Preventing of Rejection of Vascularized Composite Allografts by Targeting T Cell Metabolism
1Plastic and Reconstructive Surgery, Johns Hopkins SOM, Baltimore
2Oncology, Johns Hopkins SOM, Baltimore.
Meeting: 2018 American Transplant Congress
Abstract number: C283
Keywords: Rejection, T cell activation
Session Information
Session Name: Poster Session C: Lymphocyte Biology: Signaling, Co-Stimulation, Regulation
Session Type: Poster Session
Date: Monday, June 4, 2018
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall 4EF
[Background] 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. Therefore, we investigated to prevent graft rejection in vascularized composite allotransplantation (VCA) via inhibition of glycolysis and glutamine metabolism.
[Methods] Fully MHC-mismatched orthotopic hind limb transplants were performed from Balb/C to C57BL/6 mice. Recipients in the experimental groups were given various combinations of CTLA4 Ig (0.5mg) on day 0, 2, 4 and 6 post-transplant and triple metabolic inhibitors (2-DG, metformin and DON). Allograft survival was followed and flow cytometric analysis was performed to evaluate mixed chimerism and Foxp3 expressing Treg cells.
[Results]Continuous triple metabolic inhibitor therapy induced long term survival more than 100 days. 30 days treatment of triple therapy induced 39.5 days MST and combination with CTLA4 Ig and triple therapy induced 44 days MST indicating continuous metabolic inhibitors are necessary for long-term allograft survival. Mixed chimerism was detected in recipients receiving triple therapy with 0.3% in T cells, 0.15% in B cells and 0.8% in CD11b cells. Combination with CTLA4 Ig and 30 days of triple therapy induced increased mixed chimerism with 0.9%, 1.17%, and 6.96% respectively. However, increased CD4+CD25+Foxp3- T cells were found in both groups while CD4+CD25+Foxp3+ T cells were maintained representing ongoing antigen recognition by T cells.
[Conclusion] These data support the notion that the inhibition of glycolysis and glutamine metabolic pathways represents a potent means to prevent acute rejection and promote long-term graft acceptance in VCA.
CITATION INFORMATION: Oh B., Cheng C., Furtmüller G., Donovan K., Lee W., Powell J., Brandacher G. Preventing of Rejection of Vascularized Composite Allografts by Targeting T Cell Metabolism Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:
Oh B, Cheng C, Furtmüller G, Donovan K, Lee W, Powell J, Brandacher G. Preventing of Rejection of Vascularized Composite Allografts by Targeting T Cell Metabolism [abstract]. https://atcmeetingabstracts.com/abstract/preventing-of-rejection-of-vascularized-composite-allografts-by-targeting-t-cell-metabolism-2/. Accessed May 12, 2025.« Back to 2018 American Transplant Congress