Rapamycin Nano-Micelle Ophthalmic Solution Reduces Corneal Allograft Rejection by Potentiating Myeloid-Derived Suppressor Cells' Function

Abstract

Allograft rejection is the major cause of corneal allograft failure. Rapamycin (RAPA) has been reported as an effective and novel immunosuppressive agent for patients undergoing corneal transplantation. However, its high water insolubility and low bioavailability have strongly constrained its clinical application. In this study, we successfully developed a RAPA nano-micelle ophthalmic solution and found that corneal allograft survival in recipients treated with RAPA nano-micelle ophthalmic solution was significantly prolonged for more than 2 months, with less inflammatory infiltration, decreased production of pro-inflammatory factors, and elevated recruitment of myeloid-derived suppressor cells (MDSCs). MDSCs from mice treated with RAPA nano-micelle ophthalmic solution could significantly inhibit the proliferation of CD4+T cells through increased expressions of inducible nitric oxidase (iNOS) and arginase-1 (Arg-1). The activity blockade of Arg-1 and iNOS pharmacologically reversed their immunosuppressive ability. Moreover, the effects of RAPA were antagonized by the administration of anti-Gr-1 antibody or by inhibiting the activity of iNOS pharmacologically. In addition, RAPA nano-micelle also effectively alleviated allograft rejection in high-risk rabbit penetrating keratoplasty (PKP) models with corneal vascularization. Collectively, our results demonstrate that RAPA nano-micelle ophthalmic solution could improve the immunosuppressive activity of MDSCs through elevated expression of Arg-1 and iNOS, which highlights the possible therapeutic applications of RAPA against corneal allograft rejection.

Myeloid-derived suppressor cells expand after transplantation and their augmentation increases graft survival

“…It is known that MDSCs facilitate immune control of alloreactive responses 13‐17 . Cancer studies show that MDSCs suppress anti‐tumor T cell responses through a number of mechanisms including inhibition of Arg‐1 and the production of nitric oxide (NO) 2,18‐20 . MDSCs also expand the Treg population via interactions with programmed death‐ligand 1 (PD‐L1) 21 .…”

Increased CD14+HLA-DR−/low Myeloid-Derived Suppressor Cells Correlate With Disease Severity in Systemic Lupus Erythematosus Patients in an iNOS-Dependent Manner

“…MDSCs can promote tumor metastasis and angiogenesis by inhibiting the immune response and T cell proliferation (4). Also, MDSCs express Gr-1 and CD11b surface molecular markers that are divided into two types: granulocytic and monocytic phenotypes (5, 6). Anti-Gr-1 monoclonal antibody contains two molecules, Ly6G and Ly6C.…”

Rapamycin-based graft-versus-host disease prophylaxis increases the immunosuppressivity of myeloid-derived suppressor cells without affecting T cells and anti-tumor cytotoxicity

“…As RAPA was recently identified to improve MDSC functions in autoimmunity and solid organ transplantation [9,10,12,13], we examined the effect of RAPA on the immunosuppressive potential of MDSCs induced in the context of allogeneic BMT. Therefore, splenic MDSCs (CD11b + Gr-1 + ) of RAPA-and PBS-treated recipient mice (H-2 b , CD45.2) were isolated 10 days after BMT and were co-cultured with CFSE-labeled B6.SJL-derived spleen cells (H-2 b , CD45.1) stimulated with irradiated allogeneic B6D2F1-derived spleen cells (H-2 bxd , CD45.2) in vitro.…”

“…De-novo differentiation of regulatory T cells (T regs ) in vivo and in vitro is supported by RAPA [4,7,8]. Recently, an activating effect of RAPA on the organ-specific recruitment, expansion and activation of myeloid-derived suppressor cells (MDSCs), a subset of immune suppressive cells of myeloid origin, was also reported [9][10][11][12][13], although few studies describe the requirement of mTOR activity for MDSC functionality [14][15][16][17].…”