Germinal center (GC) develops in secondary lymphoid tissues in response to thymus-dependent antigens (Ag), Ag-specific B cells are first activated in the T cell rich zones by T cells. Following conjugate formation between the T and B cell, Ag-specific B cell differentiation take place in two distinct sites, antibody forming cells (AFC) foci and GC. Recently has it been recognized that (i) B cell clonal expansion, (ii) somatic hypermutation in the variable (V) -region genes of immunoglobulin, (iii) selection on the basis of their ability to receive Ag-specific signals, (iv) isotypeswitching, and (v) the subsequent induction to differentiate into plasma cells or memory B cells take place in GCs. CD401igand-CD40 interaction is suggested to play crucial roles in these differentiation of GC B cells. We found that a significant proportion of mouse GC B cells expresses receptors (R) for IL-4 and IL-5. IL-4 in the presence of anti-CD40 mAb enhances viability of GC B cells, is essential for inducing differentiation of GC B cells into Ag-specific IgG1 AFC, and enhances the IL-5R expression on GC B cells. IL-5 further augments the IgG1 AFC response. We also discuss GC development and function of GC B cells in some mutant mice.

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We investigated whether signal (s) via CD44 may modulate the adhesive interactions between lymphoid cells and human gingival fibroblasts (HGF) . When OS/37 (anti-CD44 mAb) was added to the culture, the adhesion of freshly-isolated peripheral T cells to HGF was enhanced. Interestingly, the pretreatment of HGF with OS/ 37 enhanced adhesion not only resting T cells but also K562 (erythroleukemia line), which is CD44 negative, to HGF. These results suggest that acting on CD44 on HGF, OS/37 induced increased adhesion between lymphocytes and HGF. In order to clarify the molecule (s) involved in the enhanced cell adhesion by OS/37, a panel of mAbs was prepeared to HGF and lymphoid cells and one clone, 3S-B2, was selected on the basis of its ability to inhibit the enhanced cell adhesion by OS/37. Flow cytometric analysis using transfectants revealed that 3S-B2 recognized CD43 expressed on lymphoid cells. Present study suggests that signal (s) via CD44 on HGF may intracellularly transduce a certain signal to induce the CD43-dependent adhesion pathway between HGF and lymphoid cells.

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In the present study, we examined the effect of interleukin 12 (IL-12) on the evolution of murine type II collagen-induced arthritis (CIA) . CIA mice injected intraperitoneally with IL-12 (500ng / mouse /d) demonstrated delayed onset and reduced severity of arthritis. Although IL-12 administration augmented lymphocyte proliferation and interferon-γ production against specific and non-specific stimulation, anti-collagen antibody production was significantly suppressed in CIA, as compared with control mice. Since IL-12 induced the production of serum tumor necrosis factor (TNF) -α and corticosterone, the suppression of CIA by IL-12 may, in part, depend upon the augmentation of serum corticosterone, induced by endogenous TNF-α.
These data suggest that IL-12 is an important immunomodulator of the pathogenesis of CIA, which acts by regulating not only the humoral and cellular immune responses, but also the expression of immunoregulatory mediators.

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Aggregation of the high-affinity receptor for immunoglobulin E, FcεRI, on mast cells and basophils leads to the release of mediators responsible for allergic symptoms in the presence of receptor-bound IgE and multivalent allergens. Reagents to inhibit the IgE-binding to FcεRI have been vigorously investigated in the last two decades. The mouse anti-human FcεRIα monoclonal antibody CRA 2, that we established previously, efficiently inhibits human IgE-binding to the human FcεRI. Therefore, its Fab fragments have therapeutic potential in the treatment of allergy. Here we described the humanization of CRA 2 by CDR-grafting onto human variable region frameworks. The humanized CRA 2 had almost the same activities of binding to the FcεRI and inhibition for IgE-binding to the FcεRI as the original mouse CRA 2. Furthermore, pretreatment of human peripheral blood basophils with the Fab fragments of the humanized CRA 2 as well as those of the mouse CRA 2 prevented the subsequent degranulation of human basophils activated by crosslinking of the FcεRI with IgE and anti-IgE antibody. In the humanized CRA 2, all amino acid residues except CDR were replaced with the residues encoded by human germline genes. The successful humanization of CRA 2 may be an important step in the development of immunotherapy to manipulate the IgE network.

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Indometacin farnesil (IMF) is a prodrug of indomethacin (IND) designed to reduce the occurrence of side-effects by esterification of the carboxyl group on IND with farnesol (FAR) . Previous studies have shown that IMF has characteristics of disease modifying anti-rheumatic drug in that it has a component of slow acting effect in treatment of rheumatoid arthritis patients. We therefore examined the effects of IMF on human B cells. Ig production was induced from highly purified B cells obtained from healthy donors by stimulation with Staphylococcus aureus Cowan I (SA) plus IL-2. At pharmacologically attainable concentrations, IMF, but not IND, suppressed the production of IgM and IgG. Of note, IMF, but not IND, showed additive suppressive effects on the B cell Ig production in the presence of either intramolecular disulfide form of bucillamine (SA-981) or gold sodium thiomalate. FAR showed similar suppressive effects on B cells to those of IMF.
These results indicate that IMF suppresses the human B cell functions by a different mechanism from that of bucillamine or gold sodium thiomalate. Thus, the data suggest that IMF may enhance the antirheumatic effects of bucillamine or gold sodium thiomalate.

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Propolis obtained from the bee's nest has been widely used as healthy, supplementary food and is also reported that it has antibiotic, anti-ulcer, anti-tumor effects and immunostimulant action. However, its strength of pharmaceutical actions is slightly different in each report. The aim of this study is to investigate whether three kinds of propolis delivered from Italy and Brazil has similar strength of antimicrobial effects and also to study whether two kinds of propolis prepared by different extract methods has same antimicrobial activity or not.
Antimicrobial activity against Helicobactor pylori, dermatophytic fungi and Gram positive bacteria were confirmed, while antibiotic activity against Gram negative bacteria was not recognized in our study. Among them, Italian propolis showed the strongest antimicrobial activity. However, antibacterial effects of propolis were not well enough to employ clinical use. Brazilian propolis obtained from different extract methods showed similar antibacterial effects, but there was a slightly significance between the two propolis. Propolis has antibacterial effect, however its strength is influenced in production area and manufacturing methods.

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