Expression and function of inducible co-stimulator in patients with systemic lupus erythematosus: possible involvement in excessive interferon-γ and anti-double-stranded DNA antibody production

Inducible co-stimulator (ICOS) is the third member of the CD28/cytotoxic T-lymphocyte associated antigen-4 family and is involved in the proliferation and activation of T cells. A detailed functional analysis of ICOS on peripheral blood T cells from patients with systemic lupus erythematosus (SLE) has not yet been reported. In the present study we developed a fully human anti-human ICOS mAb (JTA009) with high avidity and investigated the immunopathological roles of ICOS in SLE. JTA009 exhibited higher avidity for ICOS than a previously reported mAb, namely SA12. Using JTA009, ICOS was detected in a substantial proportion of unstimulated peripheral blood T cells from both normal control individuals and patients with SLE. In CD4(+)CD45RO(+ )T cells from peripheral blood, the percentage of ICOS(+ )cells and mean fluorescence intensity with JTA009 were significantly higher in active SLE than in inactive SLE or in normal control individuals. JTA009 co-stimulated peripheral blood T cells in the presence of suboptimal concentrations of anti-CD3 mAb. Median values of [(3)H]thymidine incorporation were higher in SLE T cells with ICOS co-stimulation than in normal T cells, and the difference between inactive SLE patients and normal control individuals achieved statistical significance. ICOS co-stimulation significantly increased the production of IFN-γ, IL-4 and IL-10 in both SLE and normal T cells. IFN-γ in the culture supernatants of both active and inactive SLE T cells with ICOS co-stimulation was significantly higher than in normal control T cells. Finally, SLE T cells with ICOS co-stimulation selectively and significantly enhanced the production of IgG anti-double-stranded DNA antibodies by autologous B cells. These findings suggest that ICOS is involved in abnormal T cell activation in SLE, and that blockade of the interaction between ICOS and its receptor may have therapeutic value in the treatment of this intractable disease

Functional tooth restoration by next-generation bio-hybrid implant as a bio-hybrid artificial organ replacement therapy

Bio-hybrid artificial organs are an attractive concept to restore organ function through precise biological cooperation with surrounding tissues in vivo. However, in bio-hybrid artificial organs, an artificial organ with fibrous connective tissues, including muscles, tendons and ligaments, has not been developed. Here, we have enveloped with embryonic dental follicle tissue around a HA-coated dental implant, and transplanted into the lower first molar region of a murine tooth-loss model. We successfully developed a novel fibrous connected tooth implant using a HA-coated dental implant and dental follicle stem cells as a bio-hybrid organ. This bio-hybrid implant restored physiological functions, including bone remodelling, regeneration of severe bone-defect and responsiveness to noxious stimuli, through regeneration with periodontal tissues, such as periodontal ligament and cementum. Thus, this study represents the potential for a next-generation bio-hybrid implant for tooth loss as a future bio-hybrid artificial organ replacement therapy

AILIM/ICOS-mediated elongation of activated T cells is regulated by both the PI3-kinase/Akt and Rho family cascade

Abstract T-cell migration and movement is a critical component of a fully functional immune system. Activationinducible lymphocyte immunomediatory molecule/inducible co-stimulator (AILIM/ICOS), which is a member of CD28 co-stimulatory receptor family, induces both activated T-cell migration underneath tumor necrosis factor a-treated human umbilical vein endothelial cell layers and also the morphological polarization of activated T cells. In our current study, we have investigated the signaling mechanisms underlying the morphological polarization of activated T cells, initiated by AILIM/ICOS signaling. AILIM/ICOS signaling induces the activation of phosphoinositide-3 (PI3)-kinase, the product of which, phosphatidylinositol 3,4,5-trisphosphate (PIP3), was found to be localized in the lamellipodia at the front part of the cells. Phosphorylated Akt is also co-localized with PIP3 and filamentous actin in lamellipodia and the PI3-kinase/Akt signaling cascade has critical roles in T-cell polarization and lamellipodia formation via the re-organization of the actin cytoskeleton. Rho family members and their downstream effectors, Rho-associated kinase and p21-activated kinase (PAK), are also involved in AILIM/ICOS-mediated elongation. The PAK family members are serine/threonine kinase downstream effectors of both Rac and Cdc42. PAK3 is induced by the activation of T cells, whereas PAK1 is constitutively expressed in both naive and activated T cells. During the elongation, not only PAK1 but also PAK3 play an essential role through the phosphorylation of their conservative autophosphorylation sites and catalytic domain. Ser-244 phosphorylation, which is a putative Akt phosphorylation site, on PAK3 but not on PAK1 also regulates the morphological polarization of activated T cells by AILIM/ICOS signaling. Both the PI3-kinase/Akt and Rho family cascades operate coordinately to induce the forward migration of activated T cells by AILIM/ICOS signaling