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

基本信息

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
项目类别：
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

项目摘要

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了解和预防与血小板输注相关的同种免疫。针对供体 MHC 抗原的同种免疫血小板输注后经常发生，并可能导致并发症，例如血小板无效和移植排斥反应。基于紫外线的病原体减少技术 (PRT) 旨在降低病原体感染的风险输血-传染病的传播。现在已经在小鼠身上证明 PRT 具有额外的作用预防对处理过的血小板的同种异体反应以及调节对后续血小板的反应的好处未经处理的同种异体抗原暴露。该提案的目的是建立一个还原论小鼠模型，以确定调节对 PRT 处理的血小板的同种反应的机制。这包括识别抗原与未经处理的同种异体 PRP 相比，对 PRT 处理的反应所需，从而识别出哪些细胞呈递这些抗原，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接受者。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 PRT 处理的同种异体输注后观察到的免疫调节富血小板血浆；并且这种效应是由耐受 DC 的定位和激活状态的变化介导的，这反过来又将 T 细胞反应从激活转变为耐受。具体目标是： (1) 确定控制同种异体 PRP 输注反应的同种异体抗原的类型和来源以及 PRT 在体内调节这些反应； (2) 确定哪些APC群体参与免疫对未经处理和 PRT 处理的同种异体 PRP 体内输注的反应； (3) 确定影响 PRT 处理和未处理的同种异体 PRP 输注对体内 T 细胞活化和分化的影响。到鉴定相关同种异体抗原，将使用仅在 MHC 中同种异体的供体小鼠品系区域，或仅在I类或II类MHC区域，PRP的不同成分将被输注并细胞将探测 PRT 触发的死亡途径，以确定抗原的来源。相关APC 群体将通过测量 DC 子集的激活、分化和定位来确定输注 PRT 处理和未经处理的 PRP 后的脾脏，并通过观察直接与间接呈现。激活和耐受性同种异体反应之间的平衡将通过以下方式评估检查体内细胞因子环境以及离体 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观察 PRT 治疗的血小板输注后的情况，并指导操纵免疫反应的努力同种异体抗原以获得临床益处。增强对这种反应的理解和控制可能有助于改善同种异体输血以及实体器官和造血干细胞移植后的患者结果。