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 language | English (US) |
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Pages (from-to) | 2030-2041 |
Number of pages | 12 |
Journal | American Journal of Transplantation |
Volume | 16 |
Issue number | 7 |
DOIs | |
State | Published - Jul 1 2016 |
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)