Intracameral Cyclosporine Drug Delivery System in High-risk Keratoplasty
Authors: Virgilio Galvis, Alejandro Tello, Néstor I. Carreño, Mario L. Revelo
Journal: Ophthalmology (2013)

We read with great interest the innovative work of Shi et al1Shi W. Chen M. Xie L. et al.A novel cyclosporine A drug-delivery system for prevention of human corneal rejection after high-risk keratoplasty: a clinical study.Ophthalmology. 2013; 120: 695-702Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar on cyclosporine intraocular drug delivery system for high-risk keratoplasty. It is not true that endothelial graft rejection often occurs within 2 weeks after transplantation, as authors stated. Many reports show similar data: Average interval between 8 and 10.5 months after graft. In fact, a recent study found that early rejections (within 6 months postoperatively) were almost 3 times less frequent than late rejections.2Perera C. Jhanji V. Lamoureux E. et al.Clinical presentation, risk factors and treatment outcomes of first allograft rejection after penetrating keratoplasty in early and late postoperative period.Eye (Lond). 2012; 26: 711-717Crossref PubMed Scopus (8) Google Scholar In high-risk keratoplasty cases, the panorama is not very different, as in the clinical trial by Sinha et al cited by the authors: patients presented rejection in average between 6.5 and 7.9 months after the surgery.Corneal transplant rejection (a cell-mediated phenomenon) includes 2 phases: The “afferent arm” (host sensitization to the donor antigens by means of antigen-presenting cells [APCs], which takes around 1 week) and the “efferent arm” (proliferation and delivery of T cells). The immune privilege of the eye includes anterior chamber associated immune deviation (ACAID), extensively studied by Niederkorn,3Niederkorn J.Y. Dynamic immunoregulatory processes that sustain immune privilege in the eye.in: Dartt D.A. Dana R. D'Amore P. Niederkorn J.Y. Immunology, inflammation and diseases of the eye. Elsevier, San Diego2011: 38-43Google Scholar which in around 10 days induces the production of several cells populations, including regulatory T cells (CD4+CD25+ regulatory T cells and CD8+ regulatory T cells), which modulate the immune system, abrogating the expression of delayed-type hypersensitivity and cytotoxic T-lymphocyte responses. However, protection of the corneal graft provided by several mechanisms (including expression of immunosuppressive factors, ACAID, and the lack of afferent lymphatic and blood vessels in corneas without neovascularization) is not infallible. One possible cause is that although ACAID is trying to produce cells that eventually might make the immune system tolerate the donor tissue, the “afferent arm” of the immune system, via the lymphatic system, is trying to sensitize the body to react against that foreign tissue. In primates, ≤25% of the contents of the anterior chamber are drained by the uveal/scleral pathway and finally reach the lymph nodes. If lymphatic vessels are present in the cornea, which accompany the blood neovessels, the amount of APCs reaching the nodes increases significantly. Furthermore, in “high-risk” cases, high levels of specific chemokines emanate from the vascularized corneas. All these factors promote the onset of corneal rejection.It is very interesting that in animal models systemic cyclosporine had a significant, although temporary, effect on avoiding corneal graft rejection, which is in line with its presumed main mechanism of action on the “efferent arm” of the phenomenon.4Claerhout I. Beele H. Verstraete A. et al.The effect of duration and timing of systemic cyclosporine therapy on corneal allograft survival in a rat model.Graefes Arch Clin Exp Ophthalmol. 2001; 239: 152-157Crossref PubMed Scopus (10) Google ScholarIn the original study by the authors in animals, published in 2001, the intraocular implant of cyclosporine also significantly prolonged corneal graft survival, but did not approach the tissue survival time in autografted rats.Looking at the impressive results in humans now shown by the authors, we wonder if the high levels of cyclosporine in the anterior chamber reached early after transplantation, might also have a significant effect on the “afferent arm” regulating the ocular APCs (dendritic cells, macrophages, B cells, and epithelial Langerhans' cells) in a similar way as its effects in APCs in other parts of the body (skin, peripheral blood).5Tajima K. Amakawa R. Ito T. et al.Immunomodulatory effects of cyclosporine A on human peripheral blood dendritic cell subsets.Immunology. 2003; 108: 321-328Crossref PubMed Scopus (75) Google Scholar If this is the case, cyclosporine acting on the “afferent arm” would help to maintain the immune privilege of the anterior segment, thus making the immune system to ignore the alloantigen. However, this benefit would last only while concentrations of cyclosporine in the anterior chamber were elevated (we assume to be the first months after surgery). Now, by the results in this series of high-risk cases, followed for ≥12 months, it is clear that the beneficial effect is more durable (with a percentage of episodes of rejection of 18.5% at 12 months, and only 4.3% of graft failure over the entire follow-up period). It is possible that, by preventing early sensitization, intraocular cyclosporine gives time to ACAID to act causing tolerance of the alloantigens.This study opens up a whole new perspective on the modulation of the immune response directly into the anterior chamber, and will certainly allow the use of other substances with different properties (such as tacrolimus or fingolimod), or even combinations of substances, substantially improving the prognosis in cases of “high-risk” corneal and keratolimbal allografts. We read with great interest the innovative work of Shi et al1Shi W. Chen M. Xie L. et al.A novel cyclosporine A drug-delivery system for prevention of human corneal rejection after high-risk keratoplasty: a clinical study.Ophthalmology. 2013; 120: 695-702Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar on cyclosporine intraocular drug delivery system for high-risk keratoplasty. It is not true that endothelial graft rejection often occurs within 2 weeks after transplantation, as authors stated. Many reports show similar data: Average interval between 8 and 10.5 months after graft. In fact, a recent study found that early rejections (within 6 months postoperatively) were almost 3 times less frequent than late rejections.2Perera C. Jhanji V. Lamoureux E. et al.Clinical presentation, risk factors and treatment outcomes of first allograft rejection after penetrating keratoplasty in early and late postoperative period.Eye (Lond). 2012; 26: 711-717Crossref PubMed Scopus (8) Google Scholar In high-risk keratoplasty cases, the panorama is not very different, as in the clinical trial by Sinha et al cited by the authors: patients presented rejection in average between 6.5 and 7.9 months after the surgery. Corneal transplant rejection (a cell-mediated phenomenon) includes 2 phases: The “afferent arm” (host sensitization to the donor antigens by means of antigen-presenting cells [APCs], which takes around 1 week) and the “efferent arm” (proliferation and delivery of T cells). The immune privilege of the eye includes anterior chamber associated immune deviation (ACAID), extensively studied by Niederkorn,3Niederkorn J.Y. Dynamic immunoregulatory processes that sustain immune privilege in the eye.in: Dartt D.A. Dana R. D'Amore P. Niederkorn J.Y. Immunology, inflammation and diseases of the eye. Elsevier, San Diego2011: 38-43Google Scholar which in around 10 days induces the production of several cells populations, including regulatory T cells (CD4+CD25+ regulatory T cells and CD8+ regulatory T cells), which modulate the immune system, abrogating the expression of delayed-type hypersensitivity and cytotoxic T-lymphocyte responses. However, protection of the corneal graft provided by several mechanisms (including expression of immunosuppressive factors, ACAID, and the lack of afferent lymphatic and blood vessels in corneas without neovascularization) is not infallible. One possible cause is that although ACAID is trying to produce cells that eventually might make the immune system tolerate the donor tissue, the “afferent arm” of the immune system, via the lymphatic system, is trying to sensitize the body to react against that foreign tissue. In primates, ≤25% of the contents of the anterior chamber are drained by the uveal/scleral pathway and finally reach the lymph nodes. If lymphatic vessels are present in the cornea, which accompany the blood neovessels, the amount of APCs reaching the nodes increases significantly. Furthermore, in “high-risk” cases, high levels of specific chemokines emanate from the vascularized corneas. All these factors promote the onset of corneal rejection. It is very interesting that in animal models systemic cyclosporine had a significant, although temporary, effect on avoiding corneal graft rejection, which is in line with its presumed main mechanism of action on the “efferent arm” of the phenomenon.4Claerhout I. Beele H. Verstraete A. et al.The effect of duration and timing of systemic cyclosporine therapy on corneal allograft survival in a rat model.Graefes Arch Clin Exp Ophthalmol. 2001; 239: 152-157Crossref PubMed Scopus (10) Google Scholar In the original study by the authors in animals, published in 2001, the intraocular implant of cyclosporine also significantly prolonged corneal graft survival, but did not approach the tissue survival time in autografted rats. Looking at the impressive results in humans now shown by the authors, we wonder if the high levels of cyclosporine in the anterior chamber reached early after transplantation, might also have a significant effect on the “afferent arm” regulating the ocular APCs (dendritic cells, macrophages, B cells, and epithelial Langerhans' cells) in a similar way as its effects in APCs in other parts of the body (skin, peripheral blood).5Tajima K. Amakawa R. Ito T. et al.Immunomodulatory effects of cyclosporine A on human peripheral blood dendritic cell subsets.Immunology. 2003; 108: 321-328Crossref PubMed Scopus (75) Google Scholar If this is the case, cyclosporine acting on the “afferent arm” would help to maintain the immune privilege of the anterior segment, thus making the immune system to ignore the alloantigen. However, this benefit would last only while concentrations of cyclosporine in the anterior chamber were elevated (we assume to be the first months after surgery). Now, by the results in this series of high-risk cases, followed for ≥12 months, it is clear that the beneficial effect is more durable (with a percentage of episodes of rejection of 18.5% at 12 months, and only 4.3% of graft failure over the entire follow-up period). It is possible that, by preventing early sensitization, intraocular cyclosporine gives time to ACAID to act causing tolerance of the alloantigens. This study opens up a whole new perspective on the modulation of the immune response directly into the anterior chamber, and will certainly allow the use of other substances with different properties (such as tacrolimus or fingolimod), or even combinations of substances, substantially improving the prognosis in cases of “high-risk” corneal and keratolimbal allografts. A Novel Cyclosporine A Drug-Delivery System for Prevention of Human Corneal Rejection after High-risk Keratoplasty: A Clinical StudyOphthalmologyVol. 120Issue 4PreviewTo evaluate the efficacy of a novel cyclosporine A (CsA) drug-delivery system (DDS) in the anterior chamber for suppressing the occurrence of rejection and improving the survival of corneal allografts after high-risk keratoplasty. Full-Text PDF Author replyOphthalmologyVol. 120Issue 9PreviewWe appreciate the interest of Galvis et al in our paper. Clinically observed incidence of endothelial immune rejection seems to be recognized as the final result of sustained immune rejection. Endothelial immune rejection response is a process from the initial antigen recognition to gradual accumulation and eruption. The period of the first 2 weeks after surgery is primarily regarded as an optimal drug administration timepoint rather than the occurrence time of endothelial rejection. Obviously, prompt and direct achievement of sufficient intraocular drug levels may inhibit the launch of an immune response and delay the incidence of immune rejection. Full-Text PDF