Role of T Cell Recruitment and Chemokine-Regulated Intra-Graft T Cell Motility Patterns in Corneal Allograft Rejection

Tan, Yaohong; Abdulreda, Midhat H.; Cruz-Guilloty, Fernando; Cutrufello, Nicholas J.; Shishido, Alexander; Martínez, Roberto Simón; Duffort, Stéphanie; Xia, Xin; Echegaray-Mendez, J.; Levy, Robert B.; Berggren, Per Olof; Pérez, Víctor L.

doi:10.1111/ajt.12228

Cited by 23 publications

(17 citation statements)

References 47 publications

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“…Numerous studies have suggested that T-cells play an important role in corneal graft rejection,53–55 and the Lck inhibitors have proved to be able to prevent solid organ transplant rejection, including kidney and heart transplantation 56–58. This evidence indicated that nintedanib, with the ability of inhibiting Lck, might have an effect to prevent corneal graft rejection by immune suppression.…”

Section: Discussionmentioning

confidence: 98%

Inhibition of lymphangiogenesis in vitro and in vivo by the multikinase inhibitor nintedanib

Lin¹,

Gong²

2017

DDDT

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PurposeTo investigate the feasibility of nintedanib, a novel triple angiokinase inhibitor, for inhibiting lymphatic endothelial cell (LEC)-induced lymphangiogenesis in vitro and inflammatory corneal lymphangiogenesis in vivo.Materials and methodsMethylthiazolyldiphenyl-tetrazolium bromide (MTT) test, transwell system, and tube-formation assay were used to evaluate the effects of nintedanib on the proliferation, migration, and tube formation of LECs stimulated by vascular endothelial growth factor-C (VEGF-C), basic fibroblast growth factor (bFGF), or platelet-derived growth factor-BB (PDGF-BB). The murine model of suture-induced corneal neovascularization was used to assess the anti-hemangiogenic and anti-lymphangiogenic effects of nintedanib via systemic and topical applications. Corneal flatmounts were stained with lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) and CD31, and the areas of involved blood and lymph vessels were analyzed morphometrically. Corneal cryosections were stained with F4/80 to evaluate inflammatory cell recruitment.ResultsWe observed a significant enhanced effect of LEC proliferation, migration, and tube formation with the administration of VEGF-C, PDGF-BB, and bFGF, respectively, which was diminished by nintedanib. Both topical and systemic applications of nintedanib inhibited suture-induced hemangiogenesis and lymphangiogenesis in the murine cornea. A reduction in F4/80+ cell infiltration was observed at day 14 after corneal suture for both systemic and topical applications of nintedanib. In comparison with controls, 61% of F4/80+ cell recruitment was inhibited via the systemic application of nintedanib, while 49% of F4/80+ cell recruitment was inhibited with the topical application of nintedanib.ConclusionNintedanib was shown to inhibit in vitro lymphangiogenesis stimulated by VEGF-C, bFGF, and PDGF-BB. Applied topically or systemically, it effectively inhibited corneal hemangiogenesis and lymphangiogenesis, accompanied by reduced inflammatory cell recruitment, which represents a new promising treatment for graft rejection after penetrating keratoplasty.

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Section: Discussionmentioning

confidence: 98%

Inhibition of lymphangiogenesis in vitro and in vivo by the multikinase inhibitor nintedanib

Lin¹,

Gong²

2017

DDDT

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“…Blockade of VLA-1 in a murine model of corneal transplantation has been shown to dramatically decrease infiltration of inflammatory cells, including T cells, and improve corneal allograft survival [41]. Interestingly, emerging data has shown that corneal allograft rejection is not only dependent on frequencies of infiltrating T cells but is also associated with a distinct phenotype of T cells that are highly mobile within the allograft stroma [43]. CCR5/CXCR3 signaling plays a significant role in the motility patterns of infiltrating T cells.…”

Section: Trafficking and Homing Of Effector T Cellsmentioning

confidence: 99%

“…CCR5/CXCR3 signaling plays a significant role in the motility patterns of infiltrating T cells. Blockade of CCR5/CXCR3 pathway alters the phenotype of graft-infiltrating T cells to that of less mobile cells and significantly promotes corneal allograft survival [43]. …”

Section: Trafficking and Homing Of Effector T Cellsmentioning

confidence: 99%

Effector and Regulatory T Cell Trafficking in Corneal Allograft Rejection

Amouzegar

Chauhan

2017

Mediators of Inflammation

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Corneal transplantation is among the most prevalent and successful forms of solid tissue transplantation in humans. Failure of corneal allograft is mainly due to immune-mediated destruction of the graft, a complex and highly coordinated process that involves elaborate interactions between cells of innate and adaptive immunity. The migration of immune cells to regional lymphoid tissues and to the site of graft plays a central role in the immunopathogenesis of graft rejection. Intricate interactions between adhesion molecules and their counter receptors on immune cells in conjunction with tissue-specific chemokines guide the trafficking of these cells to the draining lymph nodes and ultimately to the site of graft. In this review, we discuss the cascade of chemokines and adhesion molecules that mediate the trafficking of effector and regulatory T cells during corneal allograft rejection.

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“…Our group has utilized the eye to study in vivo and in real time the development of immune responses after inflammatory insults and transplantation [38–40]. The direct access to this organ and its transparency provides a unique opportunity to perform intravital microscopy of fluorescently labeled immune cells to monitor their recruitment and allow isolation for characterization of their phenotype and effector/regulatory functions.…”

Section: Ocular Graft-versus-host Disease: a Model To Visualize And Dmentioning

confidence: 99%

The allure and peril of hematopoietic stem cell transplantation: overcoming immune challenges to improve success

et al. 2013

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Since its inception in the mid-twentieth century, the complication limiting the application and utility of allogeneic hematopoietic stem cell transplantation (allo-HSCT) to treat patients with hematopoietic cancer is the development of graft-versus-host disease (GVHD). Ironically, GVHD is induced by the cells (T lymphocytes) transplanted for the purpose of eliminating the malignancy. Damage ensuing to multiple tissues, e.g., skin, GI, liver, and others including the eye, provides the challenge of regulating systemic and organ-specific GVH responses. Because the immune system is also targeted by GVHD, this both: (a) impairs reconstitution of immunity post-transplant resulting in patient susceptibility to lethal infection and (b) markedly diminishes the individual’s capacity to generate anti-cancer immunity—the raison d’etre for undergoing allo-HSCT. We hypothesize that deleting alloreactive T cells ex vivo using a new strategy involving antigen stimulation and alkylation will prevent systemic GVHD thereby providing a platform for the generation of anti-tumor immunity. Relapse also remains the major complication following autologous HSCT (auto-HSCT). While GVHD does not complicate auto-HSCT, its absence removes significant grant anti-tumor responses (GVL) and raises the challenge of generating rapid and effective anti-tumor immunity early post-transplant prior to immune reconstitution. We hypothesize that effective vaccine usage to stimulate tumor-specific T cells followed by their amplification using targeted IL-2 can be effective in both the autologous and allogeneic HSCT setting. Lastly, our findings support the notion that the ocular compartment can be locally targeted to regulate visual complications of GVHD which may involve both alloreactive and self-reactive (i.e., autoimmune) responses.

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Role of T Cell Recruitment and Chemokine-Regulated Intra-Graft T Cell Motility Patterns in Corneal Allograft Rejection

Cited by 23 publications

References 47 publications

Inhibition of lymphangiogenesis in vitro and in vivo by the multikinase inhibitor nintedanib

Inhibition of lymphangiogenesis in vitro and in vivo by the multikinase inhibitor nintedanib

Effector and Regulatory T Cell Trafficking in Corneal Allograft Rejection

The allure and peril of hematopoietic stem cell transplantation: overcoming immune challenges to improve success

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