Cell Death Pathways and Heart Transplant Rejection

细胞死亡途径和心脏移植排斥

• 批准号: 10162490
• 负责人: Peter Scott Heeger
• 金额: $ 55.08万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10162490
• 关键词: Acute; Address; Allografting; Animal Model; Animals; Antigen-Presenting Cells; Antigens; Apoptosis; B-Lymphocytes; CASP8 gene; Cell Death; Cells; Chronic; Clinical; Complement; Complement Activation; Data; Development; Donor person; End stage renal failure; Epidemiology; Failure; Functional disorder; Graft Rejection; Graft Survival; Health; Heart Transplantation; Homologous Transplantation; Human; Immunity; Inflammation; Inflammation Mediators; Inflammatory; Injury; Innate Immune Response; Ischemia; Kidney Transplantation; Knock-in; Knock-out; Laboratories; Lead; Lectin; Ligands; Link; Mannose; Mannose Binding Lectin; Mediating; Memory; Modeling; Molecular; Mus; Organ; Organ Donor; Outcome; Pathogenicity; Pathologic Processes; Pathway interactions; Patients; Pattern; Pattern recognition receptor; Pharmacology; Phase; Play; Production; RIPK1 gene; RIPK3 gene; Reagent; Reperfusion Injury; Reperfusion Therapy; Resistance; Risk; Role; Series; Signal Transduction; T-Lymphocyte; TNF gene; Testing; Therapeutic Intervention; Tissue Donors; Toll-like receptors; Translating; Transplant Recipients; Transplantation; Tumor Necrosis Factor Receptor; allograft rejection; animal data; base; cell injury; complement deficiency; cytokine; delayed graft function; graft failure; heart allograft; immunogenicity; improved; inhibitor/antagonist; insight; isoimmunity; mouse model; new therapeutic target; novel strategies; post-transplant; pre-clinical; prevent; targeted treatment; transplant model

The long-term survival of allografts and patients receiving deceased donor organs remain poor. There is evidence to suggest that cold ischemia (CI) and the subsequent reperfusion during transplants causes cellular injury, which leads to an induction of T cell alloimmunity against donor tissue and ultimately graft rejection. The mechanism by which ischemia reperfusion (IR) initiates cellular injury, the manner of the injury, and how this injury impacts alloresponse are poorly understood. To better mimic human deceased donor transplants, the Fairchild laboratory developed an allograft heart transplant model whereby the donor organ is subjected to extended CI prior to transplantation followed by administration of an CTLA4Ig costimulatory blockade. Allograft hearts subjected to CI were rejected whereas those not subjected to CI survived. Preliminary studies using this model indicated that complement deficiency in the recipients prolonged the survival of CI-treated allografts, correlating with reduced circulating TNFα. As TNFα is a known inducer of necroptosis, an inflammatory cell death, additional studies showed that organs from CYLD-deficient donors, (which are defective in necroptosis) survived longer than wild type organs whereas organs from SHARPIN- deficient donors (which have accelerated necroptosis) were rapidly rejected. Based on these studies, we have proposed and will test the unifying hypothesis that complement activation following CI/IR during transplants leads to the induction of TNFα, which then induces necroptosis of cells in donor tissues. In turn, this inflammatory cellular injury activates T cell alloimmunity to cause rejection. This collaborative study brings together in a highly synergistic manner the unique strengths of three laboratories to address the above hypothesis. (1) In Aim 1, we will examine the role of mannose-binding lectin (MBL)-initiated complement activation in triggering TNF-dependent necroptosis in our allograft transplant model using MBL, TNF and TNFRs knockouts/knockins. (2) In Aim 2, the role of the TNF cell death pathway in CI-initiated rejection will be further dissected using donor organs derived from various knockouts/knockins of CYLD, RIPK1, RIPK3, Caspase-8 and SHARPIN. (3) Necroptosis releases damage-associated molecular patterns (DAMPs) and thus in Aim 3, we will examine how DAMPs are sensed by host antigen-presenting cells and how this leads to induction of the T cell alloresponse. All three aims are highly significant, as they will provide insights into which molecules during (1) initiation, (2) cellular injury and (3) effector phases of graft rejection may be targeted for therapeutic blockade in transplants. The approach has strong potential to directly and positively impact outcomes of transplant patients.

同种异体移植物和接受死亡供体器官的患者的长期存活率仍然很差。那里 有证据表明冷缺血 (CI) 和移植过程中随后的再灌注会导致 细胞损伤，导致诱导针对供体组织并最终移植的 T 细胞同种免疫 拒绝。缺血再灌注（IR）引发细胞损伤的机制、损伤的方式、 人们对这种伤害如何影响异体反应知之甚少。为了更好地模仿人类已故捐赠者 为了移植，Fairchild 实验室开发了一种同种异体心脏移植模型，其中供体器官是 移植前接受延长 CI，随后给予 CTLA4Ig 共刺激 封锁。接受 CI 的同种异体移植心脏被排斥，而未接受 CI 的同种异体移植心脏则存活下来。 使用该模型的初步研究表明，接受者的补体缺乏会延长 CI 处理的同种异体移植物的存活率与循环 TNFα 的减少相关。由于 TNFα 是已知的诱导剂 坏死性凋亡，一种炎症细胞死亡，其他研究表明，来自 CYLD 缺陷供体的器官， （存在坏死性凋亡缺陷）比野生型器官存活时间更长，而来自 SHARPIN- 的器官 有缺陷的供体（加速了坏死性凋亡）很快被拒绝。基于这些研究，我们有 提出并将测试移植期间 CI/IR 后补体激活的统一假设 导致 TNFα 的诱导，然后诱导供体组织中细胞的坏死性凋亡。反过来，这 炎症细胞损伤激活T细胞同种免疫引起排斥反应。这项合作研究带来 以高度协同的方式结合三个实验室的独特优势来解决上述问题 假设。 (1) 在目标 1 中，我们将研究甘露糖结合凝集素 (MBL) 启动的补体的作用 在我们的同种异体移植模型中，使用 MBL、TNF 和 TNFR 敲除/敲除。 (2) 在目标 2 中，TNF 细胞死亡途径在 CI 引发的排斥反应中的作用将是 使用源自 CYLD、RIPK1、RIPK3 的各种敲除/敲入的供体器官进行进一步解剖， Caspase-8 和 SHARPIN。 (3) 坏死性凋亡释放损伤相关分子模式（DAMP），从而 在目标 3 中，我们将研究宿主抗原呈递细胞如何感知 DAMP，以及这如何导致 诱导 T 细胞同种异体反应。这三个目标都非常重要，因为它们将提供有关以下方面的见解： 移植物排斥的（1）起始阶段、（2）细胞损伤阶段和（3）效应阶段期间的分子可能是针对 移植中的治疗封锁。该方法具有直接和积极影响的巨大潜力 移植患者的结果。

项目成果

T follicular helper cells restricted by IRF8 contribute to T cell-mediated inflammation.

• DOI: 10.1016/j.jaut.2018.09.001
• 发表时间: 2019-01
• 期刊: Journal of autoimmunity
• 影响因子: 12.8
• 作者: Zhang R;Qi CF;Hu Y;Shan Y;Hsieh YP;Xu F;Lu G;Dai J;Gupta M;Cui M;Peng L;Yang J;Xue Q;Chen-Liang R;Chen K;Zhang Y;Fung-Leung WP;Mora JR;Li L;Morse HC 3rd;Ozato K;Heeger PS;Xiong H
• 通讯作者: Xiong H