Preventing Allograft Rejection by Targeting Immune Metabolism

Abstract

SUMMARY Upon antigen recognition and co-stimulation, T lymphocytes up-regulate the metabolic machinery necessary to proliferate and sustain effector function. This metabolic reprogramming in T cells regulates T cell activation and differentiation but is not just a consequence of antigen recognition. While such metabolic reprogramming promotes the differentiation and function of T effector cells, the differentiation of regulatory T cells employs different metabolic reprogramming. We therefore hypothesized that inhibition of glycolysis and glutamine metabolism might prevent graft rejection by inhibiting effector generation and function and promoting regulatory T cell generation. We devised an anti-rejection regimen involving a glycolytic inhibitor, 2-Deoxyglucose (2-DG), an anti-Type II diabetes drug (metformin) and an inhibitor of glutamine metabolism, 6-Diazo-5-oxo-L-norleucine (DON). Using this triple drug regimen we were able to prevent/delay graft rejection in fully mismatched skin and heart allograft transplantation models.

Metabolic regulation of immune responses: therapeutic opportunities

“…Inhibition of glycolysis and OxPhos using 2-deoxyglucose and metformin, respectively, was shown to reduce disease severity in mouse models of lupus (94). Also, the combined inhibition of glycolysis, OxPhos, and glutaminolysis prevented graft rejection in fully mismatched skin and heart allograft transplantation models (95). While these two studies did not look at the impact of these drugs on effector T cells versus Tregs, the overall impact of metabolic inhibition in these disease models was the attenuation of autoreactive and alloreactive T cell responses (94,95).…”

“…In jci.org Volume 126 Number 6 June 2016 addition, drugs that directly target glycolysis and OxPhos, such as 2-deoxyglucose and metformin, are well tolerated in humans and have been used for decades (114). While it is not clear how effective these drugs are at inhibiting metabolism in immune cells in vivo, these drugs in combination do effectively inhibit pathological T cell responses in mouse models, arguing that metabolic regulation of human T cell responses is feasible (94,95). A significant amount of work remains to determine how other strategies targeting specific metabolic enzymes or metabolites might be implemented or indeed tolerated in humans.…”

HIF1α and metabolic reprogramming in inflammation

“…2-DG, glutamine metabolism with the glutamine analog DON, and augmenting FAO with metformin (75). Thus, there are multiple pharmacological modalities that could potentially be used to alter immune metabolic programs.…”

“…The blockade of acetyl-CoA carboxylase 1 (ACC1), a crucial enzyme in fatty acid synthesis, also limits Th17 proliferation and attenuates Th17-mediated pathologies (74). Pharmacological inhibition of glycolysis and glutaminolysis and promotion of FAO reduced the proliferation of lymphocytes, particularly effector T cells, in a transplantation model (75).…”

The Therapeutic Potential of T Cell Metabolism

“…This is a metabolic process whereby nutrients, in particular glutamine, can be directed to the TCA cycle to provide carbons for metabolites that flow out of the mitochondria (e.g., citrate) and subsequently flow into the acetyl-CoA pool for macromolecular synthesis (e.g., fatty acids and cholesterol). Perhaps not surprisingly, controlling the influx of amino acids, in particular the branched chain amino acids and glutamine, has emerged as a potential pharmacologic target in controlling aberrant lymphocyte proliferation (14).…”