Reconstitution of T cell immunity after UCB transplantation: The role of Treg

描述(申请人提供)：脐带血(UCB)目前被认为是骨髓的替代来源，用于移植造血干细胞，用于缺乏匹配的骨髓捐赠者的血液病成人。UCB的优点是细胞可立即获得，对供者没有风险，对供者和接受者之间的人类白细胞抗原相容的需求较低。虽然这种方法的安全性和有效性得到了很好的证明，但还没有研究解决这些患者的免疫重建状况和机制。早期对单个脐带血移植的研究表明，与非血缘关系的骨髓移植受者相比，非血缘关系的脐血移植受者的移植物抗宿主病减少。相比之下，与非血缘关系的骨髓移植受者相比，UBC受者感染相关的发病率和死亡率似乎更高。导致UBC移植这种不同结果的机制尚未确定。我们最近成功地分离了调节性T细胞(Treg)，并从脐带血中获得了Treg细胞系。我们发现，与PBMC来源的Treg细胞相比，UCB-Treg细胞株表现出更强的抑制活性，并诱导95%的同种异体MLR抑制。此外，我们的研究表明，UCB-Treg细胞系具有T细胞无能的功能和分子特性，包括缺陷激活Ras-MEK-ERK1/2，增强激活Rap1，上调p27kip1。因此，脐带血中含有大量具有T细胞无能和有效抑制功能的Treg分子。我们的发现提出了一个有趣的假设，即Treg可能对脐带血移植的独特结果负责。随着脐带血T细胞在移植后重新填充到受者体内，这些患者可能会有来自脐带血移植物的高度有效的Treg。在遇到受体的同种异体抗原后，这些Treg会被激活，在体内扩张，并抑制宿主特异性效应T细胞的反应，从而预防GvHD。然而，这些脐带血来源的Treg也可能抑制病原体特异性和肿瘤特异性效应T细胞的反应，并损害病原体特异性和潜在的肿瘤特异性免疫。本研究的目的是确定Treg在脐带血移植后病原体特异性免疫、GVH特异性和GVL特异性T细胞反应重建中的作用。马萨诸塞州总医院/达纳·法伯癌症研究所正在进行两个无关脐带血器官顺序移植的第二阶段研究。使用这些患者移植前和移植后的材料，我们将进行以下研究，以评估Treg在以下方面的作用：1)病原体特异性免疫恢复；2)GVH特异性和GVL特异性T细胞反应。

DESCRIPTION (provided by applicant): Umbilical cord blood (UCB) is currently considered an alternative to bone marrow as a source of hematopoietic stem cells for transplantation and it use in adults with hematologic cancers who lack an HLA- matched bone marrow donor. The advantages of UCB are the immediate availability of cells, the absence of risk to the donor and a lower need to HLA compatibility between donor and recipient. Although safety and efficacy of this approach is well documented, no studies have addressed the status and the mechanisms of immune reconstitution in these patients. Early studies with single UCB transplants have demonstrated reduced GvHD in unrelated UBC transplant recipients compared to unrelated BMT recipients. In contrast, infection related morbidity and mortality appears to be higher in UBC recipients compared to unrelated BMT recipients. The mechanisms responsible for this distinct outcome of UBC transplantation have not been determined. We have recently succeeded to isolate regulatory T cells (Treg) and to generate Treg cell lines from UCB. We found that UCB-Treg lines exhibited more potent suppressor activity compared to PBMC- derived Treg lines and induced 95% suppression of allogeneic MLR. Furthermore, our studies revealed that UCB-Treg lines had functional and molecular properties of T cell anergy, including defective activation of Ras-MEK-Erk1/2, enhanced activation of Rap1, and upregulation of p27kip1. Thus, UCB contains a significant number of Treg with a molecular profile of T cell anergy and potent suppressor function. An intriguing hypothesis raised by our findings is that Treg may be responsible for the unique outcome of UCB transplantation. As UCB T cells repopulate the recipient after transplant, it is possible that these patients will have highly potent Treg originated from the UCB graft. After encounter of recipient's alloantigens these Treg will be activated, expand in vivo and inhibit responses of host-specific effector T cells, thereby preventing GvHD. However these UCB derived Treg may also inhibit responses of pathogen-specific and tumor-specific effector T cells and compromise pathogen-specific and potentially tumor-specific immunity. The goal of the present proposal is to determine the role of Treg in the reconstitution of pathogen-specific immunity, GvH-specific and GvL-specific T cell responses after UCB transplantation. A phase II study of sequential transplantation of two unrelated cord blood units is in progress at Massachusetts General Hospital/Dana Farber Cancer Institute. Using material prior and after transplant from these patients we shall undertake the following studies to evaluate the role of Treg on: 1) Recovery of pathogen-specific immunity 2) GvH-specific and GvL-specific T cell responses.