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

项目 3：同种异体干细胞中的红细胞输注和供体 T 细胞激活

• 批准号: 9100838
• 负责人: Edmund K Waller
• 金额: $ 34.2万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9100838
• 关键词: Acute Graft Versus Host Disease; Address; Adult; Adverse effects; Affect; Age; Allogenic; Antigen-Presenting Cells; Biological Markers; Biology; Blood Banks; Cancer Relapse; Cell physiology; Cells; Cessation of life; Clinical; Clinical Data; Clinical Research; Collection; Communicable Diseases; Data; Development; Diagnosis; Erythrocyte Transfusion; Erythrocytes; Event; Goals; Hematopoietic Stem Cell Transplantation; Homologous Transplantation; Human; Immune; Immune response; Immunity; Immunology; Incidence; Inflammation; Inflammatory; Intervention; Knowledge; Lead; Malignant Neoplasms; Modeling; Monitor; Mus; Natural Immunity; Natural Killer Cells; Opportunistic Infections; Outcome; Pathology; Pathway interactions; Patients; Plasma; Publishing; Recurrent disease; Regulation; Research; Research Support; Risk; Schedule; Stem cell transplant; Stem cells; T-Cell Activation; T-Lymphocyte; Testing; Time; Transfusion; Transplant Recipients; Transplantation; Viral Tumor Antigens; Work; abstracting; aged; cancer immunotherapy; clinically relevant; cytokine; design; graft vs host disease; hazard; immune activation; immune function; improved; improved outcome; insight; metabolomics; mortality; mouse model; novel; pre-clinical; preclinical study; prospective; reconstitution; success

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.

抽象的 本研究的长期目标是改善异体造血干细胞的临床结果 通过改善干细胞移植中的红细胞 (RBC) 输注实践来进行移植 (HSCT) 我们的 PPG 合作者最近的研究表明，红细胞单位的代谢发生了显着变化。 储存期间可能会对输血接受者产生不利影响 更好地了解红细胞如何产生。 输血影响供体 T 细胞的激活、增殖和移植物抗宿主病 (GvHD) 活性 需要细胞，因为这代表了我们目前对免疫学的理解存在重大差距 为了解决这一空白，我们开发了新型 P��F1 小鼠异基因造血干细胞移植模型 红细胞输注，使用规定的红细胞收集和储存条件。初步数据证明了这一点。 红细胞输注对移植中供体 T 细胞活化和增殖的调节作用 受者：新鲜红细胞输注增加了观察到的 GvHD 发生率，而输注高龄红细胞则增加了观察到的 GvHD 发生率 储存的红细胞抑制供体 T 细胞的活化并显着降低小鼠同种异体的 GvHD 死亡率 对 345 名异基因 HSCT 患者的回顾性分析表明，HSCT 患者的死亡率显着增加。 使用多变量模型评估接受更多红细胞输注的患者发生 3-4 级急性 GvHD 的风险 控制与 GvHD 相关的其他临床因素，并在移植后进行审查输血 GvHD 的诊断基于小鼠和人类的补充初步数据。 检验总体假设的研究，即移植后早期输注同种异体红细胞进行 HSCT 受体导致供体 T 细胞的激活和 GvHD 的增加，我们的总体假设将在以下进行检验。 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体T细胞的活化？ 2. 测试输注红细胞的保存条件对小鼠供体T细胞活化的影响 allo-HSCT 模型，并使用红细胞生物标志物来识别调节 T 细胞激活的红细胞单位。 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，红细胞输血是同种异体后免疫反应的有效调节剂 造血干细胞移植和输血实践的改变可以提高同种异体移植后的生存率。 完成拟议的工作将产生对红细胞输血作为一种新途径的机制见解。 从该项目中获得的知识可以改善免疫调节的结果。 对癌症免疫治疗具有广泛影响的同种异体 HSCT 接受者 该项目与项目 1 相互作用。 2 和 4 并利用核心 A、B 和 C。