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Combined donor specific transfusion and anti-CD154 therapy achieves airway allograft tolerance
  1. W Chalermskulrat1,
  2. K P McKinnon2,3,
  3. W J Brickey2,3,
  4. I P Neuringer1,
  5. R C Park1,
  6. D G Sterka1,
  7. B R Long2,
  8. P McNeillie1,
  9. R J Noelle4,
  10. J P Ting2,3,
  11. R M Aris1
  1. 1Division of Pulmonary Diseases and Critical Care Medicine and the Lung Transplantation Program, University of North Carolina, School of Medicine, Chapel Hill, NC, USA
  2. 2Department of Microbiology and Immunology, University of North Carolina, School of Medicine, Chapel Hill, NC, USA
  3. 3Lineberger Comprehensive Cancer Center, University of North Carolina, School of Medicine, Chapel Hill, NC, USA
  4. 4Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH, USA
  1. 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

Abstract

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.

  • 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
  • lung transplantation
  • chronic rejection
  • tolerance
  • co-stimulatory blockade

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Footnotes

  • Published Online First 27 October 2005

  • This research was supported by the American Lung Association (ALA) (WC and IPN), the Cystic Fibrosis Foundation (RMA and WC), and the National Institute of Health HL67178 (IPN), AI29564 (JPT) and DK38108 (JPT).

  • Competing interests: none declared.