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

Preventing Allograft Rejection by Targeting Immune Metabolism.

Author information

1
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.
2
Sidney-Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
3
Vascularized Composite Allotransplantation Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
4
Department of Neurology and Brain Science Institute, NeuroTranslational Drug Discovery Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
5
Department of Biological Chemistry, Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
6
Sidney-Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Electronic address: poweljo@jhmi.edu.

Abstract

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.

PMID:
26489460
PMCID:
PMC4626381
DOI:
10.1016/j.celrep.2015.09.036
[Indexed for MEDLINE]
Free PMC Article

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