Project 4-Animal transplant models to characterize immune and regenerative effects of alcohol

项目4-动物移植模型来表征酒精的免疫和再生作用

基本信息

批准号：
10356017
负责人：
ZHAOLI SUN
金额：
$ 33.69万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10356017
关键词：
AMD3100 Abstinence Acute Adaptive Immune System Address Affect Alcohol abuse Alcohol consumption Alcoholic Hepatitis Alcoholic Liver Diseases Alcohols Alloantigen Allograft Tolerance Allografting Animal Model Animals Apoptosis B-Cell Activation B-Lymphocytes Body Weight Bone Marrow Bone Marrow Stem Cell Cadaver Cell Culture Techniques Cell physiology Chronic Clinical Clinical Research Clinical Trials Combined Modality Therapy Dose Endothelium Equilibrium Ethanol Europe FK506 FOXP3 gene Freedom Heavy Drinking Hepatectomy Immune Immunoglobulins Immunosuppression Impairment In Vitro Infection Knowledge Life Liver Liver Failure Liver Regeneration Living Donor Liver Transplantation Living Donors Measures Modeling Natural Immunity Natural regeneration Organ Transplantation Outcome Partial Hepatectomy Patients Peripheral Pharmacology Predisposition Production Rattus Regulatory T-Lymphocyte Risk Savings Steroids System T-Cell Activation T-Lymphocyte Testing Therapeutic immunosuppression Tissues Transgenic Organisms Transplant Recipients Transplantation adaptive immunity alcohol effect alcohol exposure alcohol relapse allograft rejection antibody-mediated rejection base cell type cohort dietary control dosage effective therapy feeding human model improved insight interdisciplinary approach isoimmunity liver allograft liver injury liver transplantation mortality novel progenitor recidivism reconstitution recruit regenerative response stem cells tissue regeneration transplant centers transplant model

项目摘要

SUMMARY Early liver transplant (ELT) without period of 6 months abstinence has become a life-saving therapy for severe alcoholic hepatitis (SAH) patients. Chronic and active alcohol abuse impacts innate and adaptive immunity and predisposes to infections. This susceptibility is further complicated by immunosuppressive therapy after LT. Further, living donor liver transplant (LDLT) is considered for patients with SAH especially when the patient has a statistically low priority for cadaveric organ transplantation based on the allocation system. However, the impact of active alcohol abuse on alloimmunity is largely unknown. Alcohol use also damages bone marrow stem cells that may be important for liver regeneration, raising a concern for LDLT. By using our established rat liver transplantation model our studies address the two serious problems in ELT for patients with SAH: immunosuppressive therapy and using a living donor for LT. We hypothesize that chronic and active alcohol abuse impacts T cell alloimmunity and allows reduction of immunosuppression (IS) after liver transplantation. Further, chronic and active alcohol abuse impairs regeneration of small liver allografts and limits the use of a living donor for patients with SAH. We propose that pharmacological mobilization of endogenous stem cells overcomes the impact of alcohol damage to stem cells and promotes regeneration of small liver allografts. This treatment could make patients with SAH suitable for transplantation with small livers, and possibly provide tolerance and freedom from long term immunosuppression. Our proposed studies involve: 1) evaluating the impact of chronic and active alcohol exposure on allograft rejection and immunosuppression after LT, 2) determining the effect of chronic and acute alcohol exposure on regeneration of small liver allografts, and 3) developing a stem cell mobilizing strategy to promote regeneration and tolerance of small liver allografts in chronic plus binge alcohol feeding rats. The knowledge generated from these novel studies will improve clinical outcomes by optimizing IS therapy in patients with SAH after ELT, provide new insights in LDLT for patients with SAH and enable tolerance for the allograft in patients with SAH.

概括无需6个月禁欲的早期肝移植（ELT）已成为挽救生命的疗法严重酒精性肝炎（SAH）患者。慢性和主动酗酒会影响先天和适应性免疫力下降，容易感染。这种易感性因免疫抑制而进一步复杂化 LT 后的治疗。此外，SAH 患者尤其考虑活体肝移植 (LDLT) 当根据分配情况，患者在尸体器官移植方面的统计优先级较低时系统。然而，主动酗酒对同种免疫的影响在很大程度上尚不清楚。还使用酒精损害对肝再生可能很重要的骨髓干细胞，引起对 LDLT 的关注。经过使用我们建立的大鼠肝移植模型，我们的研究解决了 ELT 中的两个严重问题 SAH 患者：免疫抑制治疗并使用活体捐献者进行 LT。我们假设慢性主动酗酒会影响 T 细胞同种免疫，并可减少饮酒后的免疫抑制 (IS) 肝移植。此外，长期和主动酗酒会损害小同种异体肝脏移植物的再生和限制 SAH 患者使用活体捐献者。我们建议药物动员内源性干细胞克服酒精对干细胞损伤的影响，促进干细胞再生小同种异体肝脏移植物。这种治疗可以使 SAH 患者适合进行小肝脏移植，并可能提供耐受性并免于长期免疫抑制。我们提出的研究涉及：1) 评估长期和活跃的酒精暴露对同种异体移植排斥的影响和 LT 后的免疫抑制，2) 确定慢性和急性酒精暴露对再生的影响小肝同种异体移植物，以及 3) 开发干细胞动员策略以促进再生和慢性加酗酒的大鼠对小同种异体肝脏移植物的耐受性。知识产生于这些新研究将通过优化 ELT 后 SAH 患者的 IS 治疗来改善临床结果，为 SAH 患者的 LDLT 提供新的见解，并使 SAH 患者能够耐受同种异体移植物。