Notch Signaling in Alloimmunity

描述(由申请人提供)：在实体器官或造血干细胞移植(allo-HSCT)中，同种异体T细胞反应驱动对异体组织的反应性。在allo-HSCT后，供者的同种异体反应性T细胞诱导有益的移植物抗肿瘤活性和有害的移植物抗宿主病，这是一种威胁生命的并发症，限制了allo-HSCT的有效性。移植物抗宿主病是一个严重的医学问题，现有的治疗干预措施往往无效。此外，现有的控制移植物抗宿主病的策略削弱了抗肿瘤反应，导致癌症复发的风险增加。发现新的免疫调节方法来控制同种异体T细胞反应的有害影响，而不消除它们有益的抗癌活性，对于提高allo-HSCT的长期成功和广泛应用至关重要。我们已经确定了Notch信号在同种异体反应性T细胞介导allo-HSCT后移植物抗宿主病中的一个新的关键作用。在几种allo-HSCT小鼠模型中，抑制供者T细胞中规范的Notch信号显著降低移植物抗宿主病的严重性和死亡率。缺口剥夺的T细胞正常增殖，并在淋巴-造血器官中表现出更多的扩张，表明没有整体免疫抑制。值得注意的是，Notch剥夺的同种异体反应T细胞在体内获得了有效的细胞毒作用，并保持了强大的抗白血病活性，显著提高了受者的总体存活率。然而，它们产生多种炎性细胞因子的能力降低了。缺口抑制也减少了同种异体反应性T细胞在肠道中的积累，肠道是GVHD的关键靶器官。因此，Notch信号代表了一个有希望的治疗靶点，在控制移植物抗宿主疾病的同时，在异基因造血干细胞移植后保持供者T细胞显著的抗癌活性。我们推测，在同种异体T细胞反应中，Notch是一种新的重要的T细胞功能调节因子。为了详细探讨这一假说，我们将确定介导异基因HSCT后T细胞中Notch激活的特定Notch配体和受体；研究Notch缺陷的同种异体反应性T细胞减少GVHD诱导的细胞和分子机制；并确定在Notch抑制时介导CD4+和CD8+T细胞持续抗癌活性的细胞毒途径。这些研究将为同种异体免疫的分子调控带来新的见解，并可能导致开发新的方法来限制同种异体移植后T细胞反应性的破坏性后果。。 公共卫生相关性：针对宿主抗原的同种异体T细胞反应介导移植物抗宿主病，移植物抗宿主病是异基因造血干细胞移植最严重的并发症。这项建议的目的是评估Notch信号在T细胞同种免疫调节中的作用。该项目的完成不仅将揭示Notch信号通路在免疫系统中的新功能，还将为Notch信号在T细胞介导的疾病(包括移植物抗宿主疾病、器官排斥和自身免疫)中的治疗操作铺平道路。

DESCRIPTION (provided by applicant): Allogeneic T cell responses drive reactivity to foreign tissues in the setting of solid organ or hematopoietic stem cell transplantation (allo-HSCT). After allo-HSCT, donor alloreactive T cells induce both beneficial graft-versus-tumor activity and harmful graft-versus-host-disease, a life- threatening complication that limits the effectiveness of allo-HSCT. Graft-versus-host-disease is a serious medical problem for which existing therapeutic interventions are often ineffective. In addition, existing strategies to control graft-versus-host disease impair anti-tumor responses, leading to an increased risk of cancer relapse. Discovering novel immunomodulatory approaches to control the harmful effects of allogeneic T cell responses without eliminating their beneficial anti-cancer activity is essential to improve the long-term success and widespread applicability of allo-HSCT. We have identified a new critical role for Notch signaling in alloreactive T cells mediating graft-versus-host disease after allo-HSCT. Inhibition of canonical Notch signaling in donor T cells markedly reduced the severity and mortality of graft-versus-host disease in several mouse models of allo-HSCT. Notch-deprived T cells proliferated normally and showed increased expansion in lympho-hematopoietic organs, demonstrating the absence of global immunosuppression. Notably, Notch-deprived alloreactive T cells acquired efficient cytotoxicity in vivo and retained potent anti-leukemia activity, leading to markedly improved overall survival of the recipients. However, their ability to produce multiple inflammatory cytokines was reduced. Notch inhibition also decreased the accumulation of alloreactive T cells in the intestine, a key GVHD target organ. Thus, Notch signaling represents a promising therapeutic target to control graft-versus-host disease while preserving significant anti- cancer activity in donor T cells after allo-HSCT. We hypothesize that Notch is a new essential regulator of T cell function in allogeneic T cell responses. To explore this hypothesis in detail, we will determine the specific Notch ligands and receptors that mediate Notch activation in T cells after allogeneic HSCT; investigate the cellular and molecular mechanisms underlying the decreased induction of GVHD by Notch-deficient alloreactive T cells; and identify the cytotoxic pathways that mediate the persistent anti-cancer activity of CD4+ and CD8+ T cells upon Notch inhibition. These studies will bring novel insights into the molecular regulation of alloimmunity and might lead to the development of new approaches to limit damaging consequences of T cell reactivity after allogeneic transplantation. . PUBLIC HEALTH RELEVANCE: Allogeneic T cell responses against host antigens mediate graft-versus-host disease, the most serious complication of allogeneic hematopoietic stem cell transplantation. The goal of this proposal is to evaluate the role of Notch signaling in the regulation of T cell alloimmunity. Completion of this project will not only reveal novel functions of the Notch signaling pathway in the immune system, but also pave the way for therapeutic manipulation of Notch signaling in T cell-mediated disorders, including graft-versus-host disease, organ rejection and autoimmunity.