Kyoko Tomita

Osaka University, Ōsaka-shi, Osaka-fu, Japan

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Publications (5)15.46 Total impact

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    ABSTRACT: In order to de-target undesirable transduction in the liver by an adenovirus (Ad) vector, we previously demonstrated that insertion of sequences perfectly complementary to liver-specific miR-122a into the 3'-untranslated region (UTR) of transgene specifically reduced the transgene expression in the liver by approximately 100-fold; however, a certain level of residual transgene expression was still found in the liver. In order to further suppress the hepatic transduction, we developed a two-Ad vector system that uses microRNA (miRNA)-regulated transgene expression system and the Cre-loxP recombination system, i.e., insertion of miR-122a target sequences and loxP sites into the transgene expression cassette and co-administration of a Cre recombinase-expressing Ad vector. In addition, to maintain as much as possible the transgene expression in the spleen, which is the target organ of this study, spleen-specific miR-142-3p target sequences were inserted into the 3'-UTR of the Cre recombinase gene to suppress Cre recombinase expression in the spleen. Spleen is an attractive target for immunotherapy because the spleen plays important roles in the immune system. Co-administration of Ad vector possessing CMV promoter-driven Cre recombinase expression cassette with miR-142-3p target sequences resulted in a further 24-fold reduction in the hepatic transgene expression by the Ad vector containing miR-122a target sequences and loxP sites, compared with co-administration of control Ad vector. On the other hand, there was no significant reduction of transgene expression in the spleen.
    Molecular Pharmaceutics 11/2012; · 4.57 Impact Factor
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    ABSTRACT: Mucosal delivery of antigens induces antigen-specific immune responses in both systemic and mucosal compartments, and is an attractive approach for preventing initial infection with mucosal pathogens. It has been shown that the intramuscular (i.m.) immunization of plasmid DNA by in vivo electroporation (DNA e.p.) induces both cellular and humoral immune responses in the airway-mucosal compartment as well as in the systemic compartment, implying there is a mechanism that bridges between the systemic and mucosal immune responses. An important question is whether the i.m. DNA e.p.-immunization alone can induce antigen-specific immune responses in the gut-mucosal compartment. Here, we investigated the induction of antigen-specific CD8(+) T cells and antibodies in both systemic and gut-mucosal compartments following i.m. DNA e.p.-immunization to mice. Surprisingly, the i.m. DNA e.p.-immunization induced the antigen-specific CD8(+) T cells and antigen-specific antibodies in the gut-mucosal as well as the systemic compartment. These results suggest that the i.m. DNA e.p.-immunization should be considered as an effective vaccine strategy for the prevention of gut-mucosal infectious diseases.
    Vaccine 10/2012; · 3.77 Impact Factor
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    ABSTRACT: Adenovirus vector (Adv) vaccination at a systemic site, such as intramuscular (i.m.) immunization, can induce antigen-specific CD8(+) T cell responses in both systemic and mucosal compartments. It remains unclear, however, how antigen-specific CD8(+) T cell response is induced in the mucosa. In this study, we found that type-I IFN signaling is required for the induction of mRNA expression of retinal dehydrogenase in the draining lymph nodes following the i.m. Adv vaccination. We show that type-I IFN signaling is required for the induction of antigen-specific CD8(+) T cell response in the gut-mucosal compartment following the i.m. Adv vaccination.
    Biochemical and Biophysical Research Communications 07/2012; 425(1):89-93. · 2.28 Impact Factor
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    ABSTRACT: Pre-existing anti-adenovirus neutralizing antibodies (AdNAbs) are a major barrier in clinical gene therapy using adenovirus vectors; however, the transduction profile of adenovirus vectors in the presence of AdNAbs following intratumoral injection has not been fully examined, although such vectors are often intratumorally injected in clinical studies. In this study, we evaluated the correlation between the titer of AdNAbs in the serum and the transduction profiles in the tumor and the liver following intratumoral administration into mice possessing various titers of AdNAbs. Adenovirus vector-mediated transduction in the tumor was inhibited by AdNAbs; however, when the titer of AdNAbs was less than 200, the levels of inhibition in the transduction efficiencies within the tumor ranged from approximately 2- to 100-fold. A more than 2500-fold reduction of adenovirus vector-mediated transduction was found in most of the mice when the titers of AdNAbs were >200. On the other hand, the transduction efficiencies in the liver were largely reduced almost to the levels of the mock-transduced mice even at the low titers of AdNAbs. These results provide crucial information for the clinical use of adenovirus vectors.
    Anticancer research 04/2012; 32(4):1145-52. · 1.71 Impact Factor
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    ABSTRACT: Carrier cells delivering a conditionally replicating adenovirus (CRAd), which selectively replicates in tumor cells and induces tumor cell lysis, have promising potential for treatment of cancer because CRAd-loaded carrier cells evade inhibition by neutralizing anti-adenovirus (Ad) antibodies and because the carrier cells are locally retained at the injection point after local injection. A previous study by Hamada et al. demonstrated that carrier cells (CRAd-containing cell fragments derived from the carrier cells) are engulfed into the target cells, probably through a pathway independent of the primary receptor for Ad, the coxsackievirus and Ad receptor (CAR) (Mol Ther, 15: 1121-1128; 2007); however, it remains to be elucidated whether carrier cells infected with a conventional CRAd, which is composed of subgroup-C Ad serotype-5 (Ad5), mediate antitumor effects on CAR-negative cells. In order to examine whether carrier cells delivering a conventional CRAd (Carrier-F5) induce lysis of CAR-negative tumor cells, CAR-positive and CAR-negative tumor cells were incubated with Carrier-F5. Carrier-F5 mediated efficient killing of CAR-positive tumor cells; however, CAR-negative tumor cells were almost refractory to Carrier-F5. On the other hand, carrier cells loaded with a fiber-substituted CRAd containing fiber proteins of Ad serotype-35 (Ad35) (CRAd-F35), which binds to human CD46 for infection, showed efficient killing of both CAR-positive and CAR-negative tumor cells. Intra-tumoral injection of carrier cells loaded with CRAd-F35 (Carrier-F35) also resulted in efficient regression of both CAR-positive and CAR-negative tumors. These results demonstrated that the expression levels of receptors for Ad are an important factor for CRAd-loaded carrier cell-mediated cancer therapy, and that Carrier-F35 would have potential as a cancer treatment for not only CAR-positive tumors but also CAR-negative tumors.
    Cancer gene therapy 11/2011; 19(2):118-25. · 3.13 Impact Factor