464. Use of Equine Infectious Anaemia Virus (EIAV) To Mediate Indoleamine 2,3-dioxygenase Gene Transfer to Murine Corneal Allograft Transplantation Model Results in Prolongation of Allograft Survival In Vivo with Little Immunogenicity
Authors: Peng H. Tan, Sven C. Beutelspacher, Andrew J.T. George
Journal: Molecular Therapy (2006)

Background: Our laboratory have previously reported that viral vectors, in particular adenovirus are efficient at transducing corneal allografts but the immunogenicity associated with the vectors has negated the immunomodulatory effects of a therapeutic gene in prolonging allograft survivals 1. In this report, we have investigated the use of equine infectious anaemia virus (EIAV) in transferring a therapeutic gene, indoleamine 2,3-dioxygenase (IDO) to modulate allograft rejection. The vector transfection efficiency and its associated immunogenicity are analysed in a murine corneal allograft model.Methods & Results: First, IDO expression was analysed and functional activity was quantified in normal murine cornea. Low levels of IDO at both mRNA and protein levels could be detected in the normal cornea. However, inhibition of IDO activity in vivo had no effect on graft survival. Following EIAV-mediated IDO cDNA transfer, murine corneal endothelial cells or allografts expressed functional IDO which was effective at inhibiting allogeneic T cell proliferation. Therefore EAIV were efficient at transducing cornea allografts. Overexpression of IDO in donor corneal allografts resulted in prolonged graft survival. This was in contrary to our previous data suggesting that adenoviral vectors that did not result in a significant prolongation of allograft survival.Conclusions: Our data indicate that the low level of IDO in normal cornea is unlikely to be a significant factor in corneal immune privilege, however over-expression of IDO using EIAV in donor cornea was found to significantly extend survival of allografts. More importantly, these data suggest that EIAV was efficient at transducing corneal allografts, and little vector-induced immunogenicity was seen in the murine corneal allograft model. Therefore EIAV is good vector for transfer of immunomodulatory gene in a transplantation model without inducing pathogenic and inflammatory effects.Reference:1. Rayner SA, Larkin DF, George AJ. TNF receptor secretion after ex vivo adenoviral gene transfer to cornea and effect on in vivo graft survival. Invest Ophthalmol Vis Sci 2001; 42: 1568-1573. Background: Our laboratory have previously reported that viral vectors, in particular adenovirus are efficient at transducing corneal allografts but the immunogenicity associated with the vectors has negated the immunomodulatory effects of a therapeutic gene in prolonging allograft survivals 1. In this report, we have investigated the use of equine infectious anaemia virus (EIAV) in transferring a therapeutic gene, indoleamine 2,3-dioxygenase (IDO) to modulate allograft rejection. The vector transfection efficiency and its associated immunogenicity are analysed in a murine corneal allograft model. Methods & Results: First, IDO expression was analysed and functional activity was quantified in normal murine cornea. Low levels of IDO at both mRNA and protein levels could be detected in the normal cornea. However, inhibition of IDO activity in vivo had no effect on graft survival. Following EIAV-mediated IDO cDNA transfer, murine corneal endothelial cells or allografts expressed functional IDO which was effective at inhibiting allogeneic T cell proliferation. Therefore EAIV were efficient at transducing cornea allografts. Overexpression of IDO in donor corneal allografts resulted in prolonged graft survival. This was in contrary to our previous data suggesting that adenoviral vectors that did not result in a significant prolongation of allograft survival. Conclusions: Our data indicate that the low level of IDO in normal cornea is unlikely to be a significant factor in corneal immune privilege, however over-expression of IDO using EIAV in donor cornea was found to significantly extend survival of allografts. More importantly, these data suggest that EIAV was efficient at transducing corneal allografts, and little vector-induced immunogenicity was seen in the murine corneal allograft model. Therefore EIAV is good vector for transfer of immunomodulatory gene in a transplantation model without inducing pathogenic and inflammatory effects. Reference: 1. Rayner SA, Larkin DF, George AJ. TNF receptor secretion after ex vivo adenoviral gene transfer to cornea and effect on in vivo graft survival. Invest Ophthalmol Vis Sci 2001; 42: 1568-1573.