Enhancing Treg Immune Reconstitution After Stem Cell Transplant

描述(由申请人提供)：我们建议使用超低剂量白介素2(ULD-IL2)通过增加内源性T调节细胞水平来降低异基因造血干细胞移植(Allo SCT)后移植物抗宿主疾病的风险。异基因干细胞移植)被公认为是治疗几种血液系统恶性肿瘤以及某些免疫学和遗传性疾病的首选疗法。然而，移植物抗宿主病(GvHD)是该手术的主要不良后果之一。在接受异基因干细胞移植的患者中，大约30%到70%会发生移植物抗宿主病，这增加了发病率和死亡率，并增加了护理成本。标准的预防治疗往往无效，并可能导致严重的并发症。包括器官损伤和免疫恢复受损，从而导致危及生命的感染和复发风险增加。因此，需要更有效和毒性更低的治疗方法来预防移植后移植物抗宿主病，同时仍允许干细胞移植后的免疫重建。调节性T细胞(Tregs)调节GvHD的能力越来越受到人们的关注。有证据表明，患有GvHD的异基因干细胞移植受者的Tregs绝对数较低，而小鼠模型显示，SCT后输注供体Tregs可以预防GvHD，同时保持移植物抗白血病(GVL)效应。虽然T-regs的体外扩增和随后的输注是可能的，但成本和复杂性都很高。此外，Treg最特异的标记之一是FoxP3，这是一种转录调节因子，不能用作从CD25群体中分离出可存活的T调节器的基础。此外，目前尚不清楚体外扩增的天然Tregs是否具有与胸腺来源的调节性T细胞相同的体内免疫学特性。我们提出了一种预防GvHD的新策略，通过在异基因SCT患者体内使用ULD IL-2扩大供体来源的Tregs来预防GvHD。我们的基本假设是：(I)在异基因SCT后，通过在SCT后早期向受者注射ULD IL-2，调节性T细胞可以在体内优先扩增，作为预防GvHD的一种策略，同时(Ii)保持对微生物病原体和残留恶性肿瘤的体液、天然和细胞介导的免疫。这些假说是从广泛的临床前数据和初步临床观察中得出的，将在两个具体目标上进行验证：(1)在I/II期临床试验中，我们将确定异基因干细胞移植后患者使用ULD IL-2是否安全，并增加体内的Treg；以及(2)IL-2诱导的Treg是否影响针对白血病、病毒和细菌的细胞和体液免疫反应，以此作为其对移植后复发和感染的影响的标志。 公共卫生相关性：异基因造血干细胞移植可以治愈恶性血液病患者。然而，这种手术的一个主要副作用是移植物抗宿主病(GvHD)。为了预防这种并发症，患者通常会接受强大的免疫抑制药物，这些药物可能会导致危及生命的感染，并可能增加复发的风险。我们将确定超低剂量的IL-2是否会增加Tregs和预防GvHD，而不会增加感染或复发的风险。

DESCRIPTION (provided by applicant): We propose using ultra low dose Interleukin 2 (ULD-IL2) to reduce the risk of Graft versus host disease after allogeneic hematopoietic stem cell transplantation (Allo SCT) by increasing levels of endogenous T regulatory cells. AlloSCT) is recognized as the treatment of choice for several hematologic malignancies, as well as for selected immunologic and genetic diseases. However, graft-versus-host disease (GvHD) is one of the major adverse consequences of the procedure. GvHD occurs in approximately 30 to 70% of patients undergoing alloSCT increasing morbidity and mortality, as well as the cost of care. Standard prophylactic therapies are often ineffective and may lead to significant complications. Including organ damage and impaired immune recovery with resultant life-threatening infections and an increased risk of relapse. Thus, more effective and less toxic therapies are needed to prevent GvHD post transplant, while still allowing for immune reconstitution post SCT. There has been increasing interest in the ability of regulatory T cells (Tregs) to modulate GvHD. Evidence suggests that alloSCT recipients with GvHD have lower absolute numbers of Tregs, while murine models have shown that infusion of donor Tregs post SCT prevents GvHD while maintaining the graft-versus- leukemia (GvL) effect. Although ex vivo expansion of T regs and subsequent infusion may be possible, cost and complexity are high. Moreover, one of the most specific markers for Treg is FoxP3, a transcriptional regulator that cannot be used as a basis for separating viable T regs from within the CD25 population. Furthermore, it is unclear whether natural Tregs expanded in vitro will have the same in vivo immunological properties as thymic-derived regulatory T cells. We propose a novel strategy to prevent GvHD by expanding donor-derived Tregs in vivo using ULD IL-2 in patients after alloSCT. Our underlying hypotheses are that (i) regulatory T cells can be preferentially expanded in vivo following alloSCT by the administration of ULD IL-2 to recipients early post SCT, as a strategy to prevent GvHD while (ii) preserving humoral, innate and cell mediated immunity to microbial pathogens and to residual malignancy. These hypotheses, formulated from extensive preclinical data and pilot clinical observations will be tested in two specific aims: (1) In a phase I/II clinical trial, we will determine whether the administration of ULD IL-2 in patients post allogeneic stem cell transplantation is safe and increases Tregs in vivo; and (2) Whether IL-2 induced Tregs affect cellular and humoral immune responses against leukemia, viruses and bacteria as a marker for their effect on post transplant relapse and infection. PUBLIC HEALTH RELEVANCE: Allogeneic hematopoietic stem cell transplantation can cure patients with hematologic malignancies. However, a major side effect of this procedure is graft versus host disease (GvHD). To prevent this complication, patients usually receive powerful immunosuppressive drugs which can cause life-threatening infections and may increase the risk of relapse. We will determine whether ultra low-dose IL-2 will increase Tregs and prevent GvHD, without increasing the risk of infection or relapse.