Project Grant R21AA029741

ACTIVATION OF NK CELL-MEDIATED PROTECTIVE IMMUNITY FOR THE SYSTEMIC TREATMENT OF ALD - SUMMARY CHRONIC AND ACUTE (BINGE) ALCOHOL DRINKING ARE MAJOR PUBLIC HEALTH AND ECONOMIC PROBLEMS WORLDWIDE AND PROMINENT RISK FACTORS FOR THE DEVELOPMENT OF ALCOHOLIC LIVER DISEASE (ALD), A LETHAL AND INCURABLE CONDITION. CURRENTLY THERE ARE NO FDA-APPROVED THERAPIES FOR ANY STAGE OF ALD, UNDERSCORING THE URGENT NEED FOR THE APPROVAL OF NEW TREATMENTS. THE ACTIVATION OF HEPATIC STELLATE CELLS (HSC) AND LIVER-RESIDENT MACROPHAGES (KUPFFER CELLS, KC) REPRESENT KEY INITIATING EVENTS IN ALD AND ARE CENTRAL TO THE ONSET OF FIBROSIS AND LIVER INJURY THAT RESULTS IN CIRRHOSIS AND LIVER FAILURE. FULLY ACTIVATED HSC, WHICH EMERGE PATHOGENICALLY IN THE LIVER FOLLOWING CHRONIC HEAVY ALCOHOL CONSUMPTION, EVADE IMMUNE ATTACK BY NATURAL KILLER (NK) CELLS, DRIVING FIBROGENESIS AND LIVER INJURY. HERE, WE SEEK TO DETERMINE WHETHER BLOCKADE OF NK INHIBITORY CHECKPOINTS CAN OVERCOME IMMUNE EVASION BY FULLY ACTIVATED HSC. WE WILL ALSO TEST ANTIBODY-DIRECTED CELLULAR CYTOTOXICITY (ADCC) AS AN APPROACH TO TRIGGER NK ATTACK AND ELIMINATION OF ACTIVATED KC AND INFILTRATING LY- 6C+ MONOCYTE-DERIVED MACROPHAGES, WHICH CONSTITUTE A PARALLEL FIBROGENIC HUB IN ALD, BOTH AS A MONOTHERAPY AND IN COMBINATION WITH NK CHECKPOINT BLOCKADE. FINALLY, WE INTERROGATE WHETHER NK CELLS MANUFACTURED FROM INDUCIBLE PLURIPOTENT STEM CELLS (INK), AND ENGINEERED TO EXPRESS A CHIMERIC CD16 ANTIBODY RECEPTOR DESIGNED TO PRIME AND SENSITIZE NK CYTOLYTIC ATTACK, CAN POTENTIATE THE THERAPEUTIC EFFICACY OF ADCC. THESE STUDIES WILL ILLUMINATE MECHANISMS OF IMMUNE EVASION IN ALD, AND ESTABLISH NK CHECKPOINT BLOCKADE, ADCC AND ENGINEERED INK CELLS AS POTENTIALLY BREAKTHROUGH THERAPEUTIC STRATEGIES, BRINGING ALD INTO THE LIST OF DISEASES THAT BENEFIT FROM THE REVOLUTIONARY POWER OF IMMUNOTHERAPY. INSIGHTS GAINED FROM THESE STUDIES CAN BE DIRECTLY TRANSLATED FROM BENCH TO BEDSIDE INTO CLINICAL TRIALS, LEADING TO DIRECT PATIENT BENEFIT.