The chemokine receptors CCR5 and CXCR3 have been implicated as playing a central role in directing a Th1 inflammatory response. Here, we investigated whether a synthetic CCR5 antagonist affects the process of T cell migration to sites of inflammation. Immunization of DBA/1 mice with type II collagen resulted in typical arthritis, which is associated with cellular infiltration. Treatment with a CCR5 antagonist strikingly affected the development of arthritis by reducing both incidence and severity of disease. There was no substantial difference between collagen‐immunized mice with and without antagonist treatment in the induction of anti‐collagen T cell responses and the capacity to produce IL‐12. This endogenous IL‐12 functioned to induce comparable levels of CCR5 in these two immunized groups of T cells. Whereas a massive infiltration of inflammatory cells including CCR5+ T cells occurred in the joints of mice immunized without antagonist, cellular infiltration in the antagonist‐treated group was only marginal. These results indicate that administration of a CCR5 antagonist inhibits the development of arthritis not by affecting the generation of collagen‐sensitized T cells but by interfering with their migration to joint lesions.

The chemokine receptor CXCR3 has been shown to play a key role in the recruitment of T cells to sites of inflammation such as allografts. Here, we investigated which signals and conditions areresponsible for CXCR3 induction. CXCR3 was induced on T cells that were stimulated with anti‐CD3 plus anti‐CD28 monoclonal antibodies and then recultured without any external stimuli. CXCR3 expression was inhibited when TCR stimulation was persistent in the reculture. CXCR3 induction also depended on the stimulation with IFN‐γ because CXCR3 expression was not induced in IFN‐γ‐deficient T cells. The induction of another Th1 chemokine receptor CCR5 absolutely required IL‐12 stimulation and STAT4 involvement. In contrast, CXCR3 was induced on STAT4‐deficient T cells independently of IL‐12 stimulation as long as IFN‐γ was produced as a result of potent TCR stimulation. These results show that CXCR3 induction on TCR‐triggered T cells requires the release of these T cells from persistent TCR signaling and the stimulation with IFN‐γ and also indicate the differential regulatory mechanisms underlying the induction of two Th1 chemokine receptors.

Agaricus blazeiMurill is an edible fungus used in traditional medicine, which has various well-documented medicinal properties. In the present study, we investigated the effects of hemicellulase-derived mycelia extract (Agaricus blazeifraction H: ABH) on the immune system. First, we examined the cytokine-inducing activity of ABH on human peripheral mononuclear cells (PBMC). The results indicated that ABH induced expression of IL-12, a cytokine known to be a critical regulator of cellular immune responses. Flow cytometric analysis demonstrated the induction of IL-12 production by the CD14-positive cell population, consisting of monocytes/macrophages (Mo/Mφ). Furthermore, the elimination of Mo/Mφ attenuated IL-12 production in PBMC. ABH-induced IL-12 production was inhibited by anti-CD14 and anti-TLR4 antibodies but not by anti-TLR2 antibody. The activity of ABH was not inhibited by polymyxin B, while the activity of lipopolysaccharide used as a reference was inhibited. Oral administration of ABH enhanced natural killer (NK) activity in the spleen. These findings suggest that ABH activated Mo/Mφ in a manner dependent on CD14/TLR4 and NK activity.

Objective. To investigate the involvement of osteopontin (OPN) in bone destruction in a murine experimental arthritis model of collagen-induced arthritis (CIA).Methods. The expression of OPN was examined at both the messenger RNA (mRNA) and protein levels in various arthritic lesions in mice with CIA by in situ hybridization and immunohistochemistry, respectively. In addition, the expression of ␣v␤3 integrin, a receptor for OPN, the ligation of which is thought to be essential for bone resorption by osteoclasts, was examined by immunohistochemistry. Plasma concentrations of OPN were measured at different time points in the course of CIA by enzyme-linked immunosorbent assay.Results. OPN mRNA was detected mainly at sites of bone erosion in arthritic lesions, where activated osteoclasts were present; OPN protein was also detected at sites of bone erosion. In the arthritic synovium, OPN was predominantly expressed in the synovial lining layer, but not in lymphoid aggregates. In addition, ␣v␤3 integrin was detected coincident with OPN at sites of bone erosion (bone-pannus junction). Plasma OPN levels were markedly elevated at the time points that corresponded to arthritis flares, and higher levels were maintained during the progression of arthritis.Conclusion. OPN may mediate bone resorption by osteoclasts in arthritis through ligation with its receptor, ␣v␤3 integrin. OPN may be a useful therapeutic target molecule in the prevention of bone destruction in arthritis.

We present a systematic 115 In NQR study on the heavy fermion compounds CeRh 1−x Ir x In 5 (x=0.25, 0.35, 0.45, 0.5, 0.55 and 0.75). The results provide strong evidence for the microscopic coexistence of antiferromagnetic (AF) order and superconductivity (SC) in the range of 0.35 ≤ x ≤ 0.55. Specifically, for x=0.5, T N is observed at 3 K with a subsequent onset of superconductivity at T c =0.9 K. T c reaches a maximum (0.94 K) at x=0.45 where T N is found to be the highest (4.0 K).Detailed analysis of the measured spectra indicate that the same electrons participate in both SC and AF order. The nuclear spin-lattice relaxation rate 1/T 1 shows a broad peak at T N and follows a T 3 variation below T c , the latter property indicating unconventional SC as in CeIrIn 5 (T c =0.4 K). We further find that, in the coexistence region, the T 3 dependence of 1/T 1 is replaced by a T -linear variation below T ∼0.4 K, with the value (T 1 ) Tc (T 1 ) low−T increasing with decreasing x, likely due to low-lying magnetic excitations associated with the coexisting magnetism.