Combined Anti-CD154/CTLA4Ig Costimulation Blockade-Based Therapy Induces Donor-Specific Tolerance to Vascularized Osteomyocutaneous Allografts

C. H. Lin*, Y. L. Wang, M. R. Anggelia, W. Y. Chuang, H. Y. Cheng, Q. Mao, J. A. Zelken, C. H. Lin*, X. X. Zheng, W. P.A. Lee, G. Brandacher

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

30 Scopus citations

Abstract

Tolerance induction by means of costimulation blockade has been successfully applied in solid organ transplantation; however, its efficacy in vascularized composite allotransplantation, containing a vascularized bone marrow component and thus a constant source of donor-derived stem cells, remains poorly explored. In this study, osteomyocutaneous allografts (alloOMCs) from Balb/c (H2d) mice were transplanted into C57BL/6 (H2b) recipients. Immunosuppression consisted of 1 mg anti-CD154 on day 0, 0.5 mg CTLA4Ig on day 2 and rapamycin (RPM; 3 mg/kg per day from days 0–7, then every other day for 3 weeks). Long-term allograft survival, donor-specific tolerance and donor–recipient cell trafficking were evaluated. Treatment with costimulation blockade plus RPM resulted in long-term graft survival (>120 days) of alloOMC in 12 of 15 recipients compared with untreated controls (median survival time [MST] ≈10.2 ± 0.8 days), RPM alone (MST ≈33 ± 5.5 days) and costimulation blockade alone (MST ≈45.8 ± 7.1 days). Donor-specific hyporesponsiveness in recipients with viable grafts was demonstrated in vitro. Evidence of donor-specific tolerance was further assessed in vivo by secondary donor-specific skin graft survival and third-party graft rejection. A significant increase of Foxp3+ regulatory T cells was evident in tolerant animals. Donor cells populated peripheral blood, thymus, and both donor and recipient bone marrow. Consequently, combined anti-CD154/CTLA4Ig costimulation blockade-based therapy induces donor-specific tolerance in a stringent murine alloOMC transplant model.

Original languageEnglish
Pages (from-to)2030-2041
Number of pages12
JournalAmerican Journal of Transplantation
Volume16
Issue number7
DOIs
StatePublished - 01 07 2016
Externally publishedYes

Bibliographical note

Publisher Copyright:
© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons

Keywords

  • basic (laboratory) research/science
  • bone marrow/hematopoietic stem cell transplantation
  • immunosuppression/immune modulation
  • tolerance: chimerism
  • tolerance: costimulation blockade
  • translational research/science
  • vascularized composite and reconstructive transplantation

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