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抑制后CD4和CD8T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。。

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. .