Influence of local and systemic CTLA4Ig gene transfer on corneal allograft survival.
BACKGROUND
To analyse the effects of local (ex vivo) or systemic (in vivo) administration of adenovirus type 5 encoding CTLA4Ig (AdCTLA4Ig) on its influence to prolong corneal allograft survival and to study the underlying mechanisms.


METHODS
A MHC class I/II mismatched rat corneal transplant model was used. Recipients were randomly assigned to receive ex vivo gene-modified corneas expressing either CTLA4Ig, CTLA4Ig/IL-10 or a single intraperitoneal (i.p.) injection (1.0 x 10(9) or 1.0 x 10(10) infectious particles) of AdCTLA4Ig 1 day before transplantation and graft survival was analysed. The immunoregulatory effect of this treatment was examined by analysing intra-graft cytokine mRNA expression pattern at day 12 post-transplant. The anti-adenovirus immunity also was investigated.


RESULTS
Ex vivo gene transfer resulted in a modest but significant prolongation of graft survival (p = 0.0036 compared to no treatment). In contrast, systemic gene therapy (1.0 x 10(9) or 1.0 x 10(10) infectious particles) significantly prolonged graft survival (p = 0.0007 and 0.0001, respectively, compared to no treatment). Systemic (1.0 x 10(10) infectious particles) therapy resulted in frequent indefinite survival of allogeneic grafts which was not observed in the other therapeutic regimens. Moreover, systemic therapy prevented the intra-graft accumulation and activation of T cells and resulted in a reduced mRNA expression of both TH1 and TH2 cytokines. The generation of anti-adenovirus antibodies was also efficiently inhibited.


CONCLUSIONS
CTLA4Ig gene therapy is a successful strategy for the prevention of allogeneic graft rejection in corneal transplantation. Our work has further elucidated the mechanisms of corneal allograft rejection which may lead to novel therapeutic strategies.
Department of Ophthalmology, Charité--University Medicine Berlin, Germany.
Nianqiao
N
Gong
Uwe
U
Pleyer
Jun
J
Yang
Katrin
K
Vogt
Marcelo
M
Hill
Ignacio
I
Anegon
Hans-Dieter
HD
Volk
Thomas
T
Ritter
D000069594:Abatacept; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000906:Antibodies; D003315:Cornea / Q000378:metabolism*; D016039:Corneal Transplantation; D005260:Female; D015316:Genetic Therapy; D006082:Graft Enhancement, Immunologic; D006085:Graft Survival; D018796:Immunoconjugates / Q000097:blood / Q000235:genetics* / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D014161:Transduction, Genetic
D000906:Antibodies; D018796:Immunoconjugates; D012333:RNA, Messenger; D016753:Interleukin-10; D000069594:Abatacept