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（alloo - hsct）中，同种异体T细胞反应驱动对外来组织的反应性。同种异体造血干细胞移植后，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，这是一种危及生命的并发症，限制了同种异体造血干细胞移植的有效性。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，对于提高同种异体造血干细胞移植的长期成功和广泛适用性至关重要。我们已经确定了Notch信号在同种异体造血干细胞移植后介导移植物抗宿主病的同种异体反应性T细胞中的一个新的关键作用。在几种同种异体造血移植小鼠模型中，抑制供体T细胞中的典型Notch信号可显著降低移植物抗宿主病的严重程度和死亡率。缺口缺失的T细胞增殖正常，在淋巴造血器官中扩张增加，表明缺乏全局免疫抑制。值得注意的是，缺口缺失的同种异体反应性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，显著提高了受体的总体存活率。然而，它们产生多种炎症细胞因子的能力却降低了。Notch抑制还减少了同种异体反应性T细胞在肠道中的积累，而肠道是GVHD的关键靶器官。因此，Notch信号是控制移植物抗宿主病的一个有希望的治疗靶点，同时在同种异体造血干细胞移植后，在供体T细胞中保持显著的抗癌活性。我们假设Notch是异基因T细胞反应中T细胞功能的一个新的重要调节因子。为了详细探索这一假设，我们将确定在同种异体造血干细胞移植后T细胞中介导Notch激活的特异性Notch配体和受体；研究notch缺陷同种异体反应性T细胞诱导GVHD减少的细胞和分子机制；并鉴定在Notch抑制下介导CD4+和CD8+ T细胞持续抗癌活性的细胞毒性途径。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。

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. .