Ischemia-reperfusion injury in transplantation: novel cytoprotection strategies

移植中的缺血再灌注损伤：新型细胞保护策略

基本信息

批准号：
8469819
负责人：
Reza Abdi
金额：
$ 39.29万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8469819
关键词：
Achievement Acute Affect Alloantigen Allogenicity Allografting Animal Model Antigen-Presenting Cells Antioxidants Area Attenuated Cell physiology Cells Chronic Clinical Cytoprotection Data Dendritic Cells Dendritic cell activation Development Effector Cell Elements Engraftment Equilibrium Failure Free Radical Scavengers Free Radicals Functional disorder Generations Goals Graft Rejection Heart Heart Transplantation Human ITGAX gene Immune Immune response Immunosuppression In Vitro Incidence Inflammatory Injury Interleukin-6 Ischemia Knock-in Mouse Knock-out Laboratories Lead Ligands Link Lymphoid Lymphoid Tissue MCI-186 Mediating Modeling Mus NF-kappa B Natural Immunity Organ Organ Donor Organ Transplantation Outcome Ovum Pathway interactions Pattern Population Production Property Reperfusion Injury Research Research Personnel Research Support Role Signal Transduction Signaling Molecule Solid System T-Lymphocyte TLR2 gene TLR4 gene Therapeutic Toll-like receptors Transgenic Mice Transgenic Model Translating Transplant Recipients Transplantation adaptive immunity allograft rejection antibody-dependent cell cytotoxicity arm base chemokine clinical practice cytokine design diphtheria toxin receptor heart allograft immunogenicity improved in vivo innovation insight isoimmunity mouse model new therapeutic target novel novel strategies novel therapeutic intervention novel therapeutics prevent promoter public health relevance research study response standard care success tool trafficking

项目摘要

DESCRIPTION (provided by applicant): Ischemia/reperfusion injury (IRI) to donor organs substantially enhances the immunogenicity of grafts and increases the rate of acute and chronic allograft rejection. Grafts with more severe IRI also have significantly worse long-term survival. Thus, IRI remains the major obstacle in transplantation today, but there are currently no standard treatments for IRI post-transplantation. Therefore, studies which lead to the development of novel strategies to attenuate the effects of IRI are much needed in the current era of transplantation. Our overall hypothesis is that IRI in the graft activates allograft derived dendritic cells (ADDC) which become the critical link between the innate immunity and alloimmunity, ultimately enhancing the allogenicity of the graft. ADDC are the most potent antigen-presenting cells. Extensive preliminary data from our laboratory using various transgenic models have led to the novel observation that preventing this injury could diminish the immunogenicity of ischemic organs and promote engraftment. The overarching goals of this project are: 1) to investigate the mechanisms by which IRI enhances the immunogenicity of allografts by increasing the allogenicity of ADDC, and 2) to identify novel protective strategies to minimize IRI, with the ultimate goal of promoting long-term allograft acceptance. In AIM 1, we will examine the mechanisms by which activated ADDC by IRI link innate and alloimmunity. We will employ T reg and alloreactive transgenic mice to study whether and how the ischemia/anti-ischemic strategy affects the generation of T regs vs. alloreactive T cells. In AIM 2, we will explore the mechanisms by which ischemia-induced TLR2/TLR4 activation results in higher DC allostimulatory capacity and trafficking properties. We will identify the key signaling molecules in ischemic DC upstream of NFkB and downstream of TLR4 and TLR2, with particular focus on MyD88 and TRIF. Ischemic DC will be evaluated for their cytokine elaboration profiles, allostimulatory capacity, and chemokine dependent in vitro and in vivo trafficking patterns. The organ shortage has become a major obstacle hampering the success of organ transplantation worldwide, prompting clinicians to expand their criteria for the acceptance of marginal organs, which are more susceptible to IRI. Our proposed comprehensive studies will provide highly innovative data and insights into the pathophysiology of IRI-induced activation of innate and alloimmunity. This research will identify novel therapeutic targets and set forth novel strategies and innovations in the areas of donor management to attenuate the deleterious effects of IRI which are urgently needed in the current era of transplantation. We believe that this research, supported by the wealth of preliminary data, innovative approaches, sophisticated models and the commitment and expertise of the investigators, has all the necessary elements to achieve the stated goals. The findings from this proposal could be easily translated into clinical practice and have a significant impact on reducing the burden of IRI in clinical transplantation.

描述（由申请人提供）：供体器官的缺血/再灌注损伤（IRI）显着增强了移植物的免疫原性，并增加了急性和慢性同种异体移植排斥的速度。 IRI更严重的移植物的长期生存也明显较差。因此，IRI仍然是当今移植的主要障碍，但目前尚无对IRI转移后的标准治疗方法。因此，在当前移植时代，需要发展导致衰减IRI影响的新型策略的研究。我们的总体假设是，移植物中的IRI激活同种异体移植的树突状细胞（ADDC），这成为先天免疫和同种异体免疫之间的关键联系，最终增强了移植物的同种异性。 ADDC是最有效的抗原呈递细胞。使用各种转基因模型来自我们实验室的广泛初步数据导致了新的观察结果，即防止这种损伤可以减少缺血器官的免疫原性并促进植入。该项目的总体目标是：1）研究IRI通过提高ADDC的同种异体性来增强同种异体移植的免疫原性的机制，以及2）确定新型的保护策略以最大程度地减少IRI，并以促进长期同种异体接受率的最终目标。在AIM 1中，我们将研究IRI链接与天生和同种免疫的ADDC的机制。我们将采用T Reg和同种异体转基因小鼠来研究缺血/抗缺血策略是否以及如何影响T regs的产生与同种异体T细胞的产生。在AIM 2中，我们将探索缺血诱导的TLR2/TLR4激活的机制，从而导致较高的DC全刺激能力和运输特性。我们将确定NFKB上游以及TLR4和TLR2下游的缺血性DC中的关键信号分子，特别关注MyD88和TRIF。缺血性直流将评估其细胞因子阐述谱，同种刺激能力以及趋化因子在体外和体内运输模式。器官短缺已成为阻碍世界范围内器官移植成功的主要障碍，促使临床医生扩大了其接受边际器官的标准，而边际器官更容易受到IRI的影响。我们提出的综合研究将提供高度创新的数据和洞察力，以了解Iri引起的先天和同种免疫性激活的病理生理学。这项研究将确定新颖的治疗靶标，并在捐助者管理领域制定新的策略和创新，以减轻IRI的有害影响，而IRI在当前移植时代急需。我们认为，这项研究在初步数据，创新方法，复杂模型以及研究人员的承诺和专业知识的支持下，具有实现既定目标的所有必要要素。该提案的发现可以很容易地转化为临床实践，并对减轻IRI负担在临床移植中产生重大影响。