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: 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
• 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

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.

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