Herpes simplex virus keratitis: histopathologic inflammation and corneal allograft rejection

Ophthalmology. 2009 Jul;116(7):1301-5. doi: 10.1016/j.ophtha.2009.03.031.


Objective: To identify whether histopathologic and immunoassay biomarkers of inflammation are predictive for allograft rejection after penetrating keratoplasty (PKP) for herpes simplex virus (HSV) keratitis.

Design: Retrospective, interventional case series with prospective component of pathologic evaluation of frozen tissue.

Participants: Sixty-two consecutive patients with HSV keratitis who underwent PKP.

Methods: A chart review and histopathologic examination of the excised host corneal button was performed to identify associations between clinical data and histopathologic presence of inflammation. Enzyme-linked immunosorbent assay for interleukin (IL)-8 and monocyte chemotactic protein-1 (MCP-1) chemokines and immunohistochemical staining for human leukocyte antigen (HLA)-DR and intercellular adhesion molecule-1 (ICAM-1) antigens was also performed in inflamed and noninflamed specimens.

Main outcome measures: To determine whether the presence of subclinical inflammation at the time of PKP predicts allograft rejection.

Results: Although 81% of patients had clinically quiescent disease, histopathology revealed that 74% had active corneal inflammation, a finding that was associated with the presence of clinical neovascularization (P = 0.01). Allograft rejections were experienced by 34% of the patients in this cohort. The histopathologic presence of inflammation was a risk factor for allograft rejection (P = 0.02). Corneal specimens demonstrating inflammation had significantly increased IL-8 (P = 0.0005) and MCP-1 (P = 0.003) levels, and greater immunoreactivity for HLA-DR and ICAM-1 when compared with specimens without inflammation. Treatment with IL-10 ex vivo significantly inhibited IL-8 (P = 0.006), and MCP-1 (P = 0.01) chemokines, and qualitatively substantially reduced HLA-DR, but not ICAM-1, expression.

Conclusions: Histopathologic inflammation is a risk factor for corneal allograft rejection.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers / metabolism
  • Chemokine CCL2 / metabolism
  • Chemokines / metabolism
  • Child
  • Child, Preschool
  • Cornea / metabolism
  • Cornea / pathology*
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Graft Rejection / diagnosis*
  • Graft Rejection / etiology
  • Graft Rejection / metabolism
  • HLA-DR Antigens / metabolism
  • Humans
  • Inflammation / diagnosis*
  • Inflammation / metabolism
  • Intercellular Adhesion Molecule-1 / metabolism
  • Interleukin-8 / metabolism
  • Keratitis, Herpetic / metabolism
  • Keratitis, Herpetic / surgery*
  • Keratoplasty, Penetrating*
  • Male
  • Middle Aged
  • Retrospective Studies
  • Risk Factors
  • Transplantation, Homologous
  • Young Adult


  • Biomarkers
  • CCL2 protein, human
  • Chemokine CCL2
  • Chemokines
  • HLA-DR Antigens
  • Interleukin-8
  • Intercellular Adhesion Molecule-1