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。.

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. .