Upon antigen recognition and co-stimulation, T cells up-regulate the metabolic machinery necessary to proliferate and sustain effector function. Hallmarks of this response include a switch to aerobic glycolysis and an increased demand for glutamine. This metabolic reprogramming in T cells plays a critical role in regulating T cell activation and differentiation rather than just the result of T cell activation. Based on these observations, we hypothesize that inhibition of glycolysis and glutamine metabolism might represent a novel means of preventing graft rejection. In addition, what has emerged from recent studies is that mechanistically mTOR (mammalian target of rapamycin) regulates T cell differentiation and function in part by regulating metabolic programs including glycolysis and glutamine metabolism. Along these lines, we devised an effective anti-rejection regimen employing a glycolytic inhibitor, 2-Deoxyglucose (2-DG), a glutaminase inhibitor, 6-Diazo-5-oxo-L-norleucine (DON) and an mTOR complex 1 inhibitor, Metformin, in a fully mismatched heart allograft transplantation model. When recipient mice were treated with this anti-metabolic triple therapy, the grafted hearts continued beating for more than 100 days post-transplantation without rejection .Our data suggest that anti-metabolic therapy represents a novel means of inhibiting T cell effector function while preserving mechanisms of immune regulation. The therapeutic index of our approach relies on the extraordinary metabolic demand of effector T cells, which is distinct from the more flexible and adaptive regular metabolic network. Such a regimen can inhibit acute rejection and promote graft survival.

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