactivity in pathogenesis of chronic graft versus host disease

慢性移植物抗宿主病(CGVHD)，一种全身性自身免疫综合征，仍然是 异基因造血细胞移植长期存活者的发病率和死亡率。在.期间 在过去的资助期间，我们使用了cGVHD的小鼠和人源化小鼠模型以及来自 慢性移植物抗宿主病患者非淋巴组织中CD4+T细胞和B细胞及其相互作用的研究 受cGVHD影响的肝脏、肺和皮肤在慢性移植物抗宿主病的发病和持久性中起着关键作用 这种疾病。这项更新建议的前提是更深入地机械地理解 非循环组织驻留的CD4+记忆性T细胞(Trm)与组织驻留的B细胞(BRm)的相互作用 GVHD靶组织中的细胞将识别预防或治疗cGVHD的新治疗靶点。 在目标1中，我们将确定小鼠和人类Trm亚群，如PSGL1hi和PSGL1loCD4+Trm细胞 在靶组织中介导发病机制。我们将剖析供体或受者类型触发的TCR信号 抗原提呈细胞和下游信号和核转录因子，如STAT3， HOBIT/Blimp-1和组织环境警报蛋白IL-33调节Trm的分化、扩增和 功能。最后，我们将尝试开发一种在捐赠者T细胞中靶向STAT3的新技术，因为我们 观察到，供者T细胞中缺乏STAT3有效地预防了cGVHD，显著减少了 移植物抗宿主病靶组织中Trm细胞的数量和功能。在目标2中，我们将测试小鼠和 人BRM细胞产生抗原特异性的免疫球蛋白以增强cGVHD靶组织的纤维化。我们将测试 BRM的分化是否需要PSGL1loCD4+T细胞的帮助。我们预计将STAT3作为目标 供者T细胞将同时防止致病的Trm和BRM细胞的形成。这些研究都是高水平的 生物学和翻译意义，并可能导致我们对cGVHD低估的范式转变 慢性移植物抗宿主病的发病机制及防治新方法的发展。

Chronic graft versus host disease (cGVHD), a systemic autoimmune syndrome, remains the major cause of morbidity and mortality of long-term survivors of allogeneic hematopoietic cell transplantation (HCT). During the past funding period, we used murine and humanized murine models of cGVHD and biospecimens from cGVHD patients to demonstrate that CD4+ T cells and B cells and their interactions in non-lymphoid tissues affected by cGVHD such as the liver, lung and skin play a critical role in the pathogenesis and persistence of the disease. The premise of this renewal proposal is that deeper mechanistic understanding of the interactions between non-circulating tissue-resident CD4+ memory T (Trm) and tissue-resident B (Brm) cells in GVHD target tissues will identify new therapeutic targets for prevention or treatment of cGVHD. In Aim 1, we will determine how murine and human Trm subsets such as PSGL1hi and PSGL1loCD4+ Trm cells mediate pathogenesis in target tissues. We will dissect how TCR-signaling triggered by donor- or recipient-type antigen-presenting cells and down-stream signaling and nuclear transcription factors such as STAT3, HOBIT/Blimp-1 and the tissue environmental alarmin IL-33 regulate Trm differentiation, expansion and function. Finally, we will attempt to develop a novel technology to target STAT3 in donor T cells, because we have observed that STAT3 deficiency in donor T cells effectively prevents cGVHD, with a marked reduction in the numbers and function of Trm cells in GVHD target tissues. In Aim 2, we will test whether murine and human Brm cells produce antigen-specific IgG to augment fibrosis in cGVHD target tissues. We will test whether Brm differentiation requires help from PSGL1loCD4+ T cells. We anticipate that targeting STAT3 in donor T cells will simultaneously prevent formation of pathogenic Trm and Brm cells. These studies are of high biological and translational significance and may lead to a paradigm shift in our understating of cGVHD pathogenesis and development of novel approaches for preventing and treating cGVHD.