Inhibition of Hemangiogenesis and Lymphangiogenesis<i>after</i>Normal-Risk Corneal Transplantation by Neutralizing VEGF Promotes Graft Survival

Cursiefen, Claus; Cao, Jingtai; Chen, Lu; Liu, Ying; Maruyama, Kouichi; Jackson, David G.; Kruse, Friedrich E.; Wiegand, Stanley J.; Dana, M. Reza; Streilein, J. Wayne

doi:10.1167/iovs.03-1380

Cited by 301 publications

(291 citation statements)

References 27 publications

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“…Both preexisting corneal BVs and LVs are important risk factors for immune‐mediated allograft rejection after high‐risk keratoplasty 4, 31, 38. Therefore, it is mandatory to regress preexisting corneal vessels in high‐risk eyes before transplantation, and mature BVs and LVs have become new therapeutic targets to enhance surgical success rates after corneal transplantation.…”

Section: Discussionmentioning

confidence: 99%

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

Hou

Tóth

et al. 2018

American Journal of Transplantation

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Immunologic graft rejection is the main complication after corneal transplant into pathologically prevascularized so‐called high‐risk eyes. The aim of this study was to evaluate whether ultraviolet (UV) light crosslinking can regress pathologic corneal blood and lymphatic vessels and thereby improve subsequent graft survival. Using the murine model of suture‐induced corneal neovascularization, we found that corneal crosslinking with UVA light and riboflavin regressed both preexisting blood and lymphatic vessels significantly via induction of apoptosis in vascular endothelial cells. In addition, macrophages and CD45+ cell counts were significantly reduced. Consistently, corneal crosslinking reduced keratocyte density and corneal thickness without affecting corneal nonvascular endothelial cells, iris, and lens depending on the crosslinking duration. Furthermore, using the murine model of corneal transplant, long‐term graft survival was significantly promoted (P < .05) and CD4+ CD25+FoxP3+ T regulatory cells were upregulated (P < .01) in high‐risk eyes preoperatively treated with crosslinking. Our results suggest UV light crosslinking as a novel method to regress both pathologic corneal blood and lymphatic vessels and to reduce CD45+ inflammatory cells. Furthermore, this study demonstrates for the first time that preoperative corneal crosslinking in prevascularized high‐risk eyes can significantly improve subsequent graft survival and may become a promising novel therapy in the clinic.

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Section: Discussionmentioning

confidence: 99%

“…Allogeneic corneal transplantation was performed as previously described31, 32 to compare the long‐term graft survival between the CXL group and controls. Twenty‐four female BALB/c mice were used as recipients, and 12 female C57BL/6 mice were used as corneal donors.…”

Section: Methodsmentioning

confidence: 99%

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

Hou

Tóth

et al. 2018

American Journal of Transplantation

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“…Penetrating corneal transplantation was performed after suture removal. Keratoplasty was performed as described previously (37). Donor corneas were excised by trephination using a 2-mm bore, and cut with curved Vannas scissors.…”

Section: Corneal Transplantationmentioning

confidence: 99%

Topical Application of Soluble CD83 Induces IDO-Mediated Immune Modulation, Increases Foxp3+ T Cells, and Prolongs Allogeneic Corneal Graft Survival

Bock

Rößner

Onderka

et al. 2013

The Journal of Immunology

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Modulation of immune responses is one of the main research aims in transplant immunology. In this study, we investigate the local immunomodulatory properties of soluble CD83 (sCD83) at the graft-host interface using the high-risk corneal transplantation model. In this model, which mimics the inflammatory status and the preexisting vascularization of high-risk patients undergoing corneal transplantation, allogeneic donor corneas are transplanted onto sCD83-treated recipient animals. This model allows the direct and precise application of the immune modulator at the transplantation side. Interestingly, sCD83 was able to prolong graft survival after systemic application as well as after topical application, which is therapeutically more relevant. The therapeutic effect was accompanied by an increase in the frequency of regulatory T cells and was mediated by the immune-regulatory enzyme IDO and TGF-β. In vitro, sCD83 induced long-term IDO expression in both conventional and plasmacytoid dendritic cells via autocrine or paracrine production of TGF-β, a cytokine previously shown to be an essential mediator of IDO-dependent, long-term tolerance. These findings open new treatment avenues for local immune modulation after organ and tissue transplantation.

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“…VEGF-A induces both angiogenesis and lymphangiogenesis by binding to the VEGF receptor 1 (VEGFR1) and VEGFR2, although the latter process is mainly driven via the binding of VEGF-C and VEGF-D to VEGFR2 and VEGFR3 (Carmeliet and Jain 2000). It has been reported that blocking the corneal lymphatic vessels that flow directly to the DLNs is effective in preventing allograft rejection Cursiefen et al 2004;Bachmann et al 2008). Recently, two important findings in the cornea have reported that a soluble form of VEGFR1 (sVEGFR1) acts as a potent natural inhibitor of corneal angiogenesis, and a soluble form of VEGFR2 (sVEGFR2) prevents lymphangiogenesis and maintains an alymphatic cornea (Ambati et al 2006;Albuquerque et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Suppression of Allograft Rejection with Soluble VEGF Receptor 2 Chimeric Protein in a Mouse Model of Corneal Transplantation

Hayashi

Usui

Yamagami

2016

Tohoku J. Exp. Med.

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When a transparent cornea becomes opaque due to infectious diseases, trauma, or ophthalmic surgery, the impaired cornea is replaced with a donor cornea to improve visual function. In this corneal transplantation, the graft survival rate is comparatively high, partly because of lacking vascular and lymphatic vessel in cornea. However, the transplanted corneas sometimes become opaque if allograft rejection occurs. Suppression of allograft rejection is critical for favorable outcomes of corneal transplantation. The essential effects of endogenous monomeric soluble vascular endothelial growth factor receptors (VEGFRs) 1 and 2 have been reported in corneal angiogenesis and lymphangiogenesis. This study investigated the effects of dimeric soluble VEGFR2/Fc chimera protein on corneal allograft rejection for future clinical application. Allogeneic full-thickness corneal transplantation was performed in C57BL/6 to BALB/c mice. The recipients were treated by intrastromal injection of soluble VEGFR1/Fc chimera (sR1/Fc group), soluble VEGFR2/Fc chimera (sR2/Fc group), or human IgG1/Fc protein (IgG/Fc group) at 0, 7, and 14 days after surgery. Both hemangiogenesis and lymphangiogenesis were significantly suppressed in the corneas of the sR2/Fc group compared with the IgG/Fc group. All grafts failed due to corneal wound rupture in the sR1/Fc group. In the sR2/Fc group, respective donor-derived MHC class II + /CD11c + cells and CD11b-positive macrophage infiltration were reduced in the DLNs and the corneas showing a negative delayed-type hypersensitivity, compared with the IgG/Fc group. Our findings demonstrate that soluble VEGFR2/Fc chimera protein efficiently suppresses corneal allo-rejection, while reducing hemangiogenesis and lymhangiogenesis, and immune-competent cell-trafficking and may be a powerful tool for corneal allograft survival.

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Inhibition of Hemangiogenesis and LymphangiogenesisafterNormal-Risk Corneal Transplantation by Neutralizing VEGF Promotes Graft Survival

Cited by 301 publications

References 27 publications

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

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

Topical Application of Soluble CD83 Induces IDO-Mediated Immune Modulation, Increases Foxp3+ T Cells, and Prolongs Allogeneic Corneal Graft Survival

Suppression of Allograft Rejection with Soluble VEGF Receptor 2 Chimeric Protein in a Mouse Model of Corneal Transplantation

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