title: High-Risk Corneal Graft Rejection in the Setting of Previous Corneal Herpes Simplex Virus (HSV)-1 Infection.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Applied Medicine, Section of Immunity, Infection and Inflammation (Ocular Immunology), Institute of Medical Sciences, School of Medicine and Dentistry, Foresterhill, University of Aberdeen, Aberdeen, Scotland, United Kingdom.
authors.forename: Lucia
authors.initials: L
authors.lastname: Kuffova
authors.affiliation: Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States.
authors.forename: Jared E
authors.initials: JE
authors.lastname: Knickelbein
authors.affiliation: Division of Applied Medicine, Section of Immunity, Infection and Inflammation (Ocular Immunology), Institute of Medical Sciences, School of Medicine and Dentistry, Foresterhill, University of Aberdeen, Aberdeen, Scotland, United Kingdom.
authors.forename: Tian
authors.initials: T
authors.lastname: Yu
authors.affiliation: Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States.
authors.forename: Carlos
authors.initials: C
authors.lastname: Medina
authors.affiliation: Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Amescua
authors.affiliation: Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Rowe
authors.affiliation: Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States 3Departments of Immunology, Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, Unite.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hendricks
authors.affiliation: Division of Applied Medicine, Section of Immunity, Infection and Inflammation (Ocular Immunology), Institute of Medical Sciences, School of Medicine and Dentistry, Foresterhill, University of Aberdeen, Aberdeen, Scotland, United Kingdom 4Ocular Immunology.
authors.forename: John V
authors.initials: JV
authors.lastname: Forrester
mesh_terms: D056704:Adaptive Immunity; D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016039:Corneal Transplantation; D004279:DNA, Viral / Q000235:genetics; D004195:Disease Models, Animal; D019084:Fluorescent Antibody Technique, Indirect; D006084:Graft Rejection / Q000276:immunology* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000502:physiology*; D007113:Immunity, Innate; D016849:Keratitis, Herpetic / Q000473:pathology / Q000601:surgery* / Q000821:virology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D016133:Polymerase Chain Reaction; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic; D012668:Trigeminal Ganglion / Q000821:virology; D014775:Virus Activation / Q000502:physiology
chemical_list: D004279:DNA, Viral