Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 14, 2017; 23(38): 6962-6972
Published online Oct 14, 2017. doi: 10.3748/wjg.v23.i38.6962
Delayed and short course of rapamycin prevents organ rejection after allogeneic liver transplantation in rats
Salim Hamdani, Allan Thiolat, Sina Naserian, Cynthia Grondin, Stéphane Moutereau, Anne Hulin, Julien Calderaro, Philippe Grimbert, José Laurent Cohen, Daniel Azoulay, Caroline Pilon
Salim Hamdani, Allan Thiolat, Sina Naserian, Cynthia Grondin, Université Paris-Est, UMR_S955, UPEC, Inserm, U955, Equipe 21, F-94000 Créteil, France
Stéphane Moutereau, AP-HP, Laboratoire de Biochimie, Groupe Hospitalier Henri-Mondor Albert-Chenevier, F-94000 Créteil, France
Anne Hulin, AP-HP, Laboratoire de Pharmacologie-Toxicologie Biologiques, Groupe Hospitalier Henri-Mondor Albert-Chenevier, F-94000 Créteil, France
Julien Calderaro, AP-HP, Anatomie et Cytologie Pathologique, Groupe Hospitalier Henri-Mondor Albert-Chenevier, F-94000 Créteil, France
Philippe Grimbert, José Laurent Cohen, Caroline Pilon, Université Paris-Est, UMR_S955, UPEC, Inserm, U955, Equipe 21, APHP, Inserm, CIC Biothérapie, Groupe Hospitalier Henri-Mondor Albert-Chenevier, F-94000 Créteil, France
Daniel Azoulay, APHP, Service de Chirurgie HPB et Transplantation Hépatique, Groupe Hospitalier Henri-Mondor Albert-Chenevier, F-94000 Créteil, France
Daniel Azoulay, Department of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Henri Mondor Hospital, 94010 Créteil, France
Author contributions: Cohen JL, Azoulay D and Pilon C designed the research study; Hamdani S, Grondin C, Moutreau S, Hulin A and Calderaro J performed the research; Hamdani S, Cohen JL, Azoulay D and Pilon C wrote the paper; all authors analyzed the data.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Regional Ethics Committee in Animal experimentation no16, Ile de France, France (authorization no.11/12/12-10B).
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Daniel Azoulay, Professor, Department of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Henri Mondor Hospital, 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France. daniel.azoulay@aphp.fr
Telephone: +33-1-49812548 Fax: +33-1-498124 32
Received: February 28, 2017
Peer-review started: March 3, 2017
First decision: March16, 2017
Revised: April 6, 2017
Accepted: June 1, 2017
Article in press: June 1, 2017
Published online: October 14, 2017
Processing time: 229 Days and 7.6 Hours
Abstract
AIM

To test whether a delayed and short course of rapamycin would induce immunosuppressive effects following allogeneic orthotopic liver transplantation (OLT) in rats.

METHODS

Allogeneic 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 rapamycin.

RESULTS

An 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 rejected.

CONCLUSION

Our 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.

Keywords: Myeloid-derived suppressor cells; Liver transplantation; Rapamycin; Regulatory T cells

Core tip: Rapamycin is an immunosuppressive drug that is rarely used for liver transplantation treatment due to its side effects. Here, we show that a delayed and short course of rapamycin initiated on day 4 following allogeneic orthotopic liver transplantation in rats resulted in the survival of grafted rats for more than 100 d. The analysis of the cellular compartment revealed an increase in two cellular subpopulations, specifically myeloid-derived suppressor cells and CD8+CD45RClow T cells. The treated liver grafted-rats rejected third-party allogeneic skin grafts, but tolerated skin from syngeneic liver donor rats. Our results identify one of the mechanisms by which the state of tolerance is established.