Sung-Jae Park

Blocking of monocyte‐associated B7‐H1 (CD274) enhances HCV‐specific T cell immunity in chronic hepatitis C infection

The establishment of a chronic hepatitis C (CHC) infection is associated with defective HCV‐specific T cell responses. Recent studies suggest that negative T cell regulators such as programmed death 1 (PD‐1) contribute to the impairment of virus‐specific T cell functions in chronic viral infections. However, the implication of peripheral monocytes from CHC patients in the inhibition of HCV‐specific T cell responses is only partially defined. In this study, we found that B7‐H1, a ligand of PD‐1, was significantly up‐regulated on monocytes of CHC patients. Proliferation of T cells in response to anti‐CD3 antibody was directly suppressed by B7‐H1+CD14+ monocytes, and this suppression was reversed by addition of antagonistic B7‐H1 mAb. Furthermore, blocking of monocyte‐associated B7‐H1 (moB7‐H1) significantly enhanced the frequency of IFN‐γ‐producing, HCV‐specific CD4+ and CD8+ effector T cells and the production of Th1 cytokines, such as IL‐2 but not Th2 cytokines, including IL‐4 and IL‐10. Upon B7‐H1 blockade, production of perforin was also increased in CD8+ T cells stimulated with HCV peptides. Our findings suggest that moB7‐H1 inhibits HCV‐specific CD4+ and CD8+ T lymphocyte proliferation and suppresses Th1 cytokine production and perforin secretion. Blockade of the B7‐H1 pathway thus represents an attractive approach in the treatment of chronic HCV infection.

The tryptophan metabolite 3-hydroxyanthranilic acid suppresses T cell responses by inhibiting dendritic cell activation

The generation of tryptophan (Trp) metabolites by indoleamine 2,3-dioxygenase (IDO) is an effective mechanism for T cell suppression. However, the effect of Trp metabolites on dendritic cells (DCs) remains unclear. Here, we investigated whether the tryptophan metabolite 3-hydroxyanthranilic acid (3-HAA) directly inhibits DC activation and is responsible for T cell suppression. We found that 3-HAA treatment significantly reduced IL-12, IL-6, and TNF-α production in bone marrow-derived DCs (BMDCs) stimulated with LPS. Maturation markers CD40, CD80, CD86, and I-A were also significantly reduced. Moreover, treatment with 3-HAA decreased the ability of DCs to stimulate T cell activation and differentiation in vitro and in vivo. Finally, we observed that phospho-JNK and phospho-38 levels were reduced in 3-HAA-treated DC2.4 cells and BMDCs. These results suggest that the tryptophan metabolite 3-HAA suppresses T cell responses by inhibiting DC activation.

Addition of Anti-neu Antibody to Local Irradiation Can Improve Tumor- Bearing BALB/c Mouse Survival through Immune-Mediated Mechanisms

This study investigated the therapeutic effects of combined local irradiation and anti-HER2/neu antibody in a mixed tumor mouse model comprised of a nonmetastatic neu-positive tumor and a metastatic neu-negative tumor. While local irradiation alone could control the primary tumor in a dose-dependent manner, it did not improve mouse survival. Combined treatment comprised of local irradiation and anti-neu antibody of tumor-bearing BALB/c mice significantly improved mouse survival (P < 0.5), even though the tumor growth was similar to that of the irradiated-alone group. The combined treatment significantly reduced metastatic tumor masses in the lung and increased immune cell infiltration in primary tumor tissues. However, immune deficient nude mice with tumors did not exhibit prolonged survival in response to the combined treatment. Collectively, these results show that combined local irradiation and anti-neu antibody can elicit an immune-mediated abscopal effect to extend survival. Although the mechanism for abscopal effects induced by the combined treatment of radiation and anti-HER2/neu antibody was not elucidated, to our knowledge this is the first published study to describe the abscopal effect induced by the combination of local irradiation and the anti-HER2/neu antibody.

Morphological change of PMO and SBA-15 by metamorphic reconstruction

The morphological change of periodic mesoporous organosilicas (PMO) and mesoporous silica SBA-15 with ordering and reconstruction of framework has been investigated. Sphere-shaped particles of PMO with disordered mesostructure generated at early reaction time transformed to gyroid- and multipod-shaped particle with hexagonal symmetry with increasing reaction time. With ordering of disordered worm-like channel within sphere-shaped particles, the assembled spheres elongated to multipod-shaped particles via oval followed by bat-shaped particle. The morphology of SBA-15 was easily controlled by varying the aging temperature with the same reaction mixture. Particles with sphere shape at low aging temperature were transformed to thick plate-shape and finally to rod-shape at higher aging temperature. The variation of external mophology of PMO and SBA-15 may be atributed to the metamorphic reconstruction.

NecroX-5 prevents breast cancer metastasis by AKT inhibition via reducing intracellular calcium levels

A major goal of breast cancer research is to prevent the molecular events that lead to tumour metastasis. It is well-established that both cytoplasmic and mitochondrial reactive oxygen species (ROS) play important roles in cell migration and metastasis. Accordingly, this study examined the molecular mechanisms of the anti-metastatic effects of NecroX-5, a mitochondrial ROS scavenger. NecroX-5 inhibited lung cancer metastasis by ameliorating migration in a mouse model. In human cancer cells, the inhibition of migration by NecroX-5 is cell type-dependent. We observed that the effect of NecroX-5 correlated with a reduction in mitochondrial ROS, but mitochondrial ROS reduction by MitoQ did not inhibit cell migration. NecroX-5 decreased intracellular calcium concentration by blocking Ca2+ influx, which mediated the inhibition of cell migration, AKT downregulation and the reduction of mitochondrial ROS levels. However, the reduction of mitochondrial ROS was not associated with supressed migration and AKT downregulation. Our study demonstrates the potential of NecroX-5 as an inhibitor of breast cancer metastasis.