Interferon-alpha and interleukin-12 are induced differentially by Toll-like receptor 7 ligands in human blood dendritic cell subsets.

Dendritic cells (DCs) play a crucial role in the immune responses against infections by sensing microbial invasion through toll-like receptors (TLRs). In humans, two distinct DC subsets, CD11c(-) plasmacytoid DCs (PDCs) and CD11c(+) myeloid DCs (MDCs), have been identified and can respond to different TLR ligands, depending on the differential expression of cognate TLRs. In this study, we have examined the effect of TLR-7 ligands on human DC subsets. Both subsets expressed TLR-7 and could respond to TLR-7 ligands, which enhanced the survival of the subsets and upregulated the surface expression of costimulatory molecules such as CD40, CD80, and CD86. However, the cytokine induction pattern was distinct in that PDCs and MDCs produced interferon (IFN)-alpha and interleukin (IL)-12, respectively. In response to TLR-7 ligands, the Th1 cell supporting ability of both DC subsets was enhanced, depending on the cytokines the respective subsets produced. This study demonstrates that TLR-7 exerts its biological effect in a DC subset-specific manner.

Hodgkin's reed-sternberg cell line (KM-H2) promotes a bidirectional differentiation of CD4+CD25+Foxp3+ T cells and CD4+ cytotoxic T lymphocytes from CD4+ naive T cells.

A recent report revealed that a large population of Hodgkin's lymphoma-infiltrating lymphocytes (HLILs) consisted of regulatory T cells. In this study, we cocultured CD4+ naive T cells with KM-H2, which was established as a Hodgkin's Reed-Sternberg cell line, to clarify their ability to induce CD25+ Forkhead box P3+ (Foxp3+) T cells. The characteristic analyses of T cells cocultured with KM-H2 revealed the presence of CD4+CD25+ T cells. They expressed CTLA-4, glucocorticoid-induced TNFR family-related gene, and Foxp3 and could produce large amounts of IL-10. Conversely, KM-H2 also generated CD4+ CTLs, which expressed Granzyme B and T cell intracellular antigen-1 in addition to Foxp3+ T cells. They exhibit a strong cytotoxic effect against the parental KM-H2. In conclusion, KM-H2 promotes a bidirectional differentiation of CD4+ naive T cells toward Foxp3+ T cells and CD4+ CTLs. In addition to KM-H2, several cell lines that exhibit the APC function were able to generate Foxp3+ T cells and CD4+ CTLs. Conversely, the APC nonfunctioning cell lines examined did not induce both types of cells. Our findings suggest that the APC function of tumor cells is essential for the differentiation of CD4+ naive T cells into CD25+Foxp3+ T cells and CD4+ CTLs and at least partly explains the predominance of CD25+Foxp3+ T cells in HLILs and their contribution to a better prognosis. Therefore, in APC-functioning tumors, including classical Hodgkin lymphomas, which generate Foxp3+ T cells and CD4+ CTLs, these T cell repertories play a beneficial role synergistically in disease stability.

Bone marrow monocyte lineage cells adhere on injured endothelium in a monocyte chemoattractant protein-1-dependent manner and accelerate reendothelialization as endothelial progenitor cells.

Peripheral blood (PB)-derived CD14+ monocytes were shown to transdifferentiate into endothelial cell (EC) lineage cells and contribute to neovascularization. We investigated whether bone marrow (BM)- or PB-derived CD34-/CD14+ cells are involved in reendothelialization after carotid balloon injury. Although neither hematopoietic nor mesenchymal stem cells were included in human BM-derived CD34-/CD14+ monocyte lineage cells (BM-MLCs), they expressed EC-specific markers (Tie2, CD31, VE-cadherin, and endoglin) to an extent identical to mature ECs. When BM-MLCs were cultured with vascular endothelial growth factors, hematopoietic markers were drastically decreased and new EC-specific markers (Flk and CD34) were induced. BM-MLCs were intra-arterially transplanted into balloon-injured arteries of athymic nude rats. When BM-MLCs were activated by monocyte chemoattractant protein-1 (MCP-1) in vivo or in vitro, they adhered onto injured endothelium, differentiated into EC-like cells by losing hematopoietic markers, and inhibited neointimal hyperplasia. Ability to prevent neointimal hyperplasia was more efficient than that of BM-derived CD34+ cells. MCP-dependent adhesion was not observed in PB-derived CD34-/CD14+ monocytes. Regenerated endothelium exhibited a cobblestone appearance, blocked extravasation of dye, and induced NO-dependent vasorelaxation. Basal adhesive activities on HUVECs under laminar flow and beta1-integrin expression (basal and active forms) were significantly increased in BM-MLCs compared with PB-derived monocytes. MCP-1 markedly enhanced adhesive activity of BM-MLCs (2.8-fold) on HUVECs by activating beta1-integrin conformation. Thus, BM-MLCs can function as EC progenitors that are more potent than CD34+ cells and acquire the ability to adhere on injured endothelium in a MCP-1-dependent manner, leading to reendothelialization associated with inhibition of intimal hyperplasia. This will open a novel window to MCP-1-mediated biological actions and vascular regeneration strategies by cell therapy.

Early pharmacodynamic assessment using ¹8F-fluorodeoxyglucose positron-emission tomography on molecular targeted therapy and cytotoxic chemotherapy for clinical outcome prediction.

Early prediction of therapeutic outcome is important in determining whether the ongoing therapy is beneficial. In addition to anatomical response determined using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, recent studies have indicated that change in tumor glucose use on or after treatment correlates with histopathologic tumor regression and patient outcomes. This Perspective discusses the use of (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) for pharmacodynamic evaluation in a very early phase of treatment to predict clinical outcomes in patients with advanced non-small-cell lung cancer. We conducted a study to assess whether early metabolic response determined using FDG-PET correlated with clinical outcomes in patients treated with gefitinib or those treated with carboplatin plus paclitaxel (CP). Early metabolic response to gefitinib, but not CP, correlated with the late metabolic response, anatomical response, progression-free survival, and even overall survival. A rapid effect of molecular targeted agents might not be aptly evaluated using the conventional criteria, eg, RECIST, in a very early phase of treatment before volumetric shrinkage of the tumor. Based on the findings of several studies, and on the findings from our study, use of FDG-PET might enable prediction of clinical outcomes at a very early stage of treatment, especially in patients treated with molecular targeted agents with rapid clinical efficacy.

Phase I/II study of docetaxel and S-1 in patients with previously treated non-small cell lung cancer.

INTRODUCTION: The aim of this study was to determine and evaluate the recommended dose of docetaxel in combination with a novel oral 5-fluorouracil analogue S-1 and evaluate the efficacy and safety in patients with previously treated non-small cell lung cancer. METHODS: In phase I, patients with previously treated non-small cell lung cancer were treated with docetaxel (starting dose 40 mg/m) intravenously on day 1 and oral administration of S-1 at a fixed dose of 80 mg/m on days 1 to14 every 3 weeks. The recommended dose was the dose level preceding the maximum tolerated dose; once determined, patients were enrolled in phase II. RESULTS: The recommended dose of docetaxel was 40 mg/m in combination with S-1 80 mg/m/d. Of 30 patients enrolled in phase II part, 29 patients were eligible and analyzed. No complete response and 7 (24.1%) partial responses were observed, for an overall response rate of 24.1% (95% confidence interval, 10.3-43.5%). Median overall survival was 11.8 months. The 1-year survival rate was 42%. The grade 3 to 4 hematologic toxicities were neutropenia (34.5%), leukopenia (20.6%), and anemia (10.3%). The grade 3 to 4 nonhematological toxicities included fever 2 (6.9%), diarrhea 1 (3.4%), stomatitis 1 (3.4%), cerebral infarction 1 (3.4%), and pneumonitis 1 (3.4%). There was one treatment-related death due to relapse of drug induced pneumonitis. CONCLUSIONS: This combination chemotherapy is highly active and well tolerated in previously treated patients with non-small cell lung cancer. These results are encouraging and warrant additional investigation.

Dendritic cells are decreased in blood and accumulated in granuloma in tuberculosis.

Immunity against tuberculosis consists of innate and adaptive immune responses. In this study, we investigated the dynamics of dendritic cells (DC), which are known to elicit a variety of immune responses, in patients with tuberculosis. CD11c(+) peripheral blood DC were decreased in patients with tuberculosis. Immunohistochemical analyses demonstrated that a number of fascin(+), CD11c(+), HLA-DR(+) DC were infiltrating the lymphocyte areas of the tuberculous granulomas (tubercles). Immunohistochemical analyses also demonstrated that interferon-gamma-producing Th1 cells were increased in the tubercles of the patients, indicating the presence of Th1 polarization at least in the context of inflammatory tissues. In vitro coculture of autologous naive T cells with CD11c(+) or CD11c(-) DC pretreated with Bacillus Calmette Guérin augmented the production of Th1 cells. These findings suggested that the trafficking of DC from the peripheral blood into the tubercles causes a dominant Th1 balance and thus plays an essential role in the immunity against tuberculosis.