Rapamycin Nano-Micelle Ophthalmic Solution Reduces Corneal Allograft Rejection by Potentiating Myeloid-Derived Suppressor Cells' Function.
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.
['Wei|Chao|C|', 'Wang|Yuexin|Y|', 'Ma|Li|L|', 'Wang|Xin|X|', 'Chi|Hao|H|', 'Zhang|Sai|S|', 'Liu|Ting|T|', 'Li|Zhiyuan|Z|', 'Xiang|Demeng|D|', 'Dong|Yanling|Y|', 'Wu|Xianggen|X|', 'Shi|Weiyun|W|', 'Gao|Hua|H|']
D064591:Allografts D000818:Animals D001119:Arginase D016039:Corneal Transplantation D005123:Eye D006084:Graft Rejection D007166:Immunosuppressive Agents D015948:Keratoplasty, Penetrating D008297:Male D008807:Mice, Inbred BALB C D008810:Mice, Inbred C57BL D008823:Micelles D000072737:Myeloid-Derived Suppressor Cells D053758:Nanoparticles D052247:Nitric Oxide Synthase Type II D009883:Ophthalmic Solutions D011817:Rabbits D020123:Sirolimus
rapamycin corneal allograft rejection myeloid-derived suppressor cells immunosuppression iNOS Arg-1