Long-term liver allograft survival induced by combined treatment with rAAV-hCTLA4Ig gene transfer and low-dose FK506.
BACKGROUND
Recombinant adeno-associated virus vector (rAAV) is a promising vehicle for gene delivery, but few reports have documented its application in solid organ transplantation. In a rat orthotopic liver transplantation model, we investigated the efficacy of rAAV-mediated human cytotoxic T-lymphocyte-associated antigen 4 and immunoglobulin G (hCTLA4Ig) gene transfer to induce long-term allograft survival.


METHODS
Dark Agouti and Lewis rats were used as donors and recipients, respectively, in six experimental groups: (a) syngeneic control, (b) no treatment, (c) rAAV-green fluorescent protein, (d) rAAV-hCTLA4Ig, (e) low-dose FK506 for 7 days, and (f) rAAV-hCTLA4Ig and low-dose FK506 for 7 days.


RESULTS
The liver allografts were rejected within 10 days when no treatment was given or rAAV-green fluorescent protein was delivered. rAAV-hCTLA4Ig transduction slightly prolonged the survival time to 11 days. Long-term survival was achieved using the combined treatment of rAAV-hCTLA4Ig and low-dose FK506, whereas grafts were rejected on day 33 in the low-dose FK506 group. A sustained hCTLA4 level in plasma was detected in the combined treatment group from day 5 to day 180. On postoperative day 5, combined treatment significantly decreased the interleukin-2 and interferon-gamma protein levels in the grafts and the number of infiltrating B, T, CD25+, CD4+, CD8+, and NK cells.


CONCLUSIONS
This study shows that rAAV-hCTLA4Ig gene transfer combined with low-dose FK506 can achieve long-term liver allograft survival.
Yang
Zhenfan
Z
Centre for the Study of Liver Disease and Department of Surgery, University of Hong Kong Medical Centre, Queen Mary Hospital, Hong Kong, China.
Wu
Xiaobing
X
Tsui
Tung-Yu
TY
Hou
Yunde
Y
Luk
John M
JM
Fan
Sheung-Tat
ST
D000069594:Abatacept; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D003131:Combined Modality Therapy; D016207:Cytokines / Q000032:analysis; D005822:Genetic Vectors; D006084:Graft Rejection / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects*; D018796:Immunoconjugates / Q000097:blood / Q000235:genetics*; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016031:Liver Transplantation; D008297:Male; D011183:Postoperative Complications / Q000188:drug therapy / Q000517:prevention & control; D051381:Rats; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000494:pharmacology*; D014184:Transplantation, Homologous
D016207:Cytokines; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept; D016559:Tacrolimus