Preventing Allograft Rejection by Targeting Immune Metabolism
Chen-Fang Lee,
Ying-Chun Lo,
Chih-Hsien Cheng,
Georg J. Furtmüller,
Byoungchol Oh,
Vinicius Andrade-Oliveira,
Ajit G. Thomas,
Caitlyn E. Bowman,
Barbara S. Slusher,
Michael J. Wolfgang,
Gerald Brandacher,
Jonathan D. Powell
Affiliations
Chen-Fang Lee
Sidney-Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Ying-Chun Lo
Sidney-Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Chih-Hsien Cheng
Sidney-Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Georg J. Furtmüller
Vascularized Composite Allotransplantation Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Byoungchol Oh
Vascularized Composite Allotransplantation Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Vinicius Andrade-Oliveira
Sidney-Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Ajit G. Thomas
Department of Neurology and Brain Science Institute, NeuroTranslational Drug Discovery Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Caitlyn E. Bowman
Department of Biological Chemistry, Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Barbara S. Slusher
Department of Neurology and Brain Science Institute, NeuroTranslational Drug Discovery Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Michael J. Wolfgang
Department of Biological Chemistry, Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Gerald Brandacher
Vascularized Composite Allotransplantation Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Jonathan D. Powell
Sidney-Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
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.
