Abstract
Allergic airway inflammation is generally considered to be a Th2-type immune response. Recent studies, however, have demonstrated that Th17-type immune responses also play important roles in this process, particularly in the pathogenesis of neutrophilic airway inflammation, a hallmark of severe asthma. We scrutinized several Kampo extracts that reportedly exhibit anti-inflammatory activity by using in vitro differentiation system of human and mouse naïve T cells. We found that hange-shashin-to (HST) and oren-gedoku-to (OGT) possess inhibitory activity for Th17 responses in vitro. Indeed, wogonin and berberine, major components common to HST and OGT, exhibit Th17-inhibitory activities in both murine and human systems in vitro. We therefore evaluated whether wogonin suppresses OVA-induced neutrophilic airway inflammation in OVA TCR-transgenic DO11.10 mice. Consequently, oral administration of wogonin significantly improved OVA-induced neutrophilic airway inflammation. Wogonin suppressed the differentiation of naïve T cells to Th17 cells, while showing no effects on activated Th17 cells.
Highlights
Different classes of specific immune responses are driven by the biased development of effector CD4+ T-cell subsets, that is, T helper 1 (Th1), Th2, and Th17 cells, that activate different components of cellular and humoral immunity
mixed lymphocyte reactions (MLR) meets the needs for such primary screening processes because (i) naıve CD4T cells are the major population that reacts against allogeneic antigen presenting cells, indicating that the cytokines detected in the cell-culture supernatant fluids of MLR are of newly differentiated CD4T cells; (ii) it is mediated by the physiological MHC-peptideTCR interactions; (iii) the clonal frequency of alloreactive naıve CD4T cells is markedly higher than that of foreign antigen-specific naıve CD4T cells; and (iv) alloreactive Th1, Th2, and Th17 cells are induced without the use of externally added cytokines, allowing us to target all the Th subsets in a single cell-culture well
We revealed that the administration of a D1-like-R antagonist inhibits Th17 differentiation, thereby improving clinical phenotypes, including experimental autoimmune encephalomyelitis (EAE), type 1 diabetes, glomerulonephritis, rheumatoid arthritis [8], and neutrophilic airway inflammation [9], in mouse models
Summary
Different classes of specific immune responses are driven by the biased development of effector CD4+ T-cell subsets, that is, T helper 1 (Th1), Th2, and Th17 cells, that activate different components of cellular and humoral immunity. MLR meets the needs for such primary screening processes because (i) naıve CD4T cells are the major population that reacts against allogeneic antigen presenting cells, indicating that the cytokines detected in the cell-culture supernatant fluids of MLR are of newly differentiated CD4T cells; (ii) it is mediated by the physiological MHC-peptideTCR interactions; (iii) the clonal frequency of alloreactive naıve CD4T cells is markedly higher than that of foreign antigen-specific naıve CD4T cells; and (iv) alloreactive Th1, Th2, and Th17 cells are induced without the use of externally added cytokines, allowing us to target all the Th subsets in a single cell-culture well Using these systems, we revealed that the administration of a D1-like-R antagonist inhibits Th17 differentiation, thereby improving clinical phenotypes, including experimental autoimmune encephalomyelitis (EAE), type 1 diabetes, glomerulonephritis, rheumatoid arthritis [8], and neutrophilic airway inflammation [9], in mouse models
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