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Delayed and short course of rapamycin prevents organ rejection after allogeneic liver transplantation in rats

World Journal of Gastroenterology 2017年第38期23卷 6962-6972页

作者： Salim Hamdani Allan Thiolat Sina Naserian Cynthia Grondin Stéphane Moutereau Anne Hulin Julien Calderaro Philippe Grimbert JoséLaurent Cohen Daniel Azoulay caroline pilon Université Paris-Est AP-HP Laboratoire de Biochimie Groupe Hospitalier Henri-Mondor Albert-Chenevier AP-HP Laboratoire de Pharmacologie-Toxicologie Biologiques Groupe Hospitalier Henri-Mondor Albert-Chenevier AP-HP Anatomie et Cytologie Pathologique Groupe Hospitalier Henri-Mondor Albert-Chenevier APHP Service de Chirurgie HPB et Trans-plantation Hépatique Groupe Hospitalier Henri-Mondor Albert-Chenevier Department of Hepato-Pancreato-Biliary Surgery and Liver Transplantation Henri Mondor Hospital

AIMTo test whether a delayed and short course of rapamycin would induce immunosuppressive effects following allogeneic orthotopic liver transplantation (OLT) in *** OLTs were performed using Dark Agouti livers transplanted into Lewis recipients, and syngeneic OLTs were performed using the Lewis rat strain. Rapamycin (1 mg/kg per day) was administered by gavage from day 4 to day 11 post-transplantation. Lymphocyte cellular compartments were analyzed by flow cytometry in draining lymph nodes, non-draining lymph nodes and the spleen at days 11 and 42 in rapamycin-treated rats, untreated control rats and syngeneic grafted rats. Skin grafts from Dark agouti or from F344 RT were performed at day 30 on liver grafted rats treated with *** 8-d course of rapamycin treatment initiated 4 d following transplantation resulted in the survival of grafted rats for more than 100 d. In contrast, untreated rats died of liver failure within 13 to 21 d. The analysis of the cellular compartment revealed an increase in two cellular subpopulations, specifically myeloid-derived suppressor cells (MDSCs) and CD8+CD45RClow T cells, without major modifications in the regulatory T cell (Treg) compartment in treated rats in the early stages after grafting. We evaluated the ability of treated rats to reject third-party allogeneic skin grafts to confirm their immune competence. In contrast, when skin was collected from rats syngeneic to the grafted liver, it was not *** results demonstrate that short and delayed rapamycin treatment allows for tolerance in allogeneic OLT. The results also allowed for the identification of the mechanisms of tolerance induced by rapamycin by identifying MDSCs and CD8+CD45RClow T cells as associated with the state of tolerance.

关键词： Myeloid-derived suppressor cells Liver transplantation Rapamycin Regulatory T cells

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