Topical application of sphingosine 1-phosphate receptor 1 prolongs corneal graft survival in mice

Abstract

The present study aimed to investigate the effects of topical application of sphingosine 1‑phosphate receptor 1 (S1P1) on allogeneic corneal transplantation in mice. A total of 45 BALB/c mice received corneal grafts from C57BL/6 donors. The recipients were randomly divided into three groups and treated with eye drops containing 0.5% S1P1, 1% cyclosporine A or saline as a negative control. The serum levels of interleukin (IL)‑2, IL‑10, tumor growth factor (TGF)‑β1 and interferon (IFN)‑γ were measured by ELISA. The numbers of CD4+ T cell and T‑regulatory (Treg) cell phenotypes were measured by flow cytometry. The cytokine mRNA expression was analyzed by quantitative polymerase chain reaction. The results demonstrated that corneal graft survival was prolonged in the S1P1 group [mean survival time (MST), 24.11±1.58 days], and 1% cyclosporine A (MST, 25.0±1.91 days) compared with the controls (MST, 13.44±0.48 days; P<0.01). S1P1 and cyclosporine A decreased CD4+ T‑cell levels (P<0.05) in the peripheral blood compared with those of the controls. However, an increase of CD4+ T cells in the spleen was noted in the S1P1 group (P<0.05) and Treg cells were also increased in the cervical lymph nodes in the S1P1 group (P<0.01). TGF‑β1 mRNA transcription in the corneal grafts increased following treatment with S1P1 (P<0.05) and TGF‑β1 in the serum following treatment with S1P1 also increased (P<0.01). In conclusion, S1P1 had a significant effect in corneal allograft rejection inhibition.

Sphingosine-1-Phosphate Signaling in Immune Cells and Inflammation: Roles and Therapeutic Potential

“…Topical application of FTY720 increases the percentage of CD4 + T cells and T reg in cervical LN, increases TGF- β 1 mRNA expression, and decreases infiltration of CD4 + T cells in corneal allografts [ 117 ]. Corneal graft survival is prolonged by topical application of S1PR1, and S1PR1 selective agonist may be effective in the inhibition of corneal allograft rejection [ 118 , 119 ].…”

Lymphangiogenesis Guidance Mechanisms and Therapeutic Implications in Pathological States of the Cornea

“…S1PR1 has been found to be expressed in human corneal fibroblasts [137], suggesting that the cornea could be used as a model for further studies of guidance by S1PR1. Application of topical S1PR1 was found to increase the duration of corneal graft survival following transplantation, but the underlying effect on LEC guidance in the cornea during this inflammatory state has yet to be understood [74].…”

Therapeutic approaches for induction of tolerance and immune quiescence in corneal allotransplantation

“…Therapeutic modalities targeting sphingosine 1-phosphate receptor 1 (S1P1), the cell receptor involved in sequestration of lymphocytes in lymphoid tissues, have also yielded promising results. Topical and systemic treatment with S1P1 receptor both lead to retention of CD4 + T cells in peripheral lymphoid tissues and decrease the frequencies of these cells in the blood (95, 96). Systemic combination therapy with S1P1 receptor agonist and cyclosporine/rapamycin, and topical combination therapy with S1P receptor agonist and cyclosporine have both been associated with prolonged corneal allograft survival in mice (95, 96).…”

“…Topical and systemic treatment with S1P1 receptor both lead to retention of CD4 + T cells in peripheral lymphoid tissues and decrease the frequencies of these cells in the blood (95, 96). Systemic combination therapy with S1P1 receptor agonist and cyclosporine/rapamycin, and topical combination therapy with S1P receptor agonist and cyclosporine have both been associated with prolonged corneal allograft survival in mice (95, 96). Thus, strategies that inhibit Th1 and Th17 cells, either through inducing apoptosis or via inhibiting their migration to graft site, can potentially induce long-term allograft acceptance.…”