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LUNG TRANSPLANTATION |
1 Division of Pulmonary Diseases and Critical Care Medicine and the Lung Transplantation Program, University of North Carolina, School of Medicine, Chapel Hill, NC, USA
2 Department of Microbiology and Immunology, University of North Carolina, School of Medicine, Chapel Hill, NC, USA
3 Lineberger Comprehensive Cancer Center, University of North Carolina, School of Medicine, Chapel Hill, NC, USA
4 Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH, USA
Correspondence to:
Correspondence to:
Dr R M Aris
Division of Pulmonary Diseases and Critical Care Medicine, CB #7020, Bioinformatics Building, Room 4131, Chapel Hill, NC 27599, USA; aris{at}med.unc.edu
Background: The state of tolerance allows long term graft survival without immunosuppressants. Lung transplantation tolerance has not been consistently achieved in either small or large animal models.
Methods: The mechanisms and effectiveness of a tolerance induction protocol consisting of donor specific transfusion (DST; day 0) and a short course of co-stimulatory blockade (anti-CD154 antibody; days –7, –4, 0 and +4) were studied in the mouse heterotopic tracheal transplant model of chronic lung rejection. C57BL/6 mice received BALB/c tracheal grafts (day 0) and were treated with DST alone, anti-CD154 alone, the combination (DST/anti-CD154), or no treatment. No non-specific immunosuppressants were used.
Results: DST/anti-CD154 in combination, but neither treatment alone, markedly prolonged the lumen patency and survival (>100 days) of fully histo-incompatible allografts (p<0.05 versus control allografts at every time point studied up to 16 weeks) without immunosuppression. This protocol was donor antigen specific as third party grafts (C3H) were promptly rejected. In addition, DST/anti-CD154 did not result in mixed chimerism but induced transplantation tolerance via a peripheral mechanism(s), which included significantly reduced cytotoxic T cell activity (p<0.001) and a significantly increased percentage of CD4+CD25+ cells (p = 0.03).
Conclusions: The DST/anti-CD154 protocol successfully induced and maintained long term, donor specific tolerance in the mouse heterotopic airway graft model of chronic lung rejection. This finding may lead us closer to successful tolerance induction in lung transplantation.
Abbreviations: APCs, antigen presenting cells; CFSE, carboxy-fluorescein diacetate succinimidyl ester; CTL, cytotoxic lymphocyte; DST, donor specific transfusion; MHC, major histocompatibility complex; OB, obliterative bronchiolitis; TCR, T cell receptor; TR, regulatory T cells
Keywords: lung transplantation; chronic rejection; tolerance; co-stimulatory blockade
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  D. C. Gondek, V. DeVries, E. C. Nowak, L.-F. Lu, K. A. Bennett, Z. A. Scott, and R. J. Noelle Transplantation Survival Is Maintained by Granzyme B+ Regulatory Cells and Adaptive Regulatory T Cells J. Immunol., October 1, 2008; 181(7): 4752 - 4760. [Abstract] [Full Text] [PDF]
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 J. F. McDyer Human and Murine Obliterative Bronchiolitis in Transplant Proceedings of the ATS, January 1, 2007; 4(1): 37 - 43. [Abstract] [Full Text] [PDF]
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