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Adipose-derived Stromal Cell Therapy Combined with a Short Course Non-Myeloablative Conditioning Promotes Long-term Graft Tolerance in Vascularized Composite Allotransplantation


Schweizer, Riccardo; Taddeo, Adriano; Waldner, Matthias; Klein, Holger J; Fuchs, Nina; Kamat, Pranitha; Targosinski, Stefan; Barth, André A; Drach, Mathias C; Gorantla, Vijay S; Cinelli, Paolo; Plock, Jan A (2020). Adipose-derived Stromal Cell Therapy Combined with a Short Course Non-Myeloablative Conditioning Promotes Long-term Graft Tolerance in Vascularized Composite Allotransplantation. American Journal of Transplantation, 20(5):1272-1284.

Abstract

The risks of chronic immunosuppression limit the utility of vascularized composite allotransplantation (VCA) as reconstructive option in complex tissue defects. We evaluated a novel, clinically translatable, radiation-free conditioning protocol that combines anti-lymphocyte serum (ALS), tacrolimus and 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 (0.5mg/kg) for 14 days and were assigned to four groups: CTRL received no conditioning; ASC-group received CTLA4-Ig (10mg/kg BW s.c. POD 2, 4, 7) and donor ASCs (1x10^6 iv, POD 2, 4, 7, 15, 28); ASC-CYP-group received CTLA4-Ig, ASC plus cyclophosphamide (50mg/kg i.p., POD 3); ASC-ALS-group received CTLA4-Ig, ASCs plus ALS (500µL i.p., 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.

Abstract

The risks of chronic immunosuppression limit the utility of vascularized composite allotransplantation (VCA) as reconstructive option in complex tissue defects. We evaluated a novel, clinically translatable, radiation-free conditioning protocol that combines anti-lymphocyte serum (ALS), tacrolimus and 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 (0.5mg/kg) for 14 days and were assigned to four groups: CTRL received no conditioning; ASC-group received CTLA4-Ig (10mg/kg BW s.c. POD 2, 4, 7) and donor ASCs (1x10^6 iv, POD 2, 4, 7, 15, 28); ASC-CYP-group received CTLA4-Ig, ASC plus cyclophosphamide (50mg/kg i.p., POD 3); ASC-ALS-group received CTLA4-Ig, ASCs plus ALS (500µL i.p., 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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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Department of Trauma Surgery
04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
04 Faculty of Medicine > University Hospital Zurich > Clinic for Reconstructive Surgery
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Immunology and Allergy
Health Sciences > Transplantation
Health Sciences > Pharmacology (medical)
Language:English
Date:1 May 2020
Deposited On:09 Jan 2020 10:08
Last Modified:29 Jul 2020 12:16
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:1600-6135
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1111/ajt.15726
PubMed ID:31774619

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