All-trans retinoid acid promotes allogeneic corneal graft survival in mice by regulating Treg-Th17 balance in the presence of TGF-β

Abstract

BackgroundAll-trans retinoid acid (ATRA) has been proven to skew Regulatory T cell-T helper 17 cell (Treg-Th17) balance toward Treg in vitro, favoring graft acceptance. However, its in vivo effect after solid organ transplantation is under investigation.ResultsBALB/c mice were given orthotopic corneal grafts from C57BL/6 donors, and recipient mice were administered with ATRA, TGF-β, and the combination of both agents for 8 weeks after surgery. We found that a mixed treatment of ATRA and TGF-β significantly promoted graft survival. Moreover, with the presence of TGF-β, ATRA upregulated CD4+CD25+Foxp3+Treg cells and suppressed Th17 cells in the blood, spleen and draining lymph nodes of recipient mice, as well as enhanced the Foxp3 expression and inhibited the RORγt expression in grafts and peripheral blood mononuclear cells (PBMCs). Simultaneously, increased number of Foxp3+ cells and decreased number of IL-17+ cells in conjunctiva were found in recipients with mixed treatment, along with reduced IL-17 level in serum and aqueous humor and increased IL-10 level in aqueous humor. Tregs isolated from recipient mice treated with ATRA + TGF-β presented the strongest suppressive activity in vitro.ConclusionsCombined application of ATRA and TGF-β may shift the Th17-Treg balance toward Tregs, hence facilitating the induction of immunological tolerance after allogenic corneal transplantation and representing a potential therapeutic approach in the treatment of posttransplant rejection.Electronic supplementary materialThe online version of this article (doi:10.1186/s12865-015-0082-3) contains supplementary material, which is available to authorized users.

Evidence of the immunomodulatory role of dual PI3K/mTOR inhibitors in transplantation: an experimental study in mice

“…Indeed, all in vivo drug treatments reduced the susceptibility of CD4 + T‐cells to differentiate toward a pro‐inflammatory TH17 effector phenotype. These results are in line with the growing body of literature recognizing the involvement of effector TH17 cells in transplant rejection . We have noted substantial differences on the effects promoted by PI‐103 in vitro and in vivo , which may be attributed to the rapid plasma and tissue clearance exhibited by this compound .…”

Expression of CD4+CD25+Foxp3+ Regulatory T Cells, Interleukin 10 and Transforming Growth Factor β in Newly Diagnosed Type 2 Diabetic Patients

“…In addition, Tregs had a substantial connection with TGF-β in our study. Foxp3 + Tregs can polarize macrophages to an anti-inflammatory phenotype that might be mediated by TGF-β [23], as it could upregulate CD4 + CD25 + Foxp3 + Tregs, suppress Th17 cells in the blood, spleen and drain lymph nodes of recipient mice, and enhance Foxp3 expression in grafts and peripheral blood mononuclear cells (PBMCs) [24]. While TGF-β can promote the differentiation of Foxp3 + CD4 + Tregs in vitro, blocking the TGF-β pathway with a specific TGF-β receptor inhibitor, somatomedins 16 (SM-16), reduced the percentage of Tregs in liver tissue [25].…”

Functional Impact of Collagens on the Activity Directed by the Promoter of theα5Integrin Subunit Gene in Corneal Epithelial Cells

“…92,94 Furthermore, both cytokines and growth factors have recently been shown to considerably improve immune tolerance after corneal transplantation. 95,96 Taken together, these results demonstrate that, along with FN, the changes occurring in the ECM's secretion of collagens have an impact on the pattern of genes that also comprises the a5 integrin subunit gene, which become deregulated in response to corneal wound healing. Further studies using pharmacologic inhibitors of key modulators from the major signal transduction pathways or blocking antibodies directed against the collagen-binding integrins expressed by HCECs will be needed to precisely determine which signal transduction cascades become activated when these cells are grown on either CI and CIV.…”