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

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

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Abstract

Purpose: The “high-risk phenotype” of corneal graft recipients is considered to be related to preexisting vascularization such as that associated with herpes simplex virus-1 (HSV-1) keratitis (HSK). The purpose of this study was to investigate the immunologic mechanisms underlying accelerated corneal graft rejection using a mouse model of HSK.

Methods: Herpes simplex virus type 1 keratitis was induced in BALB/c mice. Syngeneic and allogeneic (C57BL/6 mice) corneal grafts were performed in mice with HSK at different times after infection. Some grafts were performed on HSV-infected CD4 T cell–deficient BALB/c mice. Clinical, histologic, immunologic, and virus detection studies were performed on samples of cornea, draining lymph node (LN), and trigeminal ganglion (TG) cells.

Results: Corneal grafts in mice with HSK rejected with higher frequency and more rapid tempo compared with grafts in uninfected mice. In corneas with HSK and vascularization at the time of grafting, both syngeneic and allogeneic corneal grafts failed with similar frequency and tempo. However, in the absence of preexisting inflammation and vascularization, syngeneic grafts were accepted when the grafts were performed at a late time point after HSV infection (42 days), whereas allografts were rejected at this time. In contrast, syngeneic grafts in nonvascularized HSV-infected recipients failed if they were performed within 10 days of HSV infection, an effect that was dependent on CD4 T cells, as demonstrated using CD4 deficient mice. Importantly, a variably sustained but strongly positive anti-HSV T-cell response was detected in allografted HSK recipients with a similar but lesser response in syngeneic hosts.

Conclusions: A previous HSV-1 corneal infection predisposes donor grafts to a high risk of failure by both innate and adaptive immune mechanisms in which an anti-HSV CD4 T-cell response plays a prominent role.
Original languageEnglish
Pages (from-to)1578-1587
Number of pages10
JournalInvestigative Ophthalmology & Visual Science
Volume57
Issue number4
DOIs
Publication statusPublished - Apr 2016

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Graft Rejection
Human Herpesvirus 1
Virus Diseases
Keratitis
Transplants
Simplexvirus
T-Lymphocytes
Cornea
Trigeminal Ganglion
Infection
Inbred C57BL Mouse
Allografts
Lymph Nodes
Viruses
Inflammation
Phenotype

Keywords

  • prevascularized graft bed
  • corneal graft
  • HSV-1
  • tolerance

Cite this

Kuffova, L., Knickelbein, J. E., Yu, T., Medina, C., Amescua, G., Rowe, A. M., ... Forrester, J. V. (2016). High-Risk Corneal Graft Rejection in the Setting of Previous Corneal Herpes Simplex Virus (HSV)-1 Infection. Investigative Ophthalmology & Visual Science, 57(4), 1578-1587. https://doi.org/10.1167/iovs.15-17894

High-Risk Corneal Graft Rejection in the Setting of Previous Corneal Herpes Simplex Virus (HSV)-1 Infection. / Kuffova, Lucia; Knickelbein, Jared E.; Yu, Tian; Medina, Carlos ; Amescua, Guillermo; Rowe, Alexander M.; Hendricks, Robert L.; Forrester, John V.

In: Investigative Ophthalmology & Visual Science, Vol. 57, No. 4, 04.2016, p. 1578-1587.

Research output: Contribution to journalArticle

Kuffova, L, Knickelbein, JE, Yu, T, Medina, C, Amescua, G, Rowe, AM, Hendricks, RL & Forrester, JV 2016, 'High-Risk Corneal Graft Rejection in the Setting of Previous Corneal Herpes Simplex Virus (HSV)-1 Infection', Investigative Ophthalmology & Visual Science, vol. 57, no. 4, pp. 1578-1587. https://doi.org/10.1167/iovs.15-17894
Kuffova, Lucia ; Knickelbein, Jared E. ; Yu, Tian ; Medina, Carlos ; Amescua, Guillermo ; Rowe, Alexander M. ; Hendricks, Robert L. ; Forrester, John V. / High-Risk Corneal Graft Rejection in the Setting of Previous Corneal Herpes Simplex Virus (HSV)-1 Infection. In: Investigative Ophthalmology & Visual Science. 2016 ; Vol. 57, No. 4. pp. 1578-1587.
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abstract = "Purpose: The “high-risk phenotype” of corneal graft recipients is considered to be related to preexisting vascularization such as that associated with herpes simplex virus-1 (HSV-1) keratitis (HSK). The purpose of this study was to investigate the immunologic mechanisms underlying accelerated corneal graft rejection using a mouse model of HSK.Methods: Herpes simplex virus type 1 keratitis was induced in BALB/c mice. Syngeneic and allogeneic (C57BL/6 mice) corneal grafts were performed in mice with HSK at different times after infection. Some grafts were performed on HSV-infected CD4 T cell–deficient BALB/c mice. Clinical, histologic, immunologic, and virus detection studies were performed on samples of cornea, draining lymph node (LN), and trigeminal ganglion (TG) cells.Results: Corneal grafts in mice with HSK rejected with higher frequency and more rapid tempo compared with grafts in uninfected mice. In corneas with HSK and vascularization at the time of grafting, both syngeneic and allogeneic corneal grafts failed with similar frequency and tempo. However, in the absence of preexisting inflammation and vascularization, syngeneic grafts were accepted when the grafts were performed at a late time point after HSV infection (42 days), whereas allografts were rejected at this time. In contrast, syngeneic grafts in nonvascularized HSV-infected recipients failed if they were performed within 10 days of HSV infection, an effect that was dependent on CD4 T cells, as demonstrated using CD4 deficient mice. Importantly, a variably sustained but strongly positive anti-HSV T-cell response was detected in allografted HSK recipients with a similar but lesser response in syngeneic hosts.Conclusions: A previous HSV-1 corneal infection predisposes donor grafts to a high risk of failure by both innate and adaptive immune mechanisms in which an anti-HSV CD4 T-cell response plays a prominent role.",
keywords = "prevascularized graft bed, corneal graft, HSV-1, tolerance",
author = "Lucia Kuffova and Knickelbein, {Jared E.} and Tian Yu and Carlos Medina and Guillermo Amescua and Rowe, {Alexander M.} and Hendricks, {Robert L.} and Forrester, {John V.}",
note = "Acknowledgments The authors thank M. Robertson and R. Fordyce for technical support during the duration of the study. The work performed in Aberdeen was supported by grant from Action Medical Research UK (SP4328; London, England, UK), NHS Grampian Endowment grant (12/49; Aberdeen, Scotland, UK), and Saving Sight in Grampian (Charity No.SC002938; Aberdeen, Scotland, UK). The work performed in Pittsburgh was supported by a Fight for Sight Post-Doctoral Award (JEK; New York, NY, USA); unrestricted grants from the Western Pennsylvania Medical Eye Bank Foundation (Pittsburgh, PA, USA), Research to Prevent Blindness (New York, NY, USA), and the Eye and Ear Foundation of Pittsburgh (RLH; Pittsburgh, PA, USA); and National Institutes of Health Grants P30EY08098 (RLH; Bethesda, MD, USA) and EY10359 (RLH).",
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T1 - High-Risk Corneal Graft Rejection in the Setting of Previous Corneal Herpes Simplex Virus (HSV)-1 Infection

AU - Kuffova, Lucia

AU - Knickelbein, Jared E.

AU - Yu, Tian

AU - Medina, Carlos

AU - Amescua, Guillermo

AU - Rowe, Alexander M.

AU - Hendricks, Robert L.

AU - Forrester, John V.

N1 - Acknowledgments The authors thank M. Robertson and R. Fordyce for technical support during the duration of the study. The work performed in Aberdeen was supported by grant from Action Medical Research UK (SP4328; London, England, UK), NHS Grampian Endowment grant (12/49; Aberdeen, Scotland, UK), and Saving Sight in Grampian (Charity No.SC002938; Aberdeen, Scotland, UK). The work performed in Pittsburgh was supported by a Fight for Sight Post-Doctoral Award (JEK; New York, NY, USA); unrestricted grants from the Western Pennsylvania Medical Eye Bank Foundation (Pittsburgh, PA, USA), Research to Prevent Blindness (New York, NY, USA), and the Eye and Ear Foundation of Pittsburgh (RLH; Pittsburgh, PA, USA); and National Institutes of Health Grants P30EY08098 (RLH; Bethesda, MD, USA) and EY10359 (RLH).

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N2 - Purpose: The “high-risk phenotype” of corneal graft recipients is considered to be related to preexisting vascularization such as that associated with herpes simplex virus-1 (HSV-1) keratitis (HSK). The purpose of this study was to investigate the immunologic mechanisms underlying accelerated corneal graft rejection using a mouse model of HSK.Methods: Herpes simplex virus type 1 keratitis was induced in BALB/c mice. Syngeneic and allogeneic (C57BL/6 mice) corneal grafts were performed in mice with HSK at different times after infection. Some grafts were performed on HSV-infected CD4 T cell–deficient BALB/c mice. Clinical, histologic, immunologic, and virus detection studies were performed on samples of cornea, draining lymph node (LN), and trigeminal ganglion (TG) cells.Results: Corneal grafts in mice with HSK rejected with higher frequency and more rapid tempo compared with grafts in uninfected mice. In corneas with HSK and vascularization at the time of grafting, both syngeneic and allogeneic corneal grafts failed with similar frequency and tempo. However, in the absence of preexisting inflammation and vascularization, syngeneic grafts were accepted when the grafts were performed at a late time point after HSV infection (42 days), whereas allografts were rejected at this time. In contrast, syngeneic grafts in nonvascularized HSV-infected recipients failed if they were performed within 10 days of HSV infection, an effect that was dependent on CD4 T cells, as demonstrated using CD4 deficient mice. Importantly, a variably sustained but strongly positive anti-HSV T-cell response was detected in allografted HSK recipients with a similar but lesser response in syngeneic hosts.Conclusions: A previous HSV-1 corneal infection predisposes donor grafts to a high risk of failure by both innate and adaptive immune mechanisms in which an anti-HSV CD4 T-cell response plays a prominent role.

AB - Purpose: The “high-risk phenotype” of corneal graft recipients is considered to be related to preexisting vascularization such as that associated with herpes simplex virus-1 (HSV-1) keratitis (HSK). The purpose of this study was to investigate the immunologic mechanisms underlying accelerated corneal graft rejection using a mouse model of HSK.Methods: Herpes simplex virus type 1 keratitis was induced in BALB/c mice. Syngeneic and allogeneic (C57BL/6 mice) corneal grafts were performed in mice with HSK at different times after infection. Some grafts were performed on HSV-infected CD4 T cell–deficient BALB/c mice. Clinical, histologic, immunologic, and virus detection studies were performed on samples of cornea, draining lymph node (LN), and trigeminal ganglion (TG) cells.Results: Corneal grafts in mice with HSK rejected with higher frequency and more rapid tempo compared with grafts in uninfected mice. In corneas with HSK and vascularization at the time of grafting, both syngeneic and allogeneic corneal grafts failed with similar frequency and tempo. However, in the absence of preexisting inflammation and vascularization, syngeneic grafts were accepted when the grafts were performed at a late time point after HSV infection (42 days), whereas allografts were rejected at this time. In contrast, syngeneic grafts in nonvascularized HSV-infected recipients failed if they were performed within 10 days of HSV infection, an effect that was dependent on CD4 T cells, as demonstrated using CD4 deficient mice. Importantly, a variably sustained but strongly positive anti-HSV T-cell response was detected in allografted HSK recipients with a similar but lesser response in syngeneic hosts.Conclusions: A previous HSV-1 corneal infection predisposes donor grafts to a high risk of failure by both innate and adaptive immune mechanisms in which an anti-HSV CD4 T-cell response plays a prominent role.

KW - prevascularized graft bed

KW - corneal graft

KW - HSV-1

KW - tolerance

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DO - 10.1167/iovs.15-17894

M3 - Article

VL - 57

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JO - Investigative Ophthalmology & Visual Science

JF - Investigative Ophthalmology & Visual Science

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