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hCTLA 4‐Ig transgene expression in keratocytes modulates rejection of corneal xenografts in a pig to non‐human primate anterior lamellar keratoplasty model
Author(s) -
Vabres Bertrand,
BasBernardet Stéphanie,
Riochet David,
Chérel Yan,
Minault David,
Hervouet Jérémy,
Ducournau Yvette,
Moreau Anne,
Daguin Véronique,
Coulon Flora,
Pallier Annaïck,
Brouard Sophie,
Robson Simon C.,
Nottle Mark B.,
Cowan Peter J.,
Venturi Eric,
Mermillod Pascal,
Brachet Philippe,
Galli Cesare,
Lagutina Irina,
Duchi Roberto,
Bach JeanMarie,
Blancho Gilles,
Soulillou JeanPaul,
Vanhove Bernard
Publication year - 2014
Publication title -
xenotransplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.052
H-Index - 61
eISSN - 1399-3089
pISSN - 0908-665X
DOI - 10.1111/xen.12107
Subject(s) - transgene , xenotransplantation , corneal transplantation , transplantation , biology , genetically modified mouse , stroma , cornea , corneal transplant , immunology , andrology , medicine , ophthalmology , immunohistochemistry , surgery , gene , biochemistry
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 hCTLA 4‐Ig transgenic or α1,3‐Galactosyl Transferase (GT) Knock‐Out (KO) plus transgenic hCD 39/ hCD 55/ hCD 59/fucosyl‐transferase pig lines in an anterior lamellar keratoplasty pig to NHP model. Results Corneas from transgenic animals expressing hCTLA 4‐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 hCTLA 4‐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 hCTLA 4Ig 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 hCTLA 4‐Ig transgene dampens rejection of xenogeneic corneal grafts in this pig‐to‐NHP lamellar keratoplasty model. The hCTLA 4‐Ig transgene seems to target T‐cell responses without impacting humoral responses, the control of which would presumably require additional peripheral immunosuppression.