Cyclosporine a drug-delivery system for high-risk penetrating keratoplasty: Stabilizing the intraocular immune microenvironment.

Ting Zhang,Chao Wei,Zhiyuan Li,Suxia Li,Hua Gao,Ting Liu,Weiyun Shi,Alain Haziot

doi:10.1371/journal.pone.0196571

Ting Zhang, Chao Wei + Show 6 more

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https://doi.org/10.1371/journal.pone.0196571

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Abstract

Cyclosporine A (CsA) is an essential medication used to prevent corneal allograft rejection. Our preliminary studies revealed that CsA drug-delivery system (DDS) was more effective in preventing high-risk corneal allograft rejection than topical CsA application. However, the impacts of CsA DDS on the intraocular immune microenvironment were not fully elucidated. In the present study, we investigated the effect of CsA DDS on the cornea allograft, aqueous humor, and iris-ciliary body using a rabbit model of high-risk penetrating keratoplasty. New Zealand white rabbits were divided into four groups: a normal control group, an untreated group, a CsA eye drop group and a CsA DDS group. Graft survival was monitored for 12 weeks, and the therapeutic effects of CsA DDS were evaluated at 3 and 12 weeks after high-risk keratoplasty. In the CsA DDS group, the mean graft survival time was significantly prolonged when compared with the untreated and CsA eye drop groups. At all time-points, Langerhans cell density, inflammatory cell density, and central corneal thickness in the CsA DDS group were much lower(all p < 0.01) than the untreated and CsA eye drop groups, in which their parameters were significantly higher than the normal control group (all p < 0.01). Compared with the untreated and CsA eye drop groups, an implanted CsA DDS markedly decreased the CD11b+ and CD8+ T cell infiltration in the corneal grafts. CsA DDS treatment also greatly reduced the CD4+ T cell density and the expression of interferon-gamma, interleukin-2 (IL-2), IL-6, CD80, and CD86 mRNA both in the corneal graft and iris-ciliary body (all p < 0.01). Moreover, CsA DDS significantly reduced the IL-2 level in aqueous humor (p < 0.01). Taken together, our results suggest that CsA DDS implanted into the anterior chamber create a relative immunosuppressive microenvironment in the corneal graft, iris-ciliary body, and aqueous humor. Stabilizing the intraocular immune microenvironment could partially elucidate the mechanism of CsA DDS in suppressing corneal graft rejection.

Highlights

Immunological allograft rejection is considered the leading cause of corneal graft failure [1, 2]
The corneal allografts treated with Cyclosporine A (CsA) drug-delivery system (DDS) remained transparent for more than 12 weeks, with less neovasculature extending into the grafts
Compared with the untreated and CsA eye drop treated grafts, cyclosporine A drug-delivery system (CsA DDS) treatment gained a lower central corneal thickness (CCT), and there was no difference in CCT between the normal control and CsA DDS groups at all time-points (Fig 2)

Summary

Introduction

Immunological allograft rejection is considered the leading cause of corneal graft failure [1, 2]. The exact mechanisms leading to graft rejection have not been fully understood. Recent studies have shown that the presence of immunosuppressive molecules in aqueous humor, such as transforming growth factor-2 and soluble Fas ligand, together with the immunomodulatory features of the iris-ciliary body pigment epithelium, constitute the immuneprivileged property of anterior chamber [5, 6]. The intraocular immunosuppressive climate might influence the development of immune reaction and the long-term graft survival. More attention should be paid to the anterior chamber microenvironment for a better understanding of corneal graft immune rejection

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