• Cornea/External Disease

    Penetrating keratoplasty is the most common tissue transplant procedure performed in the United States, with about 35,000 cases performed each year1 and a 2-year success rate approaching 90%. The most common indications for penetrating keratoplasty (PK) are:

     dot Pseudophakic bullous keratopathy
     dot Regraft
     dot Keratoconus
     dot Fuch’s dystrophy

    Despite the immune privilege of the anterior segment, the survival rates2 are approximately: 


    5-Year Survival Rates

    10-Year Survival Rates

    Corneal Transplant



    High-risk Corneal Transplant



    Pathogenesis of graft failure, commonly defined as an irreversible loss of central graft clarity, is multifactorial. Immunologic rejection and endothelial failure are the two most common pathoetiologies.

    Predictably, regrafts are associated with worse prognosis. A review of repeat corneal transplantations in 86 patients3 over a 13-year follow-up period indicated that the survival probability for first, second, third, and fourth grafts is 37%, 43%, 25%, and 0%, respectively. A similar conclusion was reached in the Corneal Transplant Follow-up Study;4 there is a direct correlation between relative risk of rejection (RR) and the number of previous grafts (confidence interval, or CI):

    No. Previous Grafts





    0.92 - 2.11



    1.56 - 4.54



    1.34 - 5.65

    Immunologic rejection is associated with allograft failure in 14% to 40% of the cases. Accordingly, modulation of the immunologic allograft rejection is of paramount significance.

    Complexities of Pharmaceutical Management

    Given the immunologic complexity and toxicology of immunosuppressants, there is minimal consensus among surgeons with respect to pharmaceutical management of immunologic allograft rejection. The vast array of immunosuppressant mechanisms, eg, anti-inflammatory, reducing vascular permeability, blocking cytokine production, and inhibiting monocyte migration makes corticosteroid the first choice for allograft rejection treatment or prophylaxis.

    All respondents in a 1998 survey at the Eye Bank Meeting5 reported primarily using topical corticosteroids (ie, prednisone acetate 1%, dexamethasone, or prednisolone sodium phosphate 0.5%) for routine prophylaxis and for treatment of established rejection episodes. Use of a systemic nonsteroidal immunosuppression regimen, cyclosporine A, and/or an antimetabolite were reserved for high-risk grafts.

    Similarly, another survey at the Cornea Society6 found that topical corticosteroids are commonly used for routine prophylaxis and treatment of corneal graft rejection. For management of high-risk allografts, topical cyclosporine A was added to the treatment regimen in 48% of cases. Various studies in the literature reported use of mono- or combination therapy, usually combining corticosteroids with an antimetabolite (azathioprine) or a calcineurin inhibitor (cyclosporine A). However, success was limited.7

    The Triple-Therapy Approach

    Given the 3 components of the immune response structure -- the afferent arm, central stage, and efferent arm -- and guided by medical management of solid organ transplantation, we recently demonstrated that a triple therapy that blocks all 3 components of the immune response and effectively modulates allograft rejection. We expect that multiple-agent therapies, as shown in Figure 1, will be part of the armamentarium to prevent and treat allogenic graft rejection.

    Figure 1. The immune response triad and therapeutic agents.

    Briefly, the afferent arm is characterized by the presence, liberation, and transportation of allogenic antigens to lymphatic tissues. In addition to human leukocyte antigen (HLA) typing and inhibition of the inflammation cascade, antivascularization treatments such as antivascular endothelium growth factor receptor (anti-VEGFR), photodynamic therapy and needle diathermy, and presensitization to activate the anterior chamber-associated immune deviation have all been shown to improve allograft survival.

    Anti-inflammatory and antivascularization treatments are especially important to block the direct and indirect centripetal migration of donor antigen-presenting cells. The central stage includes activation, differentiation, and proliferation of lymphocytes. Inhibition of this stage can be accomplished mainly by using monoclonal antibodies directed against the antigen-presentation or T-cell activation steps and anti-interleukin 2 (IL-2) and antimetabolites to suppress proliferation.

    The efferent arm is, effectively, the destruction of the allograft by the cellular and humoral graft effector mechanisms. Antilymphocyte and antithymocyte globulin antibodies bind to the surface of circulating T-lymphocytes, resulting in opsonization and phagocytosis by macrophages in the spleen and liver. Calcineurin inhibitors also block the IL-2 activation of macrophages. Anti-CD40L antibody blocks T-cell CD40 ligand binding to the macrophage CD40 receptor and suppresses macrophage activation. Anti-CD3 antibody binds to and promotes phagocytosis or complement-mediated lysis of T-cells.

    Thus, the goals of multi-agent therapy are to reduce the dosage and the therapy duration by capitalizing on their synergistic mechanisms. Although use of multiple-agent therapy in noninfectious uveitis has been widely reported,7 the literature on combination immunosuppressive therapy after keratoplasty rejection is limited.

    In a recent study,8 we were the first to report the corticosteroid-azathioprine-cyclosporine (CAC) triple therapy after repeat keratoplasty. The typical induction-phase dosages of prednisone, azathioprine, and cyclosporine are 60 mg, 100 mg, and 100 mg daily, respectively. The dosages are gradually tapered over the course of the maintenance phase. One-year follow-ups demonstrated no signs of immunologic rejection, which typically present in year one. Graft clarity persisted and there was no apparent evidence of renal, hepatic, or metabolic dysfunction.

    The high success rate associated with the CAC therapy is most likely secondary to our triple-pronged attack to block the immune response on multiple fronts:

     dot Corticosteroid on inflammation and the post-transcription IL-2 pathway
     dot Cyclosporine on the IL-2 pre-transcription pathway
     dot Azathioprine on cellular proliferation

    The low incidence of adverse effects is attributed to the relatively lower dosage compared with other organ or tissue transplants such as renal or hepatic. The exceptional adverse effect profile mandates a systematic and comprehensive discussion with the patients prior to initiation of the multi-agent therapy.

    Intimate collaboration with a rheumatologist is highly recommended to monitor the hepatic, renal, and metabolic functions.

    Given the high long-term rejection rates, we encourage the use of multi-agent therapy in high-risk patients to target multiple steps in the immune response process and modulate the probability of immunologic rejection. We predict development of multi-agent induction and maintenance protocols to treat rejection before graft failure and to maintain long-term allograft survival after repeat penetrating keratoplasty.


    1.Eye Bank Association of America, 2007 statistical report.
    2.Waldock A, Cook SD. Corneal transplantation: how successful are we? Br J Ophthalmol. 2000;84(8):813-815.
    3.Bersudsky V, Blum-Hareuveni T, Rehany U, Rumelt S. The profile of repeated corneal transplantation.Ophthalmology. 2001;108(3):461-469.
    4.Vail A, Gore SM, Bradley BA, Easty DL, Rogers CA, and Armitage WJ. Conclusions of the corneal transplant follow up study. Collaborating Surgeons.  Br J Ophthalmol. 1997;81(8):631-636.
    5.Barker NH, Henderson TR, Ross CA, Coster DJ, Williams KA. Current Australian practice in the prevention and management of corneal graft rejection.Clin Experiment Ophthalmol. 2000;28(5):357-360.
    6.Randleman JB, Stulting RD. Prevention and treatment of corneal graft rejection: current practice patterns (2004).Cornea. 2006;25(3):286-290.
    7.Lustig MJ, Cunningham ET. Use of immunosuppressive agents in uveitis. Curr Opin Ophthalmol. 2003:14(6):399-412.
    8.Nguyen P, Yiu SC, Barte F, and Shinaga K. A novel pharmaceutical protocol for controlling allograft rejection of repeat penetrating keratoplasty (unpublished data, 2007).

    Author Disclosure

    Both authors have no financial relationship with the manufacturer or provider of any product or service discussed in this article or with the manufacturer or provider of any competing product or service. This study was supported in part by National Eye Institute core grants EY03040 and by grants from Research to Prevent Blindness and a Baxter Foundation Junior Faculty Award to S.C.Y.