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.
Highlights
All-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
The recipient mice treated with the combination of ATRA and TGF-β presented a graft acceptance rate of 82% at the end of the 8-week follow-up, which is significantly higher than those treated with ATRA alone (P = 0.042), TGF-β alone (P = 0.023) and a control solution (P = 0.008)
A mixed treatment of ATRA and TGF-β upregulates CD4+CD25+Foxp3+Treg cells in recipient mice The percentage of CD4+CD25+Foxp3+Treg cells in blood was significantly increased at 2wks in recipients treated with ATRA, TGF-β and the combination of both agents (P = 0.020, 0.039 and 0.040, respectively)
Summary
All-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. One of the leading causes of blindness in China [1], requires corneal transplantation to restore visual function in the majority of cases [2]. Immune privilege of corneal allografts endowed a higher success rate of corneal transplantation than other solid organ transplantation, immunological rejection is still the major cause of graft failure after penetrating keratoplasty [3,4]. CD4+CD25+Foxp3+Regulatory T cells (Treg), an important regulator in maintaining immune homeostasis, play a crucial role in protecting individuals from graft rejection [5]. These cells are considered an important target for generating tolerance to solid organ transplants. Treg and Th17 cells share a common requirement for TGF-β in their differentiation, despite expressing distinct transcriptional regulators (Foxp versus RORγt, respectively) and demonstrating opposing functions. The balance of Treg-Th17 axis and its shift toward the stabilization of Treg populations are one of the key points in maintaining graft tolerance
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