Kenichirou Tajima

Interferon-α 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)-α 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.

Immunomodulatory effects of cyclosporin A on human peripheral blood dendritic cell subsets

Cyclosporin A (CsA) is a potent immuno‐suppressant and is approved for the treatment of various disease conditions. The molecular biological mechanism of CsA has been investigated intensively in T cells and has been shown to involve the intracellular calcineurin pathway. Recently, it was reported that CsA has capacities to affect not only T cells but also antigen‐presenting cells such as B cells and dendritic cells (DCs). DCs are a master regulator of immune responses that have an integral capacity to prime naive T cells. In the present study, we investigated the biological effects of CsA on human peripheral blood DC subsets: CD11c+ myeloid and CD11c− lymphoid subsets. CsA inhibited the up‐regulation of co‐stimulatory molecules induced with or without microbial stimuli and CD40L on both CD11c+ and CD11c− subsets. In addition, CsA negatively regulated the endocytic activity of CD11c+ DC during the immature state. CsA inhibited the interleukin‐12 (IL‐12) production, but augmented the IL‐10 production from the LPS‐stimulated CD11c+ subset, whereas CsA reduced the interferon‐α (IFN‐α) production from the CD11c− subset infected with Sendai virus (SV). Both the LPS‐stimulated CD11c+ subset and SV‐infected CD11c− subset preferentially induced the development of IFN‐γ‐producing T helper‐type 1 (Th1) cells. Pretreatment of these DC subsets with CsA inhibited the Th1 skewing. These findings suggested a DC‐mediated mechanism of immunosupression by CsA.

Alteration of peripheral blood dendritic cells in patients with primary Sjögren's syndrome.

OBJECTIVE We recently identified 3 fractions of human peripheral blood (PB) dendritic cells (DC), including the monocyte-associated fractions 1 and 2 (CD1a+,CD11c+ and CD1a-,CD11c+, respectively) and the lymphoid-associated fraction 3 (CD1a-,CD11c-). We attempted to determine whether these fractions were altered in Sjögrens syndrome (SS). METHODS We examined 23 patients with primary SS and 22 normal control subjects. DC were purified from PB and analyzed by flow cytometry. Immunohistochemical staining of labial salivary glands of SS patients was performed with monoclonal antibodies against fascin, which is known to be specific for DC. RESULTS The total numbers of PB DC and fraction 1 DC were decreased in SS. Immunohistochemical staining demonstrated that fascin+,CD11c+,HLA-DR+ mononuclear cells were present and scattered among numerous fascin-hyperfiltrating cells in SS patients. Interferon-gamma (IFNgamma)-producing Th1 cells were shown to be increased in both PB and salivary glands of patients, indicating the presence of general IFNgamma-producing Th1 polarization in SS. Furthermore, numbers of Thl cells were increased when naive T cells were cocultured with fraction 1 DC in vitro. CONCLUSION These findings suggest selective trafficking of fraction 1 DC into focal sites of inflammation and subsequent promotion of Th1 balance, suggesting a novel pathogenesis of SS.

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 Hodgkins 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 Hodgkins 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.

Mycobacterium bovis Bacillus Calmette–Guérin suppresses inflammatory Th2 responses by inducing functional alteration of TSLP-activated dendritic cells

Allergic diseases such as atopic dermatitis and asthma develop as a consequence of dysregulated T(h)2 responses. Recently, it has been demonstrated that interaction between dendritic cells (DCs) and thymic stromal lymphopoietin (TSLP), an IL-7-like cytokine, is essential for evoking T(h)2 responses in allergy. In this study, we investigated whether Mycobacterium bovis Bacillus Calmette-Guérin (BCG), a strong T(h)1 response-inducing adjuvant, can alter the function of DCs activated by TSLP (TSLP-DCs). We demonstrated that BCG redirects TSLP-DCs away from inducing inflammatory T(h)2 cells that produce IL-4, IL-5, IL-13 and tumor necrosis factor (TNF)-alpha and toward regulatory T(h)1 cells that produce IFN-gamma and IL-10. We also demonstrated that this functional alteration of TSLP-DCs by BCG depended on both production of IL-12 from DCs and down-regulation of OX40 ligand, a member of the TNF family, on DCs. These findings suggest that BCG might be a useful adjuvant for the treatment of allergic diseases that are triggered by TSLP.

Bone Marrow Transplantation with a Reduced-Intensity Conditioning Regimen in a Patient with Wegener Granulomatosis and Therapy-Related Leukemia

We describe a patient with Wegener granulomatosis (WG) who underwent long-term cyclophosphamide treatment and thereafter developed acute myelogenous leukemia (AML). After the AML was induced into remission, the patient received an allogeneic stem cell transplant (allo-SCT) from his sibling after undergoing a reduced-intensity conditioning regimen. His clinical course shortly after allo-SCT was uneventful. No clinically apparent acute or chronic graft-versus-host disease developed. Repeated analysis of the peripheral blood lymphocytes after transplantation showed complete donor chimerism. The level of proteinase 3 antineutrophil cytoplasmic antibody (PR3-ANCA) remained undetectable until 4 months after transplantation, when it began to increase. When the level of PR3-ANCA peaked, the patient suddenly presented with fever and joint pain, which later spontaneously resolved in parallel with the declining titer of PR3-ANCA. He is now in remission for both AML and WG at 22 months after transplantation. The patient’s clinical course after allo-SCT may provide us with valuable information regarding the establishment of allo-SCT as a therapeutic option for WG.

Successful treatment with plasma exchange in adult-onset Still's disease with hyper-IL-18-naemia and hyperallergic state

Adult-onset Still’s disease (AOSD) is a rheumatoid disorder characterized by high fever, polyarthritis, leukocytosis, hyperferritinaemia, and mild liver involvement. We describe the case of a patient with AOSD with severe liver dysfunction. His serum levels of interleukin-10 and 18 showed a similar trend to his disease activity. Drug lymphocyte stimulation tests were positive for three drugs in the patient. Hypercytokinaemia was controlled by plasma exchange therapy.