High-Risk Corneal Graft Rejection in the Setting of Previous Corneal Herpes Simplex Virus (HSV)-1 Infection

Kuffová, Lucia; Knickelbein, Jared E.; Tian, Yu; Medina, Carlos A.; Amescua, Guillermo; Rowe, Alexander M.; Hendricks, Robert L.; Forrester, John V.

doi:10.1167/iovs.15-17894

Cited by 30 publications

(16 citation statements)

References 34 publications

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“…We showed that syngeneic corneal grafts (that normally induce only very mild and transient corneal inflammation) induced more prolonged and robust inflammation when placed on KOS HSV-1 infected corneal bed with subclinical inflammation at 28-34 dpi. Our current data agree with our previous report in that opacity in syngeneic corneal grafts placed on previously HSV-1 KOS infected corneas with subclinical inflammation did not reach a sustained opacity score of 12 (opacity of 3 in each quadrant of the graft) that would be considered to be a rejected or failed corneal graft [28]. However, the inflammation in syngeneic grafts placed on previously HSV-1 infected corneal beds was significant, and would be unacceptable in a human graft.…”

Section: Discussionsupporting

confidence: 92%

Subclinical Herpes Simplex Virus Type 1 Infections Provide Site-Specific Resistance to an Unrelated Pathogen

Rowe

Yun

Treat

et al. 2017

The Journal of Immunology

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Herpes Simplex Virus-1 (HSV-1) infections of the cornea range in severity from minor transient discomfort to the blinding disease Herpes Stromal Keratitis (HSK), yet most patients experience a single episode of epithelial keratitis followed by reestablishment of a clear cornea. We asked if a single transient episode of HSV-1 epithelial keratitis causes long-term changes in the corneal microenvironment that influence immune responses to subsequent corneal infection or trauma. We showed that C57BL/6 mouse corneas infected with HSV-1 KOS, which induces transient herpes epithelial keratitis without HSK sequelae, possessed a significant leukocytic infiltrate comprised primarily of CD4+ T cells and macrophages along with elevated chemokines and cytokines that persisted without loss of corneal clarity (subclinical inflammation). Chemokine and cytokine expression was CD4+T cell-dependent, in that their production was significantly reduced by systemic CD4+T cell depletion starting before infection, although short-term (3 day) local CD4+ T cell depletion after infection did not influence chemokine levels in cornea. Corneas with subclinical inflammation developed significantly greater trauma-induced inflammation when they were recipients of syngeneic corneal transplants, but also exhibited significantly increased resistance to infections by unrelated pathogens such as pseudorabies virus (PRV). The resistance to PRV was CD4+ T cell-dependent, since it was eliminated by local CD4+T cell-depletion from the cornea. We conclude that transient HSV-1 corneal infections cause long-term alterations of the corneal microenvironment that provide CD4-dependent innate resistance to subsequent infections by antigenically unrelated pathogens.

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Section: Discussionsupporting

confidence: 92%

Subclinical Herpes Simplex Virus Type 1 Infections Provide Site-Specific Resistance to an Unrelated Pathogen

Rowe

Yun

Treat

et al. 2017

The Journal of Immunology

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“…Timely recognition and management is required to prevent the recurrence of HSV‐related inflammation and graft rejection. A study in animals showed that both innate and adaptive immune mechanisms associated with anti‐HSV CD4 T‐cell response play a significant role . Most of the dissolved grafts were related to recurrence, showing the importance of taking appropriate postoperative measures to prevent recurrence.…”

Section: Discussionmentioning

confidence: 99%

“…showed that both innate and adaptive immune mechanisms associated with anti-HSV CD4 T-cell response play a significant role. 24 Most of the dissolved grafts were related to recurrence, showing the importance of taking appropriate postoperative measures to prevent recurrence. It is recommended to continue taking oral antiviral drugs after surgery, but our patients failed to adhere to the treatment programme.…”

Section: Hsv-related Inflammation and Graft Rejection A Study In Animentioning

confidence: 99%

Short‐term results of acellular porcine corneal stroma keratoplasty for herpes simplex keratitis

Zheng

Huang

Zhang

et al. 2019

Xenotransplantation

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Background Corneal transplantation is a common surgical intervention for restoring vision loss due to corneal damages. However, for cultural reasons, there is a huge shortage of donor corneas in China. Acellular porcine corneal stromas (APCSs) can be used as corneal substitutes in lamellar keratoplasty for corneal ulcers. This study was conducted to analyze the results of APCS use for herpes simplex keratitis (HSK). Methods The study involved HSK patients who underwent keratoplasty with APCSs from February 2016 to October 2017 in the second affiliated hospital of Zhejiang University. Patient data were collected at 7 days, 1 month, 3 months, 6 months, and at the last follow‐up (7‐25 months) postoperative. The corneal transparency, neovascularization, visual acuity, and graft stability were observed. Results Thirteen patients with HSK including five patients with corneal perforation were included in this study, nine patients underwent deep anterior lamellar keratoplasty (DALK) and five perforation patients underwent double lamellar keratoplasty. There were nine men and four women with an average age of 62.5 ± 5.6 years old (ranging from 52 to 70 years old). The mean postoperative follow‐up duration was 15.1 ± 5.8 months (ranging from 7 to 25 months). At the last visit, visual acuity improved in nine patients (69.2%) compared with preoperative (P = 0.008).The grafts of seven individuals (53.8%) were completely transparent or slightly opaque; their corneal transparency score had improved significantly compared with before the surgery (P = 0.010). Various degrees of neovascularization were present in 11 of the 13 patients (84.6%), most neovascularization gradually stabilized. Graft dissolution occurred in three eyes (23.1%) during the observation period, two underwent regrafting, the other one became stable after treatment. Three patients underwent second allograft transplantation, two of which encountered APCS graft dissolution and one of the patients requested a human donor allograft transplantation due to transparency issues despite the absence of adverse issues. Conclusion Acellular porcine corneal stroma seems to be effective in the treatment of HSK and can be used in HSK with corneal perforation by using double lamellar keratoplasty in an emergency.

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“…but were significantly decreased by 14 days in the PEDF+DHA-treated group, supporting our hypothesis that this biphasic response, which shows a faster resolution of inflammation in the PEDF+DHA-treated group, also may partially explain the increased nerve regeneration and recovery of sensitivity we observed. Recent work has shown that cornea-graft rejection in a mouse model of HSV-1 keratitis depends on the presence of CD4+ T cells (Kuffova et al, 2016). …”

Section: Discussionmentioning

confidence: 99%

PEDF plus DHA modulate inflammation and stimulate nerve regeneration after HSV-1 infection

Neumann

Kakazu

et al. 2017

Experimental Eye Research

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Herpes simplex virus type-1 (HSV-1) infection leads to impaired corneal sensation and, in severe cases, to corneal ulceration, melting and perforation. Here, we explore the potential therapeutic action of pigment epithelial-derived factor (PEDF) plus docosahexaenoic acid (DHA) on corneal inflammation and nerve regeneration following HSV-1 infection. Rabbits inoculated with 100,000 PFU/eye of HSV-1 strain 17Syn+ were treated with PEDF+DHA or vehicle. PEDF+DHA treatment resulted in a biphasic immune response with stronger infiltration of CD4+T cells, neutrophils and macrophages at 7-days post-treatment (p.t.) that was significantly decreased by 14 days, compared to the vehicle-treated group. Screening of 14 immune-related genes by q-PCR showed that treatment induced higher expression of IFN-γ and CCL20 and inhibition of IL-18 by 7 days in the cornea. PEDF+DHA-treated animals developed less dendritic corneal lesions, opacity and neovascularization. Corneal nerve density increased at 12-weeks p.t. with functional recovery of corneal sensation. Treatment with PEDF+DHA that was postponed by 3 weeks also showed increased nerve density when compared to vehicle. Our data demonstrate that PEDF+DHA promotes resolution of the inflammatory response to the virus and, most importantly, induces regeneration of damaged corneal nerves vital for maintaining ocular surface homeostasis.

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High-Risk Corneal Graft Rejection in the Setting of Previous Corneal Herpes Simplex Virus (HSV)-1 Infection

Cited by 30 publications

References 34 publications

Subclinical Herpes Simplex Virus Type 1 Infections Provide Site-Specific Resistance to an Unrelated Pathogen

Subclinical Herpes Simplex Virus Type 1 Infections Provide Site-Specific Resistance to an Unrelated Pathogen

Short‐term results of acellular porcine corneal stroma keratoplasty for herpes simplex keratitis

PEDF plus DHA modulate inflammation and stimulate nerve regeneration after HSV-1 infection

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