Induction of lymphocyte apoptosis in rat liver allograft by adenoviral gene transfection of human interleukin-10.
OBJECTIVE
Gene therapy can provide a possible avenue in organ transplantation to treat acute allograft rejection. This study was designed to investigate the effect of adenovirus-mediated human IL-10 (hIL-10) gene transfer on the apoptosis of infiltrating lymphocytes and examine the efficacy of hIL-10 gene transfer in combination with subtherapeutic doses of cyclosporine A (CsA) in a rat liver transplantation model.


METHODS
Inbred male DA and LEW rats were used for liver donors and recipients, respectively. The rats were divided into saline, Ad-lacZ, CsA, Ad-hIL-10 and Ad-hIL-10 + CsA groups. Graft survival, histopathological, enzyme-linked immunosorbent assay, reverse transcriptase-polymerase chain reaction and flow cytometry were performed in liver specimens obtained from different time points after transplantation in the 5 groups.


RESULTS
Ad-hIL-10 pretreatment inhibited allograft rejection, prolonged the survival of hepatic allografts, and downregulated the expression of IFN-gamma and IL-2 mRNA, with simultaneous upregulation of IL-4 mRNA. In addition, Ad-hIL-10 pretreatment upregulated the expression of Fas mRNA in the isolated graft-infiltrating lymphocytes and induced graft-infiltrating lymphocyte apoptosis. A single subtherapeutic dose of CsA acted synergistically with it.


CONCLUSIONS
hIL-10 gene therapy induced alloreactive lymphocyte apoptosis via Fas/FasL pathway. hIL-10 gene transfection in combination with subtherapeutic doses of CsA facilitates the long-term survival of liver grafts.
Li
Jie-qun
JQ
Department of Organ Transplantation, Second Xiangya Hospital, Central South University, Changsha, China.
Qi
Hai-zhi
HZ
He
Zhi-jun
ZJ
Hu
Wei
W
Si
Zhong-zhou
ZZ
Li
Yi-ning
YN
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D015316:Genetic Therapy; D005822:Genetic Vectors; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000628:therapy; D006801:Humans; D016753:Interleukin-10 / Q000097:blood / Q000235:genetics* / Q000627:therapeutic use; D016031:Liver Transplantation / Q000276:immunology* / Q000473:pathology*; D008214:Lymphocytes / Q000276:immunology* / Q000473:pathology*; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000097:blood / Q000235:genetics / Q000627:therapeutic use; D014162:Transfection; D014184:Transplantation, Homologous
D017931:DNA Primers; C508609:IL10 protein, human; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016753:Interleukin-10