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Updated: Aug 7, 2026
Lentiviral Vector-mediated Gene Therapy of Hepatocytes Ex Vivo for Autologous Transplantation in Swine
Published on: November 4, 2018
Prolongation of liver xenograft survival by adenovirus vector-mediated CTLA-4Ig gene transfer
Lei Guo1, Xiao kang Li, Shin Enosawa
1Department of Innovative Surgery, National Research Institute for Child Health and Development, 3-35-31 Taishido, Setagaya-ku, 154-8567, Tokyo, Japan.
Abstract:
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.
Insights
Adenovirus-mediated Cytotoxic T lymphocyte-associated antigen-4/immunoglobulin fusion products (AdCTLA-4Ig) therapy significantly reduced T-cell activation and infiltration in xenograft models. This immune regulation approach markedly prolonged recipient survival time, offering a novel therapeutic strategy.
Area of Science:
- Immunology
- Gene Therapy
- Transplantation
Background:
- Cytotoxic T lymphocyte-associated antigen-4/immunoglobulin fusion products (CTLA-4Ig) inhibit immune responses.
- Adenovirus vectors are used for gene delivery.
Purpose of the Study:
- To investigate the efficacy of an adenovirus vector containing the CTLA-4Ig gene (AdCTLA-4Ig) in a hamster-to-rat liver xenograft model.
- To evaluate the impact of AdCTLA-4Ig on recipient survival and immune cell infiltration.
Main Methods:
- Intravenous administration of AdCTLA-4Ig immediately after liver xenografting.
- Monitoring gene expression, T-cell populations (CD25(+) and CD2(+)), and recipient survival.
- Comparison with a control group receiving an adenoviral vector containing the LacZ gene (AdLacZ) or no treatment.
Main Results:
- AdCTLA-4Ig gene expression was sustained for over 4 weeks.
- Significant reduction in CD25(+) T-cells in lymph nodes 7 days post-administration.
- Marked reduction in CD2(+) T-cell infiltration into the xenograft.
- Significantly prolonged recipient survival time (9.2 days) compared to untreated (5.4 days) and AdLacZ (5.2 days) groups (P<0.001).
Conclusions:
- AdCTLA-4Ig blockade of T-cell co-stimulation inhibits T-cell activation.
- Attenuated T-cell infiltration into the xenograft leads to prolonged survival.
- AdCTLA-4Ig therapy represents a novel approach for immune regulation in xenotransplantation.
