Transient immunomodulation with anti-CD40 ligand antibody and CTLA4Ig enhances persistence and secondary adenovirus-mediated gene transfer into mouse liver - PubMed (original) (raw)

Transient immunomodulation with anti-CD40 ligand antibody and CTLA4Ig enhances persistence and secondary adenovirus-mediated gene transfer into mouse liver

M A Kay et al. Proc Natl Acad Sci U S A. 1997.

Abstract

Although recombinant adenovirus vectors offer a very efficient means by which to transfer genetic information into cells in vivo, antigen-dependent immunity limits the duration of gene expression and prevents retreatment. Recombinant murine CTLA4Ig and anti-CD40 ligand antibody block costimulatory interactions between T cells and antigen presenting cells. We previously reported that murine CTLA4Ig prolongs adenoviral-mediated gene transfer, but does not allow for secondary expression after readministration of the vector. In studies described here, when anti-CD40 ligand and recombinant murine CTLA4Ig were coadministered around the time of primary vector administration (i) prolonged adenovirus-mediated gene expression (length of experiment up to 1 year) from the livers of >90% of treated mice was observed, and (ii) secondary adenovirus-mediated gene transfer was achieved in >50% of the mice even after the immunosuppressive effects of these agents were no longer present. Nearly two-thirds of these mice had persistent secondary gene expression lasting for at least 200-300 days. Neither agent alone allowed transduction after secondary vector administration. Treated mice had decreased immune responses to the vector as shown by markedly decreased production of neutralizing antibodies, diminished spleen proliferation responses and IFN-gamma production in vitro, and reduced T cell infiltrates in the liver. These results suggest that it may be possible to obtain persistence as well as secondary adenoviral-mediated gene transfer with transient immunosuppressive therapies.

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Figures

Figure 1

Figure 1

Adenovirus-mediated hAAT expression in mice treated with (A) muCTLA4Ig, n = 27; (B) muCTLA4Ig/MR1, n = 25; (C) MR1, n = 15; (D) L6, n = 16. C3H or BALB/c mice were injected with 5 × 109 plaque-forming units of Ad/RSVhAAT or Ad/PGK hAAT by tail vein on day 0. The dose of muCTLA4Ig was 200 μg on days 0, 2, and 10; the dose of MR1 was 250 μg on days 0, 2, 4, and 6; and the dose of L6 was 200 μg on days 0, 2, and 10 or 0, 2, 4, and 6. Serum samples analyzed for hAAT were tested at least in duplicate. Each line represents an individual animal.

Figure 2

Figure 2

Secondary adenovirus-mediated hepatic gene transfer. C3H/HeJ or BALB/c mice were injected with 5 × 109 plaque-forming units (pfu) of Ad/PGKhAAT (A) or Ad/RSVhAAT (B and C) by tail vein on day 0. Mice in A and B received immunomodulatory agents as described in Fig. 1 and the mice in C received CTLA4Ig/MR1 or L6 on days −1, 0, 2, 10, 17, and 24 relative to adenovirus administration. The mice were redosed with 5 × 109 pfu of Ad/RSVcFIX: (A) 8 weeks after primary adenovirus infusion, n = 6; (B) 16 weeks after primary infusion, n = 9; (C) 18 weeks after primary infusion, n = 29. The mice received a second dose of immunomodulatory agents (•) or L6 control protein (○) at the time of Ad/RSVcFIX adenovirus admininistration on the same schedule as they received the first time. The mice designated by Δ represent naive animals that were infused with the same dose of Ad/RSVcFIX. Periodic serum samples were assayed for cFIX by ELISA in duplicate. The experiments shown correspond to experiments 2, 3, and 4 outlined in Table 1. Only mice that express cFIX after Ad/RSVcFIX administration are shown.

Figure 3

Figure 3

Splenocyte proliferation assays. Proliferation by splenocytes in response to Ad/.RSVhAAT. At the indicated days after administration of Ad/.RSVhAAT, splenocyte responses were assessed as described in the Materials and Methods. Results shown are proliferation in response to UV-inactivated Ad/RSVhAAT at the highest concentration of UV inactivated virus tested (108 pfu/ml), which was optimal. [3H]Thymidine uptake from unstimulated and anti-CD3-stimulated cells was similar in each group at each time point.

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