Systemic sclerosis (SSc) is characterized by excessive collagen deposition in the skin and internal organs. Activated fibroblasts are the key effector cells for the overproduction of type I collagen, which comprises the α1(I) and α2(I) chains encoded by COL1A1 and COL1A2, respectively. In this study, we examined the expression patterns of α1(I) and α2(I) collagen in SSc fibroblasts, as well as their co-regulation with each other. The relative expression ratio of COL1A1 to COL1A2 in SSc fibroblasts was significantly higher than that in control fibroblasts. The same result was observed for type I collagen protein levels, indicating that α2(I) collagen is more elevated than α2(I) collagen. Inhibition or overexpression of α1(I) collagen in control fibroblasts affected the α2(I) collagen levels, suggesting that α1(I) collagen might act as an upstream regulator of α2(I) collagen. The local injection of COL1A1 small interfering RNA in a bleomycin-induced SSc mouse model was found to attenuate skin fibrosis. Overall, our data indicate that α2(I) collagen is a potent regulator of type I collagen in SSc; further investigations of the overall regulatory mechanisms of type I collagen may help understand the aberrant collagen metabolism in SSc.

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Infantile hemangioma sometimes grows rapidly to a significant size around the first 2 months of life, which can be problematic and even destroy normal tissue. However, it is very difficult to predict the tumor growth at the first visit and to decide necessity of treatment. Therefore the identification of the biomarkers that can indicate a tendency to grow is clinically very important. In the present study, we evaluated the possibility that serum cytokine levels are available as the marker of hemangioma growth. Progressive hemangioma was defined as a lesion showing increased tumor size and/or coloration two weeks before and after the serum sampling, and we used membrane array to compare the twenty cytokine profiles between the sera of 3 progressive hemangioma patients and sex-/age-matched non-progressive hemangioma patients. As a result, many of the 20 cytokines were detected in the patients' sera. When a 2-fold difference in the mean levels of each group was considered meaningful, 6 of the 20 cytokines (IGF-1, IL-6, IL-8, PIGF, RANTES, TGF-β1) were down-regulated in the progressive hemangioma group compared to the non- progressive hemangioma group, and there were statistically significant difference (p < 0.05): especially, IGF-1, IL-6, IL-8, PIGF, and TGF-β1 did not expressed in all 3 progressive hemangioma patients. Accordingly, complicated cytokine network by these multiple cytokines may control the pathogenesis, and these cytokine levels may become clinically useful tumor markers. Furthermore, immunotherapy against them will be novel therapeutic approach.

We have established an immune cell therapy with immortalized induced pluripotent stem-cell–derived myeloid lines (iPS-ML). The benefits of using iPS-ML are the infinite proliferative capacity and ease of genetic modification. In this study, we introduced 4-1BBL gene to iPS-ML (iPS-ML-41BBL). The analysis of the cell-surface molecules showed that the expression of CD86 was upregulated in iPS-ML-41BBL more than that in control iPS-ML. Cytokine array analysis was performed using supernatants of the spleen cells that were cocultured with iPS-ML or iPS-ML-41BBL. Multiple cytokines that are beneficial to cancer immunotherapy were upregulated. Peritoneal injections of iPS-ML-41BBL inhibited tumor growth of peritoneally disseminated mouse melanoma and prolonged survival of mice compared to that of iPS-ML. Furthermore, the numbers of antigen-specific CD8⁺ T cells were significantly increased in the spleen and tumor tissues treated with epitope peptide-pulsed iPS-ML-41BBL compared to those treated with control iPS-ML. The number of CXCR6-positive T cells were increased in the tumor tissues after treatment with iPS-ML-41BBL compared to that with control iPS-ML. These results suggest that iPS-ML-41BBL could activate antigen-specific T cells and promote their infiltration into the tumor tissues. Thus, iPS-ML-41BBL may be a candidate for future immune cell therapy aiming to change immunological “cold tumor” to “hot tumor”.

Since the demonstrated clinical success of BRAF/MEK inhibitors in patients with metastatic melanoma harboring BRAF mutations, attention has been | POSTER