Published online Oct 14, 2017. doi: 10.3748/wjg.v23.i38.6962
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
To test whether a delayed and short course of rapamycin would induce immunosuppressive effects following allogeneic orthotopic liver transplantation (OLT) in rats.
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.
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.
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.
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.