Cyclosporine Nanomicelle Eye Drop: A Novel Medication for Corneal Graft Transplantation Treatment

Abstract

Corneal transplantation has been used to treat severe eye disease for decades, but the therapeutic effect of the operation is highly compromised by immunological allograft rejection. To improve the success rate of corneal transplantation, we studied the protective effects of cyclosporine nanomicelle eye drops (CNED) on immune rejection after high-risk corneal transplantation and its underlying mechanisms. The therapeutic effects against immune rejection of both conventional cyclosporine eye drop (CCED) and CNED in different concentrations were assessed and compared using animal models of corneal transplantation. In addition, the expression of nuclear factor-κ-gene binding (NF-κB) as well as its target intracellular adhesion molecule 1 (ICAM-1) in the corneal samples obtained from recipients treated with either CCED or CNED was also screened. The results showed that the CNED displayed significantly better effects at suppressing the immune response induced by corneal transplantation compared to CCED. CNED also significantly down-regulated the NF-κB and ICAM-1 expressions, indicating NF-κB might play an important role in the initiation of an immune response against the allograft. Our study demonstrates CNED may suppress the NF-κB pathway to attenuate the immune response, which highlights the possible therapeutic applications of cyclosporine nanomicelle eye drops in corneal transplantation. Key words cyclosporine; nuclear factor-κ-gene binding (NF-κB); corneal allograft transplantation; intracellular adhesion molecule 1 (ICAM-1)Corneal transplantation is the most successful form of solid tissue grafting that serves as a crucial therapy in treating blindness clinically.1) Immunological allograft rejection is considered to be the leading cause of corneal graft failure. Though the 5-year survival rate of low-risk keratoplasty is approximately 90%, the survival rate of high-risk keratoplasty remains below 50% due to immune-mediated rejection even with maximal local immune suppression.2) The high-risk allograft host is characterized by vascularized and inflamed recipient beds, and the pre-existing corneal blood and lymphatic vessels in recipient beds were identified as the primary risk factors for immunological allograft rejection.3) Blood vessels circulates nutrients, oxygen and cells in blood vasculature while lymphatic vessels deliver antigenic materials and donor-derived antigen-presenting cells to the lymph nodes, subsequently inducing immune response against the corneal transplant. 4)Pharmacotherapy for corneal allograft rejection has considerably reduced the rate of graft failure. However, the therapeutic strategy based on corticosteroids remains unimproved over the past decades.5) Multiple side effects of corticosteroids have been observed including cataracts, glaucoma and opportunistic infections, and the EC 50 of the drug varies in either the prevention or the treatment of allograft rejection. 6) Considering the high failure rate of transplantation and the low efficiency of current treatment strategy, the devel...

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

“…Corneal allograft rejection is a complex procedure predominantly mediated by T cells and regulated by numerous cytokines. CsA could reduce the secretion of various lymphokines, including IL-2, through down-regulating the translocation of the nuclear factor of activated T cells (NFAT) [ 39 – 41 ]. The increased level of IL-2 in the aqueous humor might be responsible for the induction of immune reaction [ 42 ].…”

Implantable Immunosuppressant Delivery to Prevent Rejection in Transplantation

“…In a transplantation study, Kuppan et al optimized the dose of an immunosuppressant that attenuated naïve T cell proliferation and differentiation through CD28 costimulation [54] (dexamethason (Dex)) released with the micelles delivery system in the islet allograft. Nanosized micelles have also been reported to be applied in cornea transplantation, with good cytoprotective capacity and safety profile [55][56][57].…”

Unexplained Bilateral Simultaneous Corneal Graft Rejection in a Healthy 18-Year-Old Male

“…In patients who are steroid responders, increased intraocular pressure can further complicate the treatment of acute endothelial graft rejection, and shifting to less potent steroid drops, or those with less propensity toward increased intraocular pressure may be necessary. Few reports even suggested the use of various concentrations of topical cyclosporine-A drops as a safe substitute to topical steroids in the treatment and prevention of corneal graft rejection, with good results [11][12][13].…”