Prolonging Survival of Corneal Transplantation by Selective Sphingosine-1-Phosphate Receptor 1 Agonist

Abstract

Corneal transplantation is the most used therapy for eye disorders. Although the cornea is somewhat an immune privileged organ, immune rejection is still the major problem that reduces the success rate. Therefore, effective chemical drugs that regulate immunoreactions are needed to improve the outcome of corneal transplantations. Here, a sphingosine-1-phosphate receptor 1 (S1P1) selective agonist was systematically evaluated in mouse allogeneic corneal transplantation and compared with the commonly used immunosuppressive agents. Compared with CsA and the non-selective sphingosine 1-phosphate (S1P) receptor agonist FTY720, the S1P1 selective agonist can prolong the survival corneal transplantation for more than 30 days with a low immune response. More importantly, the optimal dose of the S1P1 selective agonist was much less than non-selective S1P receptor agonist FTY720, which would reduce the dose-dependent toxicity in drug application. Then we analyzed the mechanisms of the selected S1P1 selective agonist on the immunosuppression. The results shown that the S1P1 selective agonist could regulate the distribution of the immune cells with less CD4+ T cells and enhanced Treg cells in the allograft, moreover the expression of anti-inflammatory cytokines TGF-β1 and IL-10 unregulated which can reduce the immunoreactions. These findings suggest that S1P1 selective agonist may be a more appropriate immunosuppressive compound to effectively prolong mouse allogeneic corneal grafts survival.

FTY720-induced enhancement of autophagy protects cells from FTY720 cytotoxicity in colorectal cancer

“…Recently, investigations based on activating PP2A activity pharmacologically in cancer have been highlighted (7). FTY720, also known as fingolimod, is an immunomodulator most widely used in multiple sclerosis and multiple organ transplantation (8)(9)(10). Structurally similar to sphingosine, it is a PP2A activator (11).…”

Pleiotropic FTY720 Is a Specific and Potent Therapy for Hypertrophic Scars

“…FTY720, a well-documented immunosuppressive agent, is associated with a variety of biological activities, including anti-allograft rejection (Gao et al, 2014;Koch et al, 2016), anticancer (Estrada-Bernal et al, 2012;Lu et al, 2014), anti-inflammation (Aktas et al, 2010;Xu et al, 2014), and antifibrosis (Kramer et al, 2009;Ni et al, 2013). These activities were achieved through the alteration of multiple cell phenotypes, such as viability, proliferation, apoptosis, migration/invasion, and/or epithelial mesenchymal transition, depending on specific disease conditions (Bohler et al, 2009;Lu et al, 2014;Wolf et al, 2009;Zhang et al, 2010;Zhang et al, 2014;Zhang L et al, 2015).…”

“…In 2010, the US Food and Drug Administration approved the use of FTY720 for treatment of multiple sclerosis (Brinkmann et al, 2010). By activating multiple sphingosine-1ephosphate (S1P) receptors (S1PRs), FTY720 effectively inhibits the infiltration of T lymphocytes, prolonging allograft survival (Gao et al, 2014;Koch et al, 2016). FTY720 also induces apoptosis in multiple cancer cell lines (Chen et al, 2014;Estrada-Bernal et al, 2012;Lu et al, 2014;Marvaso et al, 2014;Zhang et al, 2010), showing promise as an anticancer therapy.…”

Fingolimod Suppresses a Cascade of Core Vicious Cycle in Dry Eye NOD Mouse Model: Involvement of Sphingosine-1-Phosphate Receptors in Infiltrating Leukocytes

“…14,15 Recently, fingolimod was also reported to be efficacious in treating autoimmune uveitis and prolonging corneal graft survival. 13,16 In our previous study, we showed that fingolimod inhibits DED-related inflammation in the NOD mouse model. In that study, we observed that the inflammation in ocular surface was greatly ameliorated by fingolimod, and the densities and functions of goblet cells and conjunctival epithelial cells were markedly normalized.…”

“…Fingolimod is an immunomodulating prodrug; it is used in attenuating multiple sclerosis, prolonging survival of organ allograft, and suppressing autoimmune diseases. [11][12][13] Its mechanism of action is considered to be mediated by the internalization of sphingosine-1-phosphate receptors Copyright 2017 The Authors iovs.arvojournals.org j ISSN: 1552-5783 (S1PRs). 14,15 Recently, fingolimod was also reported to be efficacious in treating autoimmune uveitis and prolonging corneal graft survival.…”