title: Combined Anti-CD154/CTLA4Ig Costimulation Blockade-Based Therapy Induces Donor-Specific Tolerance to Vascularized Osteomyocutaneous Allografts.
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 (H2(d) ) mice were transplanted into C57BL/6 (H2(b) ) 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.
authors.affiliation: Center for Vascularized Composite Allotransplantation, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, and School of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: C H
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Center for Vascularized Composite Allotransplantation, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, and School of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Y L
authors.initials: YL
authors.lastname: Wang
authors.affiliation: Center for Vascularized Composite Allotransplantation, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, and School of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: M R
authors.initials: MR
authors.lastname: Anggelia
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital, Chang Gung Medical College and Chang Gung University, Taoyuan, Taiwan.
authors.forename: W Y
authors.initials: WY
authors.lastname: Chuang
authors.affiliation: Center for Vascularized Composite Allotransplantation, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, and School of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: H Y
authors.initials: HY
authors.lastname: Cheng
authors.affiliation: Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Q
authors.initials: Q
authors.lastname: Mao
authors.affiliation: Center for Vascularized Composite Allotransplantation, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, and School of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: J A
authors.initials: JA
authors.lastname: Zelken
authors.affiliation: Center for Vascularized Composite Allotransplantation, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, and School of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: C H
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Research Center of Translational Medicine, Shanghai East Hospital, Tongji University, Shanghai, China.
authors.forename: X X
authors.initials: XX
authors.lastname: Zheng
authors.affiliation: Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: W P A
authors.initials: WP
authors.lastname: Lee
authors.affiliation: Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: G
authors.initials: G
authors.lastname: Brandacher
mesh_terms: D000069594:Abatacept / Q000276:immunology*; D064591:Allografts; D000818:Animals; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D064827:Myocutaneous Flap / Q000098:blood supply*; D020123:Sirolimus / Q000494:pharmacology; D012871:Skin Diseases / Q000276:immunology* / Q000628:therapy; D014019:Tissue Donors; D019172:Transplantation Conditioning
chemical_list: D007166:Immunosuppressive Agents; D023201:CD40 Ligand; D000069594:Abatacept; D020123:Sirolimus
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