Intravenous immunoglobulin (IVIg) acts directly on conventional T cells to suppress T cell receptor signaling.

Intravenous immunoglobulin (IVIg) therapy is widely used to treat autoimmune and infectious disorders. Despite the clinical efficacy of IVIg therapy, its precise immunosuppressive mechanisms remain unclear. Here, we provide evidence that IVIg acts directly on T cells to suppress their activation upon T cell receptor (TCR) ligation. IVIg suppressed the proliferation of murine splenocytes upon stimulation with anti-CD3 antibody and T cell-tropic mitogens. These immunosuppressive effects of IVIg were still intact against purified T cells, and the depletion of naturally-occurring regulatory T cells (nTreg) had no effect on T cell regulatory activity. Instead, we found that IVIg negatively regulated TCR signaling; IVIg co-stimulation impaired IκB degradation, nuclear translocation of the nuclear factor of activated T cells (NFAT), and the activation of mitogen-activated protein kinase (MAPK, Erk1/2). These results suggest an additional new immunosuppressive role of IVIg, which acts directly on conventional T cells to suppress the TCR signaling pathway.

Intake of a fermented plant product attenuates allergic symptoms without changing systemic immune responses in a mouse model of Japanese cedar pollinosis.

BACKGROUND: Japanese cedar pollinosis (JCP) is one of the most prevalent allergies in Japan. Within the past few decades, many food factors have been demonstrated to suppress symptoms of pollinosis and mast cell degranulation directly or indirectly. Herein, we conducted a study to clarify the anti-allergic potency of a fermented plant product (FPP) in JCP model mice. METHODS: Mice were administered FPP, 10-fold-diluted FPP, or saline every day for 40 days by oral gavage and sensitized with major Japanese cedar pollen allergens (SBP). The numbers of sneezes were counted for 5 minutes after SBP nasal challenge. We analyzed the SBP-specific immunoglobulin titers, serum concentration of mast cell protease 1, and cytokine production from splenocytes stimulated with SBP. RESULTS: The numbers of sneezes by the mice administered FPP were significantly suppressed compared to those administered saline. The 10-fold-diluted FPP also suppressed the number of sneezes compared to saline, although not significantly. Serum level of mast cell protease 1 tended to be suppressed in FPP-consumed mice compared to those in saline-treated mice. The SBP-specific immunoglobulin titers and cytokine production were comparable among the groups. CONCLUSIONS: Our results suggest that FPP intake could attenuate JCP symptoms without change of systemic immune responses.

Anti-inflammatory intravenous immunoglobulin (IVIg) suppresses homeostatic proliferation of B cells.

An intravenous injection of plasma-derived immunoglobulins is used for the treatment of severe infectious and autoimmune disorders. Despite of its clinical efficacy, precise mechanisms by which intravenous immunoglobulin (IVIg) suppresses proinflammatory immune response are still enigmatic. Here, we provide in vitro evidence that IVIg inhibits homeostatic proliferation of B cells accompanied by induction of their cell aggregation. The IVIg-driven suppression of B cell proliferation and induction of cell aggregation are both unaffected by treatment with a neutralizing antibody against low-affinity Fc receptors for IgG (CD16/FcγRIII and CD32/FcγRII), known cell surface ligands for IVIg. Our observations propose a new immunosuppressive action of IVIg, which directly acts on steady-state B cells to suppress their homeostatic expansion.

Impact of Histone H1 on the Progression of Allergic Rhinitis and Its Suppression by Neutralizing Antibody in Mice.

Nuclear antigens are known to trigger off innate and adaptive immune responses. Recent studies have found that the complex of nucleic acids and core histones that are derived from damaged cells may regulate allergic responses. However, no fundamental study has been performed concerning the role of linker histone H1 in mast cell-mediated type I hyperreactivity. In this study, we explored the impact of histone H1 on mast cell-mediated allergic responses both in vitro and in vivo. In the course of a bona-fide experimental allergen sensitization model upon co-injection with alum adjuvant, ovalbumin (OVA), but not PBS, induced elevated levels of circulating histone H1. Intranasal challenge with histone H1 to OVA/alum- (but not PBS/alum)-sensitized mice induced significantly severer symptoms of allergic rhinitis than those in mice sensitized and challenged with OVA. A monoclonal antibody against histone H1 not only suppressed mast cell degranulation, but also ameliorated OVA-induced nasal hyperreactivity and IgE-mediated passive cutaneous anaphylaxis. Our present data suggest that nuclear histone H1 represents an alarmin-like endogenous mediator acting on mast cells, and that its blockage has a therapeutic potential for mast cell-mediated type I hyperreactivity.