Prolongation of liver xenograft survival by adenovirus vector-mediated CTLA-4Ig gene transfer.
Cytotoxic T lymphocyte-associated antigen-4/immunoglobulin fusion products (CTLA-4Ig), a structural homologue of CD28, has been shown to inhibit cellular and humoral immune responses. In this study, we investigated the efficacy of an adenovirus vector containing the CTLA-4Ig gene (AdCTLA-4Ig) on recipient survival after hamster-to-rat liver xenografting. AdCTLA-4Ig was administrated intravenously immediately after grafting. Gene expression was achieved a maximum of 7 days after vector injection and continued for more than 4 weeks. The proportion of CD25(+) T-cells in recipient lymph nodes was significantly reduced 7 days after administration of AdCTLA-4Ig, compared to a group given an adenoviral vector containing LacZ gene (AdLacZ) or to an untreated control group. AdCTLA-4Ig markedly reduced CD2(+) T-cell infiltration into the graft and significantly prolonged recipient survival time (9.2+/-4.12 days), compared to the untreated group (5.4+/-0.78 days) (P<0.001) and the AdLacZ-treated group (5.2+/-0.28 days) (P<0.001). These results indicate that a blockade of T-cell co-stimulation by AdCTLA-4Ig inhibited T-cell activation and attenuated CD2(+) T-cell infiltration into the xenograft, resulting in significant prolongation of recipient survival time. Thus, AdCTLA-4Ig therapy may provide a novel approach to immune regulation.
Guo
Lei
L
Department of Innovative Surgery, National Research Institute for Child Health and Development, 3-35-31 Taishido, Setagaya-ku, 154-8567, Tokyo, Japan.
Li
Xiao kang
Xk
Enosawa
Shin
S
Harihara
Yasushi
Y
Funeshima
Naoko
N
Kimura
Hiromitsu
H
Fujino
Masayuki
M
Makuuchi
Masatoshi
M
Suzuki
Seiichi
S
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D060908:CTLA-4 Antigen; D006224:Cricetinae; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D007763:Lac Operon; D016031:Liver Transplantation / Q000473:pathology / Q000502:physiology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051381:Rats; D015375:Receptors, Interleukin-2 / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D014183:Transplantation, Heterologous
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556708:Ctla4 protein, rat; D015375:Receptors, Interleukin-2