Project 3: Red cell transfusions and donor T-cell activation in allo-stem cell t

摘要 本研究的长期目标是提高异基因造血干细胞移植的临床效果 通过改善干细胞移植中的红细胞（RBC）输注实践， 受惠人士我们PPG合作者的最新研究表明，RBC单位发生了显著的代谢变化 在储存期间，可能会对输血接受者产生不良影响。更好地了解RBC 输血影响供体T细胞的活化、增殖和移植物抗宿主病（GvHD）活性。 细胞是必要的，因为这代表了我们目前对免疫学的理解存在重大差距。 同种异体移植为了解决这一差距，我们开发了新的小鼠allo-HSCT的P �� F1模型， RBC输血，使用规定的红细胞采集和储存条件。初步数据显示， 红细胞输注对供者T细胞活化和增殖的调节作用 受体：新鲜红细胞输注增加了观察到的GvHD发生率，而输注非常老的红细胞， 储存的红细胞可抑制供者T细胞的活化，显著降低小鼠同种异体移植物抗宿主病的死亡率。 HSCT受者。对345例allo-HSCT患者的回顾性分析显示， 使用多变量模型， 控制与GvHD相关的其他临床因素，并在移植后进行删失输血。 GvHD的诊断该建议建立在来自小鼠和人类的补充初步数据的基础上 旨在检验移植后早期将同种异体红细胞输注至HSCT的总体假设的研究 接受者导致供体T细胞活化和GvHD增加。我们的整体假设将在 3个具体目标： 1.红细胞输注时间表如何调节小鼠异基因造血干细胞移植中供者T细胞活化？ 2.目的：探讨红细胞保存条件对供者T细胞活化的影响， allo-HSCT模型，并使用RBC生物标志物来鉴定调节T细胞活化的RBC单位。 3.前瞻性监测红细胞输注对allo-HSCT患者供体T细胞活化的影响。 根据我们的总体假设，红细胞输注是同种异体移植后免疫反应的有效调节剂， HSCT和输血实践的改变可以提高同种异体移植后的生存率。 完成所提出的工作将产生对红细胞输注作为一种新的免疫途径的机制性见解。 具有翻译潜能的免疫调节。从这个项目中获得的知识可以改善成果， 同种异体HSCT受体在癌症免疫治疗中具有广泛的影响。该项目与项目1相互作用， 图2和图4中示出的实施例，并且利用核A、B和C。

Abstract The long-term goal of this research is to improve the clinical outcomes of allogeneic hematopoietic stem cell transplantation (HSCT) by improving red blood cell (RBC) transfusion practices in stem cell transplant recipients. Recent studies from our PPG collaborators indicate significant metabolmic changes in RBC units during storage that may lead to adverse effects in transfusion recipients. A better understanding of how RBC transfusions influence the activation, proliferation, and graft-versus-host disease (GvHD) activity of donor T- cells is needed, as this represents a significant gap in our current understanding of the immunology of allogeneic transplantation. To address this gap, we developed novel P �� F1 models of murine allo-HSCT and RBC transfusion, using defined conditions of red cell collection and storage. Preliminary data demonstrate a modulatory effect of red cell transfusions on the activation and proliferation of donor T-cells in transplant recipients: fresh RBC transfusions increased the observed incidence of GvHD while transfusion of very old stored RBC supressed the activation of donor T-cells and markedly reduce GvHD moratilty in murine allo- HSCT recipients. A retrospective analysis of 345 allo-HSCT patients demonstrated a significantly increased risk of grade 3-4 acute GvHD in patients who received more RBC transfusions using a multivariable model that controlled for other clinical factors associated with GvHD, and censored transfusions performed after the diagnosis of GvHD. This proposal builds upon complementary preliminary data from murine and human studies to test the overall hypothesis that early post-transplant transfusion of allogeneic red cells to HSCT recipients leads to the activation of donor T-cells and increased GvHD. Our overall hypothesis will be tested in 3 specific aims: 1. How does the schedule of RBC transfusion regulate donor T cell activation in murine allo-HSCT? 2. To test the effect of storage conditions of transfused red cells on donor T-cell activation in murine models of allo-HSCT, and to use RBC biomarkers to identify RBC units that modulate T-cell activation. 3. To prospectively monitor the effect of RBC transfusion on donor T-cell activation in allo-HSCT patients. According to our overall hypothesis, RBC transfusions are potent modulators of immune responses after allo- HSCT, and changes in transfusion practices can lead to improved survival after allogeneic transplants. Completing the proposed work will yield mechanistic insights into RBC transfusions as a novel pathway of immune regulation with translational potential. Knowledge gained from this project can improve outcomes for allogeneic HSCT recipients with broad impact in cancer immunotherapy. This project interacts with Projects 1, 2 and 4 and utilizes cores A, B and C.