Immunomodulatory effects of mesenchymal stem cells in a rat corneal allograft rejection model

Abstract

Mesenchymal stem cells (MSCs) are promising candidates for immunomodulatory therapy that are currently being tested in several organ transplant rejection models. In this study, we tested the immunomodulatory effects of MSC injection in a rat model of corneal allograft rejection. MSCs were isolated and cultured from bone marrow of Wistar rats. A rat corneal allograft rejection model was established using Wistar rats as donors and Lewis rats as recipients. Lewis rats were randomly separated into 12 groups and treated with MSCs alone or MSCs combined with Cyclosporin A (CsA) at different doses. In MSC-treated rats, the T cell response to ConA was evaluated, Th1/Th2 cytokines produced by T lymphocytes were measured, and the number of CD4+CD25+Foxp3+ regulatory T cells (Treg) was assessed. Results demonstrated that postoperative injection of MSCs prolonged graft survival time. MSCs significantly inhibited proliferation of pathogenic T cells in vitro and prevented T cell response in vivo (p < 0.05). Postoperative injection also reduced Th1 pro-inflammatory cytokines and elevated IL-4 cytokine secretion from T lymphocytes derived from cornea-transplanted rats. In addition, Tregs were upregulated by MSC treatment. Unexpectedly, the application of MSCs combined with low dose CsA therapy (1 mg/kg) accelerated graft rejection compared with postoperative MSC therapy alone. However, when 2 mg/kg CsA was given together with MSCs, graft survival was significantly prolonged. These results suggested that MSCs could exert therapeutic effect against corneal allograft rejection, and further investigation of combined MSC and CsA treatment be required as opposite effects were observed depending on CsA dose.