Biomedical subjects
Daizo Koinuma
Publications and source records attributed to Daizo Koinuma.
Vaccination of dendritic cells loaded with interleukin-12-secreting cancer cells augments in vivo antitumor immunity: characteristics of syngeneic and allogeneic antigen-presenting cell cancer hybrid cells.
Cancer immunotherapy by fusion of antigen-presenting cells and tumor cells has been shown to induce potent antitumor immunity. In this study, we characterized syngeneic and allogeneic, murine macrophage/dendritic cell (DC)-cancer fusion cells for the antitumor effects. The results showed the superiority of allogeneic cells as fusion partners in both types of antigen-presenting cells in an in vivo immunotherapy model. A potent induction of tumor-specific CTLs was observed in these immunized conditions. In addition, the immunization with DC-cancer fusion cells was better than that with macrophage-cancer fusion cells. Both syngeneic and allogeneic DC-cancer fusion cells induced higher levels of IFN-gamma production than macrophage-cancer fusion cells. Interestingly, allogeneic DC-cancer fusion cells were superior in that they efficiently induced Th1-type cytokines but not the Th2-type cytokines interleukin (IL)-10 and IL-4, whereas syngeneic DC-cancer fusion cells were powerful inducers of both Th1 and Th2 cytokines. These results suggest that allogeneic DCs are suitable as fusion cells in cancer immunotherapy. To further enhance the antitumor immunity in the clinical setting, we prepared DCs fused with IL-12 gene-transferred cancer cells and thus generated IL-12-secreting DC-cancer fusion cells. Immunization with these gene-modified DC-cancer fusion cells was able to elicit a markedly enhanced antitumor effect in the in vivo therapeutic model. This novel IL-12-producing fusion cell vaccine might be one promising intervention for future cancer immunotherapy.
Hepatocyte growth factor gene transfer to alveolar septa for effective suppression of lung fibrosis.
We examined therapeutic gene transfer of human hepatocyte growth factor (hHGF) to alveolar septa in mouse bleomycin-induced lung fibrosis using macroaggregated albumin-polyethylenimine complex (MAA-PEI). Intravenous administration of MAA-PEI along with 1 microg pCAG.hHGF to C57BL/6 mice increased the uptake of plasmids into alveolar capillary endothelial cells and epithelial cells, prolonged hHGF expression in the lung, and induced a level of hHGF expression equal to that seen with 10 microg of hHGF-expression plasmids alone. The exogenous source of hHGF gene expression increased the endogenous mouse HGF in the lungs and significantly decreased TNF-alpha, IL-6, and collagen synthesis after bleomycin injury. Because GFP-labeled bone marrow-derived stem cells after bleomycin injury were reduced in number by HGF, the primary mechanism of HGF is likely to be the prevention of apoptosis, as has been suggested by in vitro experiments. This novel HGF gene transfer method to alveolar septa with nonstimulatory MAA-PEI conjugates may have promising clinical applications.
[TGF-beta family (TGF-beta, activin, BMP)].
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[Bone formation and inflammation].
Role of BMP signaling is crucial in the osteoblast differentiation and bone formation. BMP induces expression of Runx2, a master gene for osteogenesis, and cooperates with Runx2 in mature osteoblast to express target genes. These functions are suppressed by TGF-beta-induced Smad7 together with Smurf1 by various mechanisms, including degradation of type I receptor, Smadl/5, and Runx2. Bone remodeling is achieved by "coupling" of osteoblasts and osteoclasts. Although excess maturation and activation of osteoclasts is well described during inflammation, effect of inflammation to the osteoblast function is still unclear. Further exploration in this area thus might lead to discovery of novel therapeutic targets of inflammatory bone diseases.
Arkadia amplifies TGF-beta superfamily signalling through degradation of Smad7.
Arkadia was originally identified as a protein that enhances signalling activity of Nodal and induces mammalian nodes during early embryogenesis; however, the mechanisms by which Arkadia affects transforming growth factor-beta (TGF-beta) superfamily signalling have not been determined. Here we show that Arkadia is widely expressed in mammalian tissues, and that it enhances both TGF-beta and bone morphogenetic protein (BMP) signalling. Arkadia physically interacts with inhibitory Smad, Smad7, and induces its poly-ubiquitination and degradation. In contrast to Smurf1, which interacts with TGF-beta receptor complexes through Smad7 and degrades them, Arkadia fails to associate with TGF-beta receptors. In contrast to Smad7, expression of Arkadia is down-regulated by TGF-beta. Silencing of the Arkadia gene resulted in repression of transcriptional activities induced by TGF-beta and BMP, and accumulation of the Smad7 protein. Arkadia may thus play an important role as an amplifier of TGF-beta superfamily signalling under both physiological and pathological conditions.
Successful treatment of a case with rapidly progressive Bronchiolitis obliterans organizing pneumonia (BOOP) using cyclosporin A and corticosteroid.
A 60-year-old woman was suffering from acute onset and progressive respiratory distress. Her radiographic findings showed bilateral volume loss in her lower lobes and consolidation predominantly distributed in peribronchovascular areas. The biopsied specimens performed by video-assisted thoracoscopic surgery revealed prominent fibromyxoid connective tissue within the terminal respiratory bronchioles and the alveolar spaces along the airways without marked interstitial fibrosis. No relevant cause was determined, and she was diagnosed as having idiopathic BOOP. Although her clinical course was fulminant with a poor reaction to steroid therapy, simultaneous administration of cyclosporin A and corticosteroid elicited a rapid improvement. This case report presents the effectiveness of cyclosporin A in the treatment of progressive BOOP.