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Year : 2013  |  Volume : 1  |  Issue : 2  |  Page : 129-133

Immunosuppressive agents: Role in corneal graft rejection

Dr. Rajendra Prasad Center for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India

Date of Submission02-May-2013
Date of Acceptance02-May-2013
Date of Web Publication20-May-2013

Correspondence Address:
Rajesh Sinha
Associate Professor, Cornea, Lens, and Refractive Surgery Services, S-7, R. P. Center, AIIMS, New Delhi - 110 029
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Source of Support: None, Conflict of Interest: None

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How to cite this article:
Sinha R, Tinwala SI, Shekhar H, Titiyal JS. Immunosuppressive agents: Role in corneal graft rejection. J Clin Ophthalmol Res 2013;1:129-33

How to cite this URL:
Sinha R, Tinwala SI, Shekhar H, Titiyal JS. Immunosuppressive agents: Role in corneal graft rejection. J Clin Ophthalmol Res [serial online] 2013 [cited 2022 Jun 26];1:129-33. Available from: https://www.jcor.in/text.asp?2013/1/2/129/112187

Developments in corneal transplantation in recent decades, particularly with respect to endothelial and lamellar transplantation, have led to a significantly improved outlook for many patients. Although success in the first year approaches 90%, long-term survival is substantially lower, with only 60% of the corneal transplants remaining clear at 10 years. Although the cornea has always been hailed as an immunologically privileged site, this privilege can easily be eroded and is seldom sufficient alone in preventing allograft rejection, the most common cause of corneal transplant failure. The decision to immunosuppress a corneal transplant recipient depends on their predicted risk of graft rejection. The most common immunosuppressive in use is corticosteroid; however, immunomodulators like cyclosporine, tacrolimus, mycophenolate, and so on, are also used to prevent corneal graft rejection. In this article, we have tried to review the information present in the literature regarding the use of these drugs and their outcome.

  Corticosteroids Top


Banerjee et al
. (Expert Opin Investig Drugs 2003;12:29-37) showed that topically administered corticosteroids have a good ocular penetration and effective immunosuppression. Prednisolone acetate 1% has very good corneal penetration even through an intact epithelium.

Mayweg et al. (Ophthalmologe 2005;102:497-501) evaluated the efficacy of the sole application of topical steroids after normal-risk keratoplasty. Twenty patients were treated exclusively with prednisolone acetate 1% eye drops, five times per day for six months postoperatively. Another 20 patients additionally received systemic fluocortolone 1 mg / kg body weight per day, tapered within three weeks postoperatively. Three graft rejections were observed in the group receiving only topical steroids. Two graft rejections were observed in the group administered combined systemic and topical steroid therapy. None of the patients developed irreversible graft failure. It was concluded that the sole topical steroid application seemed to be an effective immune prophylaxis in patients undergoing penetrating normal-risk keratoplasty.

Reis et al. (Klin Monbl Augenheilkd 2008;225:57-61) prospectively randomized patients to receive either prednisolone acetate 1 % eye drops 5x / day, tapering off by one drop every month (n = 20), or to receive FK 506 eye drops 3x / day for six months (n = 20). The patients in both groups additionally received systemic steroids for three weeks (fluocortolone 1 mg / kg body weight). The primary endpoints were the number of immune reactions and the clear graft survival, the secondary endpoint was the number of side effects. Three immune reactions in the steroid group and one immune reaction in the FK 506 group were seen within the follow-up time of three years. No irreversible graft rejections occurred in either group. Eight patients in the FK 506 group concluded the study early, due to local side effects. In this long-term follow-up the use of FK 506 eye drops following corneal transplantation resulted in a lower number of immune reactions when compared to topical steroids.

Poon et al. (Clin Experiment Ophthalmol 2008;36:415-21) recruited 108 patients with acute endothelial graft rejection. They were randomized into two groups. The first group received intensive prednisolone acetate and placebo. The second group received intensive prednisolone acetate and Restasis. No significant difference was found between the two groups for time to reversal and resolution. Thus, use of commercially available CsA as an adjunct to topical steroids does not appear to improve the outcome of graft rejection.

Unal et al. (Br J Ophthalmol 2008;92:1411-4) evaluated the efficacy of a combined treatment with commercially available 0.05% topical cyclosporine and topical corticosteroid and compared it with treatment with only topical corticosteroids, after high-risk keratoplasty. Twenty-five eyes (group 1) were treated with 0.05% cyclosporine and dexamethasone 0.1%, and 22 eyes (group 2) were treated with dexamethasone only. Rejection-free graft survival rates were 60.8% in group 1 and 54.5% in group 2. In group 1, the graft survival rate was 73.9%; in group 2, the graft survival rate was 68.1%. The difference in the graft survival rates between the groups was also not statistically significant. It was concluded that the efficacy of the 0.05% commercially available topical cyclosporine combined with dexamethasone topically was not better than that of dexamethasone alone in preventing rejection.

Shimazaki et al. (Ophthalmology 2012;119:668-73) enrolled 42 patients who underwent PKP and maintained graft clarity for >1 year with topical steroid eye drops. The patients were randomly assigned to Groups 1 or 2: Administration of 0.1% fluorometholone three times a day (steroid group) or discontinuation of steroid eye drops (no-steroid group). All patients were followed for 12 months. One patient in the steroid group and six in the no-steroid group developed endothelial rejection at an average of 5.2 ± 4.5 months after study enrollment. Thus, prolonged use of 0.1% fluorometholone was beneficial for the prevention of rejection after PKP. As no adverse consequences were noted, it was recommended to continue the use of the low-dose corticosteroids, even in non-high-risk cases.

Intracameral / Intra-vitreal / Sub-conjunctival

Birnbaum et al.
(Ophthalmologe 2007;104:813-6) suggested that intracameral application of corticosteroids by means of an anterior chamber flush is an adjunctive measure that can stop the immune reaction immediately. This measure is thus recommended in all intermediate and severe endothelial rejections.

Maris et al. (Cornea 2008;27:847-50) reported intracameral injection of triamcinolone acetonide as treatment for therapy-resistant endothelial allograft rejection after PKP. Within two weeks of the injection, marked resolution of the microcystic edema and reversal of endothelial rejection was noted. Fourteen months after injection, the best-corrected visual acuity was 20 / 20, and intraocular pressure was 17 mm Hg, without antiglaucoma therapy.

Costa et al. (Eye 2009;23:708-14) assessed the safety and effectiveness of treating corneal endothelial rejection with a subconjunctival injection of 20 mg triamcinolone acetonide in combination with a topical application of 1% prednisolone acetate, as compared to treatment with an intravenous pulse of 500 mg methylprednisolone in combination with topical application of 1% prednisolone acetate. Overall, the triamcinolone group had a better outcome with regard to the reversion of corneal transplant rejection (p = 0.025), with 15 of the 16 patients in the triamcinolone group having clear grafts, compared to only 10 of 16 patients in the methylprednisolone group. The results observed in this case-controlled study suggest that the use of subconjunctival triamcinolone acetonide may benefit patients with corneal transplant rejection.

You et al. (Cornea 2012;31:1135-40) investigated the efficacy of intravitreal triamcinolone acetonide (IVTA) injection in the treatment of endothelial graft rejection. Eleven patients (11 eyes) with acute endothelial graft rejection underwent IVTA (4 mg / 0.1 mL) injection in addition to conventional treatment, including systemic and topical steroids and cyclosporine A (group A); 13 patients (13 eyes) received conventional treatment only (group B). It was seen that the IVTA injection was effective in reducing the time to improvement of endothelial graft rejection. Increased expression of CXCL-9, 10, and 11, and their receptors in the aqueous humor of patients with endothelial graft rejection decreased after treatment.

Safety profile

Gharaee et al
. (Ocul Immunol Inflamm 2011;19:284-5) reported a case of Staphylococcus epidermidis infection after subtenon injection (STI) of triamcinolone acetonide (TA) in a 20-year-old patient with corneal graft rejection, who received STI of TA after insufficient response to topical and oral corticosteroids. After conjunctival necrosis, necrotizing scleritis progressed, although topical and systemic steroids were discontinued. Systemic ciprofloxacin, topical fortified amikacin, and vancomycin drops were used. Complete recovery was obtained after three weeks. Thus, although uncommon, infectious scleritis can occur following uncomplicated subconjunctival corticosteroid injections.

Sandhu et al. (Eye 2012;26:699-702) studied whether hypothalmic-pituitary-adrenal axis suppression is possible secondary to long-term topical ophthalmic corticosteroid use in patients who have undergone penetrating keratoplasty. The mean duration treatment was 28.2 months (range 11 - 96 months). This study found no evidence that patients using continuous long-term corticosteroid eye drops after PKP experienced inadequate adrenal response.

  Cyclosporine A Top


Price et al
. (Ophthalmology 2006;113:1785-90) assessed the incidence of immunological corneal graft rejection episodes in a prospective case series of patients treated four times a day with topical cyclosporine 0.05%. Graft rejection episodes occurred earlier and with higher incidence in subjects using cyclosporine 0.05% compared to the historical control subjects, who used steroids for a longer period of time (p < 0.0001). The results suggest that four times daily dosing with topical cyclosporine 0.05% is not as effective as the use of topical prednisolone acetate 1% for prevention of graft rejection episodes in low-risk corneal transplants, and that periodic pulsing with corticosteroids may increase the risk of rejection episodes.

Bourges et al. (Mol Vis 2006 2;12:1461-6) assessed the efficacy of a topical cyclosporine A (CsA), water-soluble prodrug, for promoting the survival of allogenic rat corneal grafts after PKP. The transplanted rats were divided into three treatment groups: Group I (PBS) and group II (0.26% Debio088) received drops five times per day. Group III received a daily intramuscular CsA injection (10 mg / kg / day). It was seen that Debio088 CsA prodrug drops given five times daily are as effective as an intramuscular injection of 10 mg / kg / day for the prevention of acute corneal graft rejection in rats.

Sonmez et al. (Int Ophthalmol 2009;29:123-5) reported regression of corneal stromal neovascularizations with the use of topical cyclosporine 0.05% in a corneal transplant patient, performed for a fungal corneal ulcer. The neovascularizations totally regressed within two months and no signs of graft rejection were present at the six-month follow up.

Sinha et al. (Graefes Arch Clin Exp Ophthalmol 2010;248:1167-72) evaluated the efficacy and safety of topical cyclosporine A 2% in the prevention of graft rejection in high-risk keratoplasty. The study group (n = 39) received topical cyclosporine A 2% drops and the control group (n = 39) received polyvinyl alcohol 1.4% drops. In addition, both groups received corticosteroid eye drops after surgery. The mean duration after which the patients developed graft rejection after keratoplasty was 7.92 + / - 1.45 months and 6.50 + / - 2.72 months in the study and control group, respectively (p = 0.20). Six patients showed complete reversal of rejection in the study group and four patients showed reversal in the control group (p = 0.03). Topical cyclosporine A 2% eye drops do not prevent occurrence of graft rejection in high-risk keratoplasty. However, the eyes receiving topical cyclosporine stand a better chance of reversal of the episode of graft rejection.

Javadi et al. (Br J Ophthalmol 2010;94:1464-7) evaluated the efficacy of 2% topical cyclosporine A in treating and preventing graft rejection episodes after PKP, in patients with a history of graft rejection episodes. A group of PKP patients were randomly given 2% topical cyclosporine (group 1) or a placebo (group 2) in addition to a corticosteroid regimen upon an episode of subepithelial or endothelial graft rejection. The episode for which 2% topical cyclosporine or placebo was started completely resolved after 25.6 (21.0) days and 33.2 (16.7) days in groups 1 and 2, respectively (p = 0.22). The rejection-free graft survival rate was 34.8% in group 1 and 31.7% in group 2 at month 20 (p = 0.89). It was concluded that 2% topical cyclosporine A did not add any advantage to the conventional corticosteroid treatment in terms of treating and preventing graft rejection in PKP patients with a previous history of rejection episodes.

Other modes of delivery

Lee et al
. (Invest Ophthalmol Vis Sci 2007;48:2023-9) determined the short- and long-term pharmacokinetics and assessed the toxicity of a cyclosporine (CsA) episcleral implant for the prevention of high-risk keratoplasty rejection. In the short-term pharmacokinetic studies, the cornea had CsA concentrations of 0.15 ± 0.06, 0.07 ± 0.02, and 0.05 ± 0.02 μg / mg, at sites centered 8, 13, and 18 mm away from the implant site, respectively. In the long-term pharmacokinetic studies, corneal CsA levels ranged from 0.18 ± 0.06 to 0.009 ± 0.004 μg / mg during the one-year study. There were no signs of ocular toxicity at one year. Episcleral implants are safe and effective at delivering therapeutic CsA levels to the cornea to potentially prevent corneal allograft rejection. The implant can be surgically inserted at the time of penetrating keratoplasties, as the implant achieves therapeutic levels as early as three hours.

Anglade et al. (Expert Opin Investig Drugs 2007;16:1525-40) evaluated ISA-247 / LX-211, which is a rationally designed analog of cyclosporine A that exhibits more predictable pharmacokinetic and pharmacodynamic properties and a four-fold greater calcineurin inhibition than its parent compound, cyclosporine A. They suggested that an alternative approach to widening the therapeutic window for the therapy of ophthalmic disorders lies in the local delivery of CNIs through polymeric implants that release the drug over long periods of time.

Shimazaki et al. (Am J Ophthalmol 2011;152:33-9) elucidated the efficacy and safety of systemic cyclosporine (CsA) in high-risk corneal transplantation. They conducted a prospective, randomized, open-labeled clinical trial in high-risk keratoplasty patients. In the CsA group, CsA was discontinued within six months in seven patients because of side effects. With a mean follow-up of 42.7 months, endothelial rejection developed in six and two eyes in the CsA and control groups, respectively. No differences were observed in the rates of graft clarity loss between the two groups (p = .16). No positive effect of systemic CsA administration for suppressing rejection in high-risk corneal transplantation was observed.

  Tacrolimus and Everolimus Top

Topical and Systemic

Svozνlkova et al.
(Immunopharmacol Immunotoxicol 2006;28:335-40) compared the effectiveness of immunosuppressive drugs on the prevention of allograft rejection in murine models of low-risk and high-risk keratoplasty. The therapy included FK 506 (tacrolimus; 0.2 mg / kg), mycophenolate mofetil (30 mg / kg), aminoguanidine (0.1 g / kg), and combination of FK506 + mycophenolate mofetil or FK506 + aminoguanidine. The results obtained from the Gray's survival model, stratified according to the type of subjects, suggest that a major rejection risk reduction was achieved using FK506; good results were also obtained for mycophenolate mofetil. Although the point estimates of both the survival and relative risk of rejection suggest a deferred effect of the combination of FK506 + mycophenolate mofetil. This finding did not prove statistically significant.

Joseph et al. (Br J Ophthalmol 2007;91:51-5) evaluated systemic tacrolimus, a specific T-cell inhibitor, used at a mean daily dose of 2.5 mg, in 43 patients undergoing high-risk corneal transplantation. Immunosuppression was continued for a period of 18 - 24 months after the high-risk corneal graft. During a mean follow-up period of 33.7 months, the clarity of the graft was maintained in 65% of the patients. Eight patients experienced rejection episodes while on tacrolimus, and this led to graft failure in five patients. They concluded that tacrolimus was relatively safe and effective in reducing rejection and prolonging graft survival in patients with high-risk keratoplasty compared with the other series where similar immunosuppression was not used.

Dhaliwal et al. (Cornea 2008;27:488-93) evaluated the long-term efficacy and side effects of off-label topical tacrolimus 0.03% ointment as a sole second line immunosuppressive agent in the management of high-risk corneal grafts. Four high-risk corneal transplant patients experienced episodes of acute rejection, which were successfully reversed with topical tacrolimus treatment. During tacrolimus treatment, there were no further episodes of graft rejection and no incidents of herpes simplex virus infection or reactivation, with the longest follow-up being four years. No adverse effects were observed.

Yalηindag et al. (Ann Ophthalmol 2008;40:152-6) evaluated the efficacy and safety of tacrolimus in the prevention of allograft rejection in high-risk allo-limbal grafts. Six eyes of six patients with severe limbal stem cell deficiency were included. All patients were started on 0.1 mg x kg 1 x day (-1) tacrolimus, orally, three days before the surgery. Limbal allo-graft transplantation for ocular surface reconstruction had a successful outcome when using systemic tacrolimus for immunosuppression.

Baspinar et al. (J Ocul Pharmacol Ther 2008;24:399-402) determined the permeation rate of everolimus through freshly isolated pig cornea (ex vivo). Everolimus is a poorly soluble drug, and is therefore, incorporated in an eye-administrable microemulsion. The stability of this microemulsion containing 0.1% (1 mg / mL) of the drug was satisfying over a period of 12 months. A concentration of 8.64 ng / mL was already reached 30 minutes after administration of the microemulsion to the cornea. This everolimus-containing microemulsion is a promising ocular formulation for preventing corneal-graft rejection.

Li et al. (Ophthalmic Res 2008;40:309-14) investigated the efficacy of topically applied everolimus to prevent corneal graft rejection in an experimental model. A total of 45 female Lewis rats were randomly assigned to receive either: (1) 0.05% everolimus microemulsion, (2) 0.025% everolimus microemulsion or (3) a vehicle as the control. Treatment was started on the day of surgery and applied five times daily. Local administration of 0.05 or 0.025% everolimus was effective in prolonging the mean survival time of corneal grafts (MST = 21 ± 6.57 days and 16.4 ± 2.3 days, respectively) as compared to vehicle control group (MST = 13.3 ± 1.7 days; p < 0.001 and p < 0.001), suggesting that topically applied everolimus is effective in prolonging corneal allograft survival in an experimental keratoplasty model.

Nanospheric suspension and drug delivery system

Shi et al
. (Curr Eye Res 2005;30:969-76) evaluated the effects of a biodegradable FK506 drug delivery system (DDS) implanted into the anterior chamber for the prolongation of corneal allograft survival in high-risk keratoplasty. The mean graft survival time was the longest (> 180 days) in the FK506-PGLC DDS group. In vivo, the FK506 concentration in aqueous humor peaked on day 28 (17.9 + / - 2.3 ng / ml) and kept a sustained release for at least 168 days. No adverse reactions were observed in the FK506-PGLC DDS group. They concluded that Biodegradable FK506-PGLC DDS implanted into the anterior chamber can effectively prevent immune rejection in the high-risk keratoplasty model, presenting a promising approach for the prolongation of corneal allograft survival.

Fei et al. (J Ocul Pharmacol Ther 2008;24:235-44) investigated the effect of a topical FK506 nanospheric suspension in a rat model of penetrating keratoplasty. In the cornea, the FK-506 concentration reached its peak within one hour of a single eye-drop instillation and then decreased by half (1667.85 + / - 611.87 ng / g) at eight hours. FK-506 cannot be detected in rabbit blood. There were significant differences in the graft-survival time between the FK-506 nanosphere group (15.09 + / - 4.81 days) and the other three groups [PBS (7.90 + / - 1.20, t = -4.594, p < 0.001), PLGA (8.44 + / - 0.88, t = - 4.074, p = 0.001) and dexamethasone (10.44 + / - 1.42, t = -2.790, p = 0.012)]. Thus, FK506 0.01% nanospheric-suspension eye drops delayed the occurrence of corneal allograft rejection and prolonged allograft survival time.

  Mycophenolate Mofetil Top

Birnbaum et al . (Transplantation 2005;79:964-8) analyzed the long-term results of 417 high-risk keratoplasties with systemic immunosuppression (cyclosporine A [CsA] or mycophenolate mofetil [MMF]). Rejection-free graft survival after one year was 75% in the CsA group and 89% in the MMF group; 60% of the grafts in the CsA group and 72% of the grafts in the MMF group were rejection-free three years postoperatively (Kaplan-Meier log-rank test p = 0.03). Clear graft survival after one and three years was 92 and 77% CsA and 96 and 87% MMF, respectively. The MMF-treated patients showed fewer side effects than the CsA-treated patients. The side effects attributable to both drugs were reversible.

Birnbaum et al. (Eye 2009;23:2063-70) studied the efficacy and safety of mycophenolate mofetil (MMF) in preventing graft rejection and in improving clear graft survival following high-risk keratoplasty. Six reversible and two irreversible graft rejections occurred in the MMF group, and five reversible and seven irreversible rejections in the control group. The Kaplan-Meier analysis revealed an immune reaction-free graft survival after a mean follow-up time of 83% in the MMF group and 64.5% in the control group (p = 0.044). Graft failure occurred in 10 MMF-treated patients (two due to rejection) and in nine patients in the control group (seven due to rejection). Thus, systemic immunosuppression with MMF over six months is relatively well-tolerated and improves rejection-free graft survival following high-risk keratoplasty and is statistically significant even in the long run.

Bertelmann et al. (Ophthalmologica 2010;224:38-41) evaluated the efficacy and safety of topically applied mycophenolate mofetil (MMF) for the prophylaxis of corneal graft rejection in an experimental keratoplasty model. The mean survival time (MST) of the grafts in the MMF-treated group was 12 days, the MST in the vehicle-treated group was 14.3 days, and the MST in the untreated group was 13.3 days. Thus, the survival curves of the three treatment groups did not differ significantly. It was concluded that topical MMF was ineffective for prophylaxis of corneal graft rejection.

Chatel et al . (Am J Ophthalmol 2010;150:179-84) examined the efficacy and safety of dual sirolimus and mycophenolate mofetil systemic immunosuppression as allograft rejection prophylaxis after penetrating keratoplasty, in patients at high rejection risk. Treatment was with oral mycophenolate mofetil in combination with sirolimus, for one year, and sirolimus alone for a further twoyears after keratoplasty, in six high-risk penetrating transplant recipients. Rejection episodes occurred in three patients, one of which led to transplant failure. Of the six transplants, five remained clear at the latest follow-up. Hepatotoxicity required discontinuation of mycophenolate in one patient, and both drugs were otherwise free of significant adverse effects. They concluded that sirolimus and mycophenolate mofetil in combination are effective in extending corneal transplant survival in most, but not all high-rejection risk patients and are generally well tolerated.

  Rapamycin Top

Shi et al. (Invest Ophthalmol Vis Sci 2006;47:3339-44) evaluated the immunosuppressive and antiangiogenic activities of the intraocular rapamycin (RAPA) drug delivery system (DDS) in a rabbit model of high-risk penetrating keratoplasty. It was seen that RAPA-PGLC DDS and RAPA eye drops could significantly prolong the survival of allografts at high risk and inhibit corneal neovascularization. However, RAPA-PGLC DDS was far more effective than RAPA eye drops in preventing corneal graft rejection.

Stanojlovic et al. (Graefes Arch Clin Exp Ophthalmol 2010 Oct;248) analyzed the immune modulatory effect of low-dose systemic treatment with rapamycin (Rapa) alone or in combination with CsA in a high-responder corneal allograft model. Combined treatment with low-dose CsA and Rapa resulted in superior graft survival, and effectively modulated the mRNA expression of inflammation and infiltration markers.

  Basiliximab Top

Schmitz et al. (Ophthalmologe 2002;99:38-45) evaluated seven patients with high-risk keratoplasty treated with basiliximab perioperatively and cyclosporine postoperatively. During the follow-up of 14 - 25 months, no immune reaction occurred, and all transplants were clear. This suggested that the preliminary data on a combination therapy with basiliximab and cyclosporine were promising. For further evaluation a prospective multicenter study is needed.

Birnbaum et al . (Klin Monbl Augenheilkd 2008;225:62-5) studied the efficacy and safety of basiliximab after penetrating risk keratoplasty. Basiliximab is a chimeric monoclonal interleukin 2-receptor antibody, which inhibits T-cell proliferation. Basiliximab is approved for treatment in patients after kidney transplantation. Twenty patients undergoing high-risk keratoplasty received, as postoperative medication, fluocortolone 1 mg / kg / d (tapered off within three weeks) and prednisolone acetate eye-drops 5x / d (tapered off within five months). In addition, 10 patients received 20 mg basiliximab immediately following surgery and four days postoperatively. Ten patients in the control group received oral CSA adapted to the blood-trough level (120 - 150 ng / mL) for six months. Four patients of the basiliximab group showed corneal immune reactions (two irreversible), while no side effects were observed. In the CSA group two immune reactions occurred (one irreversible). In two CSA-treated patients the CSA administration had to be stopped due to side effects. They concluded that basiliximab had lower efficacy in preventing immune reactions after risk keratoplasty than CSA. However, the side effect profile of basiliximab is more favorable than that of CSA.

  J2 Top

Xiao et al. (Transpl Immunol 2007;18:130-7) used a murine model of corneal allograft rejection to determine the in vivo immunosuppressive activities of J2 (a novel non-peptidic organic ligand of CD4 D1, as a potential inhibitor of CD4 D1 and thus CD4-dependent T cell responses in vitro). J2 was administrated by mouth three hours before transplantation, and thereafter, on 12 consecutive days. The results showed that J2 could significantly prolong the median survival time of the corneal allografts, compared to the untreated control group.

Zhang et al. (Zhonghua Yan KeZaZhi 2010;46:51-5) discussed the mechanism of J2 on preventing the corneal rejection in mice. It was seen that J2 could block the process of antigen presentation by inhibiting CD4 / major histocompatibility complex-II (MHC-II) moleculeonania, while secreting IL-2 and IL-10, and IFN-gamma did not have a specificity change.

  Novel Agents Top

Pleyer et al. ( Graefes Arch Clin Exp Ophthalmol 2005;243:450-5) evaluated the effect of a SEGRA compound following topical application on the course of experimental orthotopic corneal grafts. Topical application of a SEGRA compound was highly effective in prolonging the mean survival time of corneal grafts (42.2 ± 4.0 days) when compared with the untreated controls (11.7 ± 1.2 days, p = 0.00003) or animals that received only the vehicle (15.0 ± 1.5 days, p = 0.114). Their results indicated that topical application of a SEGRA compound significantly prolonged corneal graft survival in an experimental keratoplasty model. It further suggested that SEGRA could be a potentially useful drug to suppress the immune response.

Jessup et al. (Invest Ophthalmol Vis Sci 2005;46:1675-81) transferred a cDNA encoding a monomeric anti-CD4 antibody fragment to the donor corneal endothelium, to attempt to modulate orthotopic corneal allograft rejection in the rat. Anti-CD4 single-chain, variable-domain antibody fragments (scFvs) were capable of blocking allo-stimulation, but their local expression within the eye did not prolong corneal allograft survival, suggesting that sensitization might still occur.

Gong et al. (J Gene Med 2006;8:459-67) analyzed the effects of local (ex vivo) or systemic (in vivo) administration of adenovirus type 5 encoding CTLA4Ig (AdCTLA4Ig) on its influence to prolong corneal allograft survival and to study the underlying mechanisms. Ex vivo gene transfer resulted in a modest, but significant, prolongation of graft survival (p = 0.0036) compared to no treatment. In contrast, the systemic gene therapy significantly prolonged graft survival (p = 0.0007 and 0.0001, respectively) compared to no treatment. Systemic therapy resulted in frequent indefinite survivals of allogeneic grafts, which was not observed in the other therapeutic regimens. They concluded that CTLA4Ig gene therapy was a successful strategy for the prevention of allogeneic graft rejection in corneal transplantation.

Di Tommaso et al. (Eur J Pharm Biopharm 2012;81:257-64) investigated the in vivo effects of a novel CsA topical aqueous formulation. This formulation was based on nanosized polymeric micelles as drug carriers. After instillation of the novel formulation with fluorescent labeled micelles, confocal analysis of flat-mounted corneas clearly showed that the nanosized carriers were able to penetrate into all the corneal layers. The efficacy of a 0.5% CsA micelle formulation was tested and compared with a physiological saline solution and with the systemic administration of CsA. They concluded that the applied formulation had the capacity to overcome the ocular surface barriers. The micelles formed a drug reservoir in the cornea, from where a sustained release of CsA took place. This novel formulation for topical application of CsA is clearly an effective and well-tolerated alternative to the systemic treatment for the prevention of corneal graft rejection.

Wang et al. (Immunotherapy 2012;4:581-6) studied the role of sinomenine (SIN) in prolonging high-risk corneal graft survival in rats. All recipients were randomly assigned to SIN, cyclosporine A (CsA), SIN plus CsA, and control groups. Survival time was 15.88 ± 5.87 days in the SIN group, 17.67 ± 5.43 days in the CsA group, and 20.75 ± 4.77 days in the drug combination group, which were longer survival times than those in the control group (p < 0.05). Thus, SIN could prolong allograft survival and might have potential clinical usage.


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