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Combined Anti‐ CD 154/ CTLA 4Ig Costimulation Blockade‐Based Therapy Induces Donor‐Specific Tolerance to Vascularized Osteomyocutaneous Allografts
Author(s) -
Lin C. H.,
Wang Y. L.,
Anggelia M. R.,
Chuang W. Y.,
Cheng H. Y.,
Mao Q.,
Zelken J. A.,
Lin C. H.,
Zheng X. X.,
Lee W. P. A.,
Brandacher G.
Publication year - 2016
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.13694
Subject(s) - medicine , blockade , allotransplantation , immune tolerance , transplantation , cd154 , immunosuppression , bone marrow , andrology , immunology , surgery , in vitro , immune system , cd40 , cytotoxic t cell , biology , receptor , biochemistry
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 (allo OMCs ) from Balb/c (H2 d ) mice were transplanted into C57 BL /6 (H2 b ) recipients. Immunosuppression consisted of 1 mg anti‐ CD 154 on day 0, 0.5 mg CTLA 4Ig 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 allo OMC 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‐ CD 154/ CTLA 4Ig costimulation blockade‐based therapy induces donor‐specific tolerance in a stringent murine allo OMC transplant model.