The backbone of current immunosuppression regimens remains calcineurin inhibitors (CNI) in association with steroids, mycophenolate mofetil or mTOR inhibitors. However, their long-term administration is associated with significant side effects. Costimulation blockade-based therapy with CTLA4Ig has been shown to be an effective alternative to current immunosuppressive protocols with a minimal side-effect profile. However, many studies have shown higher incidence of acute rejection, especially during the early phase post-transplantation. Recently, it has been clear that metabolic reprogramming is an integral aspect of T cell activation, differentiation and function.Previous studies have demonstrated that inhibiting T-cell metabolism at the time of T-cell activation inhibits both proliferation and cytokine production and it has been shown to effectively control T-cell responses in preclinical models of autoimmunity and transplantation.In this study, we examined the effect of combining CTLA4Ig with metabolic inhibitors (MI) 2-deoxyglucose, metformin and 6-Diazo-5-oxo-L-norleucine in improving allograft survival using murine models of skin, heart and hind-limb transplantation (BALB/c to C57BL/6). Simultaneous inhibition of T-cell glycolysis, mitochondrial oxidative phosphorylation and glutamine metabolism with MI enhanced the efficacy of CTLA4Ig. Skin allograft survival was significantly prolonged in the double-treated animals compared to animals that received only CTLA4Ig or MI. Moreover, combining CTLA4Ig with only short-term MI (30 days) could achieved long term cardiac and hind-limb allograft survival. Addition of MI to CTLA4Ig further suppressed the initial alloreactive immune response and allowed for limited immunomodulation to achieve allograft tolerance. Our results indicate that targeting T cell metabolism provides a novel approach for enhancing CNI-sparing regimens with CTLA4Ig.

CITATION INFORMATION: Cheng C-.H., Lee C-.F., Furtmüller G., Oh B., Patel C., Lo Y-.C., Fryer M., Brandacher G., Powell J. Metabolic Therapy as a Platform for CTLA4Ig Costimulation Blockade in Preventing Allograft Rejection Am J Transplant. 2017;17 (suppl 3).

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