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

• 批准号: 10093989
• 负责人: ZHAOLI SUN
• 金额: $ 33.02万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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/10093989
• 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

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.

总结 没有6个月禁欲期的早期肝移植（ELT）已成为挽救生命的治疗方法， 重度酒精性肝炎（SAH）患者。慢性和主动酗酒影响先天和适应性 免疫力和易感染性。这种易感性进一步复杂化免疫抑制 此外，对于SAH患者，特别是对于患有SAH的患者，考虑活体供体肝移植（LDLT）。 当基于所述分配患者具有统计学上低的尸体器官移植优先级时 系统然而，主动酒精滥用对同种免疫的影响在很大程度上是未知的。酒精使用也 损伤骨髓干细胞，这可能对肝再生很重要，引起了对LDLT的关注。通过 利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：免疫抑制治疗和使用活体供者进行LT。 和积极的酒精滥用影响T细胞同种免疫，并允许减少免疫抑制（IS）后， 肝移植此外，慢性和活跃的酒精滥用损害小肝移植物的再生， 限制了SAH患者使用活体供体。我们建议，药理动员 内源性干细胞克服了酒精对干细胞的损伤，促进了干细胞的再生。 小的肝脏移植物。这种治疗可以使SAH患者适合小肝脏移植， 并可能提供耐受性和免于长期免疫抑制。我们建议的研究 包括：1）评估慢性和主动酒精暴露对同种异体移植排斥反应的影响， 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 3）开发干细胞动员策略以促进再生， 慢性酒精喂养大鼠小肝移植耐受性的研究知识产生于 这些新的研究将通过优化ELT后SAH患者的IS治疗来改善临床结果， 为SAH患者的LDLT提供了新的见解，并使SAH患者能够耐受同种异体移植物。