Loss of HIF-1α in CD4 T Cell Improve Outcome of Mouse Vascularized Osteomyocutaneous Allotransplantation under Costimulation Blockade
1PRS, Center for VCA, Chang Gung Memorial Hospital, Taoyuan, Taiwan
2Chang Gung Medical College and Chang Gung University, Taoyuan, Taiwan
3Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
4Pathology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
5PRS, Johns Hopkins University School of Medicine, Baltimore, MD.
Meeting: 2018 American Transplant Congress
Abstract number: A440
Keywords: Co-stimulation, knockout, T cells, Tolerance
Session Information
Session Name: Poster Session A: Tolerance / Immune Deviation
Session Type: Poster Session
Date: Saturday, June 2, 2018
Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Hall 4EF
Background: Allograft survival depends on the balance of effector T cells (Teff) and regulatory T cells (Tregs). Previous study suggested that the balance is controlled by HIF-1α. In this study, we investigated the role of HIF-1α-deficient CD4 T-cell in promoting acceptance of vascularized composite allografts.
Methods: Forty osteomyocutaneous allografts from Balb/c were transplanted to wild type (WT) and HIF-1αfl/flCD4Cre C57BL/6 mice. Animals received combined costimulation blockade (1 mg anti-CD154 at POD 0, 0.5 mg CTLA4Ig at POD 2) with or without rapamycin (3mg/kg/day for 7 days then every other day for 3 weeks). Allograft survival, ratio of Tregs/Teff cells in the periphery and allograft were assessed.
Results:Twelve of 15 WT recipients under costimulation blockade and 1-month rapamycin achieved long-term allograft survival (>120 days). In the tolerant animals, ratio of Tregs/Th1 cells and Tregs/Th17 cells in periphery at POD 30 and in allograft were greater than those in rejected animals. In MLR study, conditional HIF-1α deficiency in CD4 resulted CD4 T-cell hyporesponsiveness. HIF-1αfl/flCD4Cre mice generated greater FoxP3+ Tregs and less CD4+IL17+ cells than WT in response to allografts. Without the use of rapamycin, improved allograft survival ratewas achieved in HIF-1αfl/flCD4Cre mice compared to WT mice (> 120 vs 36.5 days). But adoptively transferred Th17 cells at POD 2 in HIF-1α fl/flCD4Cre recipients disrupted the allograft survival. Animals with long-term allograft survival showed donor-specific T cell hypo responsiveness. 
Conclusion: Loss of HIF-1α in CD4 T cells improves allograft survival in the absence of long-term immunosuppressant drugs. Targeting potential mechanisms involved in the differentiation of CD4 T cells may play an important role in improving allograft survival.
CITATION INFORMATION: Lin C-.H., Anggelia M., Yang H., Chuang W., Cheng H., Wei F-.C., Brandacher G. Loss of HIF-1α in CD4 T Cell Improve Outcome of Mouse Vascularized Osteomyocutaneous Allotransplantation under Costimulation Blockade Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:
Lin C-H, Anggelia M, Yang H, Chuang W, Cheng H, Wei F-C, Brandacher G. Loss of HIF-1α in CD4 T Cell Improve Outcome of Mouse Vascularized Osteomyocutaneous Allotransplantation under Costimulation Blockade [abstract]. https://atcmeetingabstracts.com/abstract/loss-of-hif-1-in-cd4-t-cell-improve-outcome-of-mouse-vascularized-osteomyocutaneous-allotransplantation-under-costimulation-blockade/. Accessed November 21, 2024.« Back to 2018 American Transplant Congress