Mechanisms regulating alloimmunization and tolerance with pathogen reduction and transfusion of allogeneic platelets

通过减少病原体和输注同种异体血小板来调节同种免疫和耐受性的机制

• 批准号: 9478334
• 负责人: Rachael Peretz Jackman
• 金额: $ 35.62万
• 依托单位: VITALANT
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9478334
• 关键词: Affect; Alloantigen; Allogenic; Alloimmunization; Anti-inflammatory; Antigen-Presenting Cells; Antigens; Apoptosis; Apoptotic; Blood Platelets; Blood Transfusion; Cell Adhesion Molecules; Cell Death; Cells; Chronic; Clinical; Development; Dose; Down-Regulation; Equilibrium; Event; Future; Generations; Goals; Graft Rejection; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Histocompatibility; Histocompatibility Antigens; Immune response; Immunologics; Inflammatory Response; Isoantibodies; Leukocytes; Measures; Mediating; Medicine; Mouse Strains; Mus; Organ; Organ Transplantation; Outcome; Pathway interactions; Patient-Focused Outcomes; Plasma; Platelet Transfusion; Play; Population; Prevention; Refractory; Regulatory T-Lymphocyte; Risk; Role; Solid; Source; Spleen; Stem cells; Surface; T cell differentiation; T cell response; T-Lymphocyte; Technology; Testing; Transfusion; Transplant Recipients; Transplantation; Ultraviolet Rays; Work; base; cytokine; design; disease transmission; immunoregulation; improved; in vivo; mouse model; pathogen; prevent; protective effect; response; Affect; Alloantigen; Allogenic; Alloimmunization; Anti-inflammatory; Antigen-Presenting Cells; Antigens; Apoptosis; Apoptotic; Blood Platelets; Blood Transfusion; Cell Adhesion Molecules; Cell Death; Cells; Chronic; Clinical; Development; Dose; Down-Regulation; Equilibrium; Event; Future; Generations; Goals; Graft Rejection; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Histocompatibility; Histocompatibility Antigens; Immune response; Immunologics; Inflammatory Response; Isoantibodies; Leukocytes; Measures; Mediating; Medicine; Mouse Strains; Mus; Organ; Organ Transplantation; Outcome; Pathway interactions; Patient-Focused Outcomes; Plasma; Platelet Transfusion; Play; Population; Prevention; Refractory; Regulatory T-Lymphocyte; Risk; Role; Solid; Source; Spleen; Stem cells; Surface; T cell differentiation; T cell response; T-Lymphocyte; Technology; Testing; Transfusion; Transplant Recipients; Transplantation; Ultraviolet Rays; Work; base; cytokine; design; disease transmission; immunoregulation; improved; in vivo; mouse model; pathogen; prevent; protective effect; response

PROJECT SUMMARY/ABSTRACT: The long-term goal of this project is to better understand and prevent alloimmunization associated with the transfusion of platelets. Alloimmunization to donor MHC antigens following platelet transfusion occurs frequently and can cause complications such as platelet refractoriness and transplant rejection. UV-based pathogen reduction technologies (PRT) were designed to reduce the risk of transfusion-transmission of infectious disease. It has now been shown in mice that PRT has the additional benefit of both preventing alloresponses to treated platelets as well as modulating the response to subsequent untreated alloantigen exposure. The objective of this proposal is to establish a reductionist murine model in order to identify the mechanisms regulating the alloresponse to PRT treated platelets. This includes identifying the antigens required for the response to PRT treated versus untreated allogeneic PRP, identifying the cells that are presenting these antigens, and how this affects the development of a tolerant versus activating alloresponse in the transfusion recipient. The central hypothesis is that indirect presentation of class I MHC alloantigens from apoptotic treated cells drives the immunomodulation observed following transfusion of PRT treated allogeneic PRP; and that this effect is mediated by changes in the localization and activation state of tolerizing DCs, which in turn shifts the T cell response from activating to tolerogenic. The specific aims are: (1) To determine the type and source of alloantigens controlling the response to allogeneic PRP transfusion and the ability of PRT to modulate these responses in vivo; (2) To determine what APC populations are involved in the immune response to untreated and PRT treated allogeneic PRP transfusion in vivo; and (3) To determine the impact of PRT treated and untreated allogeneic PRP transfusion on the activation and differentiation of T cells in vivo. To identify the relevant alloantigens, donor mouse strains will be utilized that are allogeneic only in the MHC region, or only in the class I or class II MHC region, different components of the PRP will be transfused and cell death pathways triggered by PRT will be probed to identify the source of antigen. The relevant APC populations will be determined by measuring the activation, differentiation, and localization of DC subsets in the spleen following transfusion of PRT treated and untreated PRP, and by looking at the role of direct versus indirect presentation. The balance between activating and tolerogenic alloresponses will be assessed by examining the cytokine milieu in vivo and the activation and differentiation of T cells ex vivo following transfusion. Completion of this project will uncover the mechanisms responsible for the immunomodulation observed following PRT treated platelet transfusion and guide efforts to manipulate the immune response to alloantigens for clinical benefit. Increased understanding and control of this response could help improve patient outcomes following allogeneic transfusion, and transplants of solid organ and hematopoietic stem cells.

项目摘要/摘要：该项目的长期目标是更好地理解和预防 与血小板的输血有关的同种免疫。对供体MHC抗原的同种异体免疫 血小板输血后经常发生，并可能引起并发症，例如血小板磨性和 移植排斥。基于紫外线的病原体还原技术（PRT）旨在降低 传染性疾病的输血传输。现在已经在老鼠中显示了PRT还有其他 两者都可以防止同种酶对处理的血小板以及调节对随后的反应 未经处理的同具有同生的暴露。 该提案的目的是建立一个还原主义的鼠模型，以确定 调节PRT处理的血小板的同种缘管的机制。这包括识别抗原 响应对PRT处理过的与未经处理的同种异体PRP所必需的，确定的细胞是 呈现这些抗原，以及这如何影响耐受剂与激活同种异体的发展 输血接受者。中心假设是从 凋亡治疗的细胞驱动PRT处理的同种异体同种异体作用后观察到的免疫调节 prp;并且这种效应是由耐受性DC的定位和激活状态的变化所介导的， 这反过来将T细胞反应从激活转移到耐受性。具体目的是：（1）确定 控制对同种异体PRP输血的反应的同种抗原的类型和来源 prt在体内调节这些反应； （2）确定免疫中涉及哪些APC种群 对未经处理和PRT处理的同种异体PRP输血的反应； （3）确定 PRT治疗和未经处理的同种异体PRP输血在体内T细胞的激活和分化方面。到 识别相关的同种抗原，仅在MHC中使用同种异体的供体小鼠菌株 区域，或仅在I类或II类MHC区域中 将探测由PRT触发的死亡途径以识别抗原的来源。相关的APC 种群将通过测量DC子集的激活，分化和定位来确定种群 通过治疗和未处理的PRP输血后的脾脏，通过查看直接与 间接表现。激活和耐受性同种酶之间的平衡将由 在体内检查细胞因子环境以及T细胞的激活和分化后体内 输血。该项目的完成将揭示负责免疫调节的机制 观察到PRT处理的血小板输血和指导努力操纵对免疫反应 同种剂可用于临床益处。对这一反应的理解和控制增加可以帮助改善 同种异体输血后的患者结局，以及固体器官和造血干细胞的移植。