UV light crosslinking regresses mature corneal blood and lymphatic vessels and promotes subsequent high-risk corneal transplant survival

Hou, Yayi; Le, Viet Nhat Hung; Tóth, Gábor; Siebelmann, Sebastian; Horstmann, Jochen; Gabriel, Tim; Bock, Felix; Cursiefen, Claus

doi:10.1111/ajt.14874

Cited by 49 publications

(42 citation statements)

References 57 publications

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“…56 Subsequently, the same group demonstrated in the mouse model of sutureinduced corneal neovascularization that "cross-linking" of corneal collagen fibers by topical riboflavin and UV A irradiation-a protocol used clinically to reduce the rate of corneal distortion in keratoconus-regressed mature blood and lymph vessel invasion and increased the survival of fully MHC-mismatched allografts. 57 Compared to control conditions, this potentially clinically applicable protocol was associated with apoptosis of intrastromal vascular endothelial cells and reduced CD45 + immune cell infiltration in the recipient corneas before transplantation. 57 Interestingly, in a recent pilot study, fine-needle vessel coagulation combined with bevacizumab treatment has shown promising results to improve graft survival in high-risk transplant patients.…”

Section: Developments In Basic Science and Animal Modelsmentioning

confidence: 91%

High-risk Corneal Transplantation: Recent Developments and Future Possibilities

et al. 2019

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HISTORICAL AND GLOBAL SIGNIFICANCE OF CORNEAL TRANSPLANTATION AND FACTORS ASSOCIATED WITH HIGH IMMUNOLOGICAL RISK The landmark report by Eduard Zirm in 1905 of a successful full-thickness corneal transplant in a 45-year-old farm laborer with lime burn preceded, by several decades, the subsequent successes of vascularized organ transplants. 1,2 Following the introduction of topical corticosteroid therapies in the 1950s, corneal transplantation (keratoplasty) has become established as the primary sight-restoring procedure for corneal blindness in developed and developing countries. 3 Furthermore, while partial-thickness (lamellar) keratoplasty has now become the preferred transplant procedure for many corneal disorders, 4 fullthickness allograft remains the most frequently utilized treatment worldwide for corneal conditions associated with significant stromal opacity or vascularization such as bacterial, fungal, or viral infections; severe atopic disorders; ocular trauma and prior graft loss. Corneal opacity Review Abstract. Human corneal transplantation (keratoplasty) is typically considered to have superior short-and long-term outcomes and lower requirement for immunosuppression compared to solid organ transplants because of the inherent immune privilege and tolerogenic mechanisms associated with the anterior segment of the eye. However, in a substantial proportion of corneal transplants, the rates of acute rejection and/or graft failure are comparable to or greater than those of the commonly transplanted solid organs. Critically, while registry data and observational studies have helped to identify factors that are associated with increased risk of corneal transplant failure, the extent to which these risk factors operate through enhancing immune-mediated rejection is less clear. In this overview, we summarize a range of important recent clinical and basic insights related to high-risk corneal transplantation, the factors associated with graft failure, and the immunological basis of corneal allograft rejection. We highlight critical research areas from which continued progress is likely to drive improvements in the long-term survival of high-risk corneal transplants. These include further development and clinical testing of predictive risk scores and assays; greater use of multicenter clinical trials to optimize immunosuppressive therapy in high-risk recipients and robust clinical translation of novel, mechanistically-targeted immunomodulatory and regenerative therapies that are emerging from basic science laboratories. We also emphasize the relative lack of knowledge regarding transplant outcomes for infection-related corneal diseases that are common in the developing world and the potential for greater cross-pollination and synergy between corneal and solid organ transplant research communities.

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Section: Developments In Basic Science and Animal Modelsmentioning

confidence: 91%

High-risk Corneal Transplantation: Recent Developments and Future Possibilities

et al. 2019

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“…It is also well known that repeat neovascularization episodes can develop rapidly and are more difficult to treat. Given the continued development of improved antiangiogenic treatments and alternative treatment strategies, such as photodynamic therapy 18 and UV light corneal crosslinking, 19 that aim to regress initial neovascularization and substantially regain corneal transparency, it is unclear how the cornea would respond to repeated injury/stimulus or removal of such antiangiogenic treatment. Specifically, it is not known whether repeat neovascularization and the accompanying inflammation would occur in the same manner as the initial neovascularization episode, or if it would differ in phenotype and aggressiveness.…”

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confidence: 99%

Repeat Corneal Neovascularization is Characterized by More Aggressive Inflammation and Vessel Invasion Than in the Initial Phase

Mukwaya

Mirabelli

Lennikov

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Treatment of corneal neovascularization can lead to vessel regression and recovery of corneal transparency. Here, we examined the response of the cornea to a repeated stimulus after initial vessel regression comparing the second wave of neovascularization with the first. METHODS. Corneal neovascularization was induced by surgical suture placement in the rat cornea for 7 days, followed by suture removal and a 30-day regression period. Corneas were then re-sutured and examined for an additional 4 days. Longitudinal slit-lamp imaging, in vivo confocal microscopy, and microarray analysis of global gene expression was conducted to assess the inflammatory and neovascularization response. Inhibitory effect of topical dexamethasone for repeat neovascularization was assessed. RESULTS. After initial robust neovascularization, 30 days of regression resulted in the recovery of corneal transparency; however, a population of barely functional persistent vessels remained at the microscopic level. Upon re-stimulation, inflammatory cell invasion, persistent vessel dilation, vascular invasion, and gene expression of Vegfa, Il1b, Il6, Ccl2, Ccl3, and Cxcl2 all doubled relative to initial neovascularization. Repeat neovascularization occurred twice as rapidly as initially, with activation of nitric oxide and reactive oxygen species, matrix metalloproteinase, and leukocyte extravasation signaling pathways, and suppression of antiinflammatory LXR/RXR signaling. While inhibiting initial neovascularization, a similar treatment course of dexamethasone did not suppress repeat neovascularization. CONCLUSIONS. Persistent vessels remaining after the initial resolution of neovascularization can rapidly reactivate to facilitate more aggressive inflammation and repeat neovascularization, highlighting the importance of achieving and confirming complete vessel regression after an initial episode of corneal neovascularization.

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“…Similarly, another study found that CXL regressed both preexisting blood and lymphatic vessels significantly via inducing apoptosis in vascular endothelial cells. 17 Both studies determined the combined effect of CXL with UVA and riboflavin on mature corneal blood and lymphatic vessel infiltration. We evaluated the effects of this procedure on corneal lymphangiogenesis and hemangiogenesis with UVA doses that we previously identified as being safe and effective for use in the rat.…”

Section: Methodsmentioning

confidence: 99%