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.

同种异体移植和接受已故供体器官的患者的长期存活率仍然很低。有

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