期刊
AMERICAN JOURNAL OF TRANSPLANTATION
卷 20, 期 5, 页码 1272-1284出版社
WILEY
DOI: 10.1111/ajt.15726
关键词
basic (laboratory) research; science; cellular transplantation (nonislet); cytokines; cytokine receptors; immunosuppressant - fusion proteins and monoclonal antibodies; belatacept; immunosuppression; immune modulation; immunosuppressive regimens; stem cells; tolerance; costimulation blockade; translational research; science; vascularized composite and reconstructive transplantation
资金
- Hartmann Muller-Stiftung fur Medizinische Forschung
- Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen Forschung [31003A_169805]
- Swiss National Science Foundation (SNF) [31003A_169805] Funding Source: Swiss National Science Foundation (SNF)
The risks of chronic immunosuppression limit the utility of vascularized composite allotransplantation (VCA) as a reconstructive option in complex tissue defects. We evaluated a novel, clinically translatable, radiation-free conditioning protocol that combines anti-lymphocyte serum (ALS), tacrolimus, and cytotoxic T-lymphocyte-associated protein 4 immunoglobulin (CTLA4-Ig) with adipose-derived stromal cells (ASCs) to allow VCA survival without long-term systemic immunosuppression. Full-mismatched rat hind-limb-transplant recipients received tacrolimus (0.5 mg/kg) for 14 days and were assigned to 4 groups: controls (CTRL) received no conditioning; ASC-group received CTLA4-Ig (10 mg/kg body weight i.p. postoperative day [POD] 2, 4, 7) and donor ASCs (1 x 10(6) iv, POD 2, 4, 7, 15, 28); the ASC-cyclophosphamide (CYP)-group received CTLA4-Ig, ASC plus cyclophosphamide (50 mg/kg ip, POD 3); the ASC-ALS-group received CTLA4-Ig, ASCs plus ALS (500 mu L ip, POD 1, 5). Banff grade III or 120 days were endpoints. ASCs suppressed alloresponse in vitro. Median rejection-free VCA survival was 28 days in CTRL (n = 7), 34 in ASC (n = 6), and 27.5 in ASC-CYP (n = 4). In contrast, ASC-ALS achieved significantly longer, rejection-free VCA survival in 6/7 animals (86%), with persistent mixed donor-cell chimerism, and elevated systemic and allograft skin T-regs, with no signs of acute cellular rejection. Taken together, a regimen comprised of short-course tacrolimus, repeated CTLA4-Ig and ASC administration, combined with ALS, promotes long-term VCA survival without chronic immunosuppression.
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