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: 9283261
• 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 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9283261
• 关键词: Affect; Alloantigen; Allogenic; Alloimmunization; Anti-Inflammatory Agents; 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; killings; 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.

项目总结/摘要：本项目的长期目标是更好地了解和预防 与血小板输注相关的同种异体免疫。供体MHC抗原同种免疫 血小板输注后经常发生，可引起并发症，如血小板不应性， 移植排斥反应基于紫外线的病原体减少技术（PRT）旨在降低 传染病的输血传播。现在已经在小鼠中显示，PRT具有额外的 预防对经处理的血小板的同种异体反应以及调节对随后的血小板的反应的益处 未经处理的同种异体抗原暴露。 本提案的目的是建立一个简化的小鼠模型，以确定 调节对PRT处理的血小板的同种异体反应的机制。这包括识别抗原 对PRT处理的与未处理的同种异体PRP的反应所需的细胞，鉴定 提呈这些抗原，以及这如何影响耐受性与激活性同种异体反应的发展， 输血者中心假设是，I类MHC同种抗原的间接呈递， 凋亡处理的细胞驱动在输注PRT处理的同种异体移植物后观察到的免疫调节。 PRP;并且这种作用是由耐受性DC的定位和活化状态的变化介导的， 这又使T细胞应答从活化性转变为致耐受性。具体目标是：（1）确定 控制同种异体PRP输注反应的同种抗原的类型和来源， PRT在体内调节这些反应;（2）确定哪些APC群体参与免疫应答， 体内对未处理和PRT处理的同种异体PRP输注的反应;和（3）确定 PRT处理和未处理的同种异体PRP输注对体内T细胞的活化和分化的影响。到 鉴定相关同种异体抗原，将使用仅在MHC中为同种异体的供体小鼠品系 在一个实施方案中，当PRP的不同组分在I类或II类MHC区域中，或仅在I类或II类MHC区域中时，PRP的不同组分将被输注，并且细胞将被输注。 将探测由PRT触发的死亡途径以鉴定抗原的来源。相关APC 将通过测量DC亚群的活化、分化和定位来确定群体。 输注PRT治疗和未治疗的PRP后的脾脏，并通过观察直接与 间接介绍。将通过以下方法评估激活性同种异体反应和致耐受性同种异体反应之间的平衡： 检查体内细胞因子环境和在体外培养后T细胞的活化和分化 输血该项目的完成将揭示负责免疫调节的机制， 在PRT处理的血小板输注后观察到的，并指导操纵免疫应答的努力， 同种异体抗原的临床益处。增加对这种反应的理解和控制有助于改善 同种异体输血、实体器官和造血干细胞移植后的患者结果。