title: hCTLA4-Ig transgene expression in keratocytes modulates rejection of corneal xenografts in a pig to non-human primate anterior lamellar keratoplasty model.
abstract: BACKGROUND
  Human corneal allografting is an established procedure to cure corneal blindness. However, a shortage of human donor corneas as well as compounding economic, cultural, and organizational reasons in many countries limit its widespread use. Artificial corneas as well as porcine corneal xenografts have been considered as possible alternatives. To date, all preclinical studies using de-cellularized pig corneas have shown encouraging graft survival results; however, relatively few studies have been conducted in pig to non-human primate (NHP) models, and particularly using genetically engineered donors.
  
  
  METHODS
  In this study, we assessed the potential benefit of using either hCTLA4-Ig transgenic or α1,3-Galactosyl Transferase (GT) Knock-Out (KO) plus transgenic hCD39/hCD55/hCD59/fucosyl-transferase pig lines in an anterior lamellar keratoplasty pig to NHP model.
  
  
  RESULTS
  Corneas from transgenic animals expressing hCTLA4-Ig under the transcriptional control of a neuron-specific enolase promoter showed transgene expression in corneal keratocytes of the stroma and expression was maintained after transplantation. Although a first acute rejection episode occurred in all animals during the second week post-keratoplasty, the median final rejection time was 70 days in the hCTLA4-Ig group vs. 21 days in the wild-type (WT) control group. In contrast, no benefit for corneal xenograft survival from the GTKO/transgenic pig line was found. At rejection, cell infiltration in hCTLA4Ig transgenic grafts was mainly composed of macrophages with fewer CD3+ CD4+ and CD79+ cells than in other types of grafts. Anti-donor xenoantibodies increased dramatically between days 9 and 14 post-surgery in all animals.
  
  
  CONCLUSIONS
  Local expression of the hCTLA4-Ig transgene dampens rejection of xenogeneic corneal grafts in this pig-to-NHP lamellar keratoplasty model. The hCTLA4-Ig transgene seems to target T-cell responses without impacting humoral responses, the control of which would presumably require additional peripheral immunosuppression.
authors.affiliation: Centre Hospitalier, Universitaire de Nantes, Nantes, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Vabres
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Le Bas-Bernardet
authors.forename: David
authors.initials: D
authors.lastname: Riochet
authors.forename: Yan
authors.initials: Y
authors.lastname: Chérel
authors.forename: David
authors.initials: D
authors.lastname: Minault
authors.forename: Jérémy
authors.initials: J
authors.lastname: Hervouet
authors.forename: Yvette
authors.initials: Y
authors.lastname: Ducournau
authors.forename: Anne
authors.initials: A
authors.lastname: Moreau
authors.forename: Véronique
authors.initials: V
authors.lastname: Daguin
authors.forename: Flora
authors.initials: F
authors.lastname: Coulon
authors.forename: Annaïck
authors.initials: A
authors.lastname: Pallier
authors.forename: Sophie
authors.initials: S
authors.lastname: Brouard
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
authors.forename: Mark B
authors.initials: MB
authors.lastname: Nottle
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Cowan
authors.forename: Eric
authors.initials: E
authors.lastname: Venturi
authors.forename: Pascal
authors.initials: P
authors.lastname: Mermillod
authors.forename: Philippe
authors.initials: P
authors.lastname: Brachet
authors.forename: Cesare
authors.initials: C
authors.lastname: Galli
authors.forename: Irina
authors.initials: I
authors.lastname: Lagutina
authors.forename: Roberto
authors.initials: R
authors.lastname: Duchi
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Bach
authors.forename: Gilles
authors.initials: G
authors.lastname: Blancho
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Soulillou
authors.forename: Bernard
authors.initials: B
authors.lastname: Vanhove
mesh_terms: D000069594:Abatacept; D000818:Animals; D030801:Animals, Genetically Modified; D015415:Biomarkers / Q000378:metabolism; D060527:Corneal Keratocytes / Q000276:immunology / Q000378:metabolism*; D016039:Corneal Transplantation / Q000379:methods*; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D018796:Immunoconjugates / Q000235:genetics / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D023421:Models, Animal; D034421:Sus scrofa / Q000235:genetics; D019076:Transgenes; D014183:Transplantation, Heterologous / Q000379:methods*
chemical_list: D015415:Biomarkers; D018796:Immunoconjugates; D000069594:Abatacept
keywords: 3-Galactosyl Transferase KnockOut; alpha1; corneal blindness; corneal xenograft; hCTLA4-Ig; lamellar keratoplasty; pig to non-human primate model; transgenic pig line