Université Paris-Est, UMR_S955, UPEC, Inserm, U955, Equipe 21, F-94000 Créteil, France.
AP-HP, Laboratoire de Biochimie, Groupe Hospitalier Henri-Mondor Albert-Chenevier, F-94000 Créteil, France.
World J Gastroenterol. 2017 Oct 14;23(38):6962-6972. doi: 10.3748/wjg.v23.i38.6962.
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 CD8CD45RC 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 CD8CD45RC T cells as associated with the state of tolerance.
检测雷帕霉素延迟短期给药方案对大鼠同种异体原位肝移植（OLT）后免疫抑制的影响。
采用 Dark Agouti 肝脏移植至 Lewis 受体大鼠的方法构建同种异体 OLT 模型，Lewis 大鼠肝脏移植至同系大鼠的方法构建同种异体 OLT 模型。雷帕霉素（1mg/kg/d）于移植后第 4 天至第 11 天灌胃给药。于雷帕霉素处理组、未处理对照组和同系移植组大鼠移植后第 11 天和第 42 天，通过流式细胞术分析引流淋巴结、非引流淋巴结和脾脏中的淋巴细胞亚群。于肝移植后第 30 天对雷帕霉素处理的大鼠进行 Dark Agouti 或 F344 RT 皮肤移植。
肝移植后第 4 天开始 8 天的雷帕霉素治疗方案可使移植物大鼠的存活时间超过 100 天。相比之下，未处理的大鼠在 13 至 21 天内死于肝衰竭。细胞亚群分析显示，在移植后早期，治疗组大鼠的髓系来源抑制细胞（MDSCs）和 CD8CD45RC T 细胞两个细胞亚群增加，而调节性 T 细胞（Treg）亚群无明显改变。我们评估了治疗大鼠排斥第三方同种异体皮肤移植物的能力，以确认其免疫能力。相比之下，当取自与移植肝脏同系的大鼠的皮肤时，它不会被排斥。
我们的结果表明，短期和延迟的雷帕霉素治疗可诱导大鼠同种异体 OLT 耐受。研究结果还通过鉴定 MDSCs 和 CD8CD45RC T 细胞与耐受状态相关，确定了雷帕霉素诱导耐受的机制。
