Notch Signaling in Alloimmunity

描述（由申请方提供）：在实体器官或造血干细胞移植（allo-HSCT）的背景下，同种异体T细胞应答驱动对外源组织的反应性。在allo-HSCT后，供体同种异体反应性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，这是一种限制allo-HSCT有效性的危及生命的并发症。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损害了抗肿瘤反应，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，而不消除其有益的抗癌活性，对于改善allo-HSCT的长期成功和广泛适用性至关重要。我们已经确定了一个新的关键作用Notch信号在同种异体反应性T细胞介导移植物抗宿主病后allo-HSCT。抑制供体T细胞中的经典Notch信号传导显著降低了几种小鼠allo-HSCT模型中移植物抗宿主病的严重程度和死亡率。Notch-deprived T细胞增殖正常，并表现出增加的淋巴造血器官的扩增，表明没有全球免疫抑制。值得注意的是，Notch剥夺的同种异体反应性T细胞在体内获得了有效的细胞毒性，并保留了有效的抗白血病活性，从而显著改善了受体的总体存活率。然而，它们产生多种炎性细胞因子的能力降低。Notch抑制还减少了同种异体反应性T细胞在肠道（关键GVHD靶器官）中的积累。因此，Notch信号传导代表了控制移植物抗宿主病同时在allo-HSCT后在供体T细胞中保留显著抗癌活性的有希望的治疗靶标。我们假设Notch是同种异体T细胞应答中T细胞功能的一种新的重要调节因子。为了详细探讨这一假设，我们将确定特异性Notch配体和受体介导的Notch激活后，同种异体造血干细胞移植的T细胞;调查的细胞和分子机制减少诱导GVHD的Notch缺陷的同种异体反应性T细胞;并确定细胞毒性途径，介导的持续抗癌活性的CD 4+和CD 8 + T细胞后，Notch抑制。这些研究将为同种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：同种异体T细胞对宿主抗原的反应介导了移植物抗宿主病，这是同种异体造血干细胞移植最严重的并发症。该提案的目标是评估Notch信号传导在T细胞同种异体免疫调节中的作用。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信号通路在T细胞介导的疾病中的治疗操作铺平道路，包括移植物抗宿主病，器官排斥和自身免疫。

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.