Preventing Allograft Rejection by Targeting Immune Metabolism

Cell Rep. 2015 Oct 27;13(4):760-770. doi: 10.1016/j.celrep.2015.09.036. Epub 2015 Oct 17.


Upon antigen recognition and co-stimulation, T lymphocytes upregulate 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. Although such metabolic reprogramming promotes the differentiation and function of T effector cells, the differentiation of regulatory T cells employs different metabolic reprogramming. Therefore, we 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 the glycolytic inhibitor 2-deoxyglucose (2-DG), the anti-type II diabetes drug metformin, and the inhibitor of glutamine metabolism 6-diazo-5-oxo-L-norleucine (DON). Using this triple-drug regimen, we were able to prevent or delay graft rejection in fully mismatched skin and heart allograft transplantation models.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Allografts
  • Animals
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / metabolism
  • Cells, Cultured
  • Deoxyglucose / therapeutic use
  • Diazooxonorleucine / therapeutic use
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Glutamine / metabolism
  • Glycolysis / drug effects
  • Glycolysis / physiology
  • Graft Rejection / prevention & control*
  • Heart Transplantation / methods
  • Metformin / therapeutic use
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Phosphorylation / drug effects
  • Phosphorylation / physiology
  • T-Lymphocytes, Regulatory


  • Diazooxonorleucine
  • Glutamine
  • Metformin
  • Deoxyglucose