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

Research output: Contribution to journalArticle

13 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 (US)
Pages (from-to)2030-2041
Number of pages12
JournalAmerican Journal of Transplantation
Volume16
Issue number7
DOIs
Publication statusPublished - Jul 1 2016
Externally publishedYes

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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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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