Preventing Allograft Rejection by Targeting Immune Metabolism.
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.
Sidney-Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Chang-Gung Transplantation Institute, Department of Liver and Transplantation Surgery, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan 333, Taiwan.
Chen-Fang
CF
Lee
Sidney-Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Ying-Chun
YC
Lo
Sidney-Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Chang-Gung Transplantation Institute, Department of Liver and Transplantation Surgery, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan 333, Taiwan.
Chih-Hsien
CH
Cheng
Vascularized Composite Allotransplantation Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Georg J
GJ
Furtmüller
Vascularized Composite Allotransplantation Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Byoungchol
B
Oh
Sidney-Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Vinicius
V
Andrade-Oliveira
Department of Neurology and Brain Science Institute, NeuroTranslational Drug Discovery Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Ajit G
AG
Thomas
Department of Biological Chemistry, Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Caitlyn E
CE
Bowman
Department of Neurology and Brain Science Institute, NeuroTranslational Drug Discovery Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Barbara S
BS
Slusher
Department of Biological Chemistry, Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Michael J
MJ
Wolfgang
Vascularized Composite Allotransplantation Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Gerald
G
Brandacher
Sidney-Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Electronic address: poweljo@jhmi.edu.
Jonathan D
JD
Powell
D064591:Allografts; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000627:therapeutic use; D003980:Diazooxonorleucine / Q000627:therapeutic use; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005973:Glutamine / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology; D006084:Graft Rejection / Q000517:prevention & control*; D016027:Heart Transplantation / Q000379:methods; D008687:Metformin / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D050378:T-Lymphocytes, Regulatory
D003980:Diazooxonorleucine; D005973:Glutamine; D008687:Metformin; D003847:Deoxyglucose