Allosteric inhibition of IgE-FcεRI interactions by simultaneous targeting of IgE F(ab')2 epitopes.

Immunoglobulin E (IgE) plays pivotal roles in allergic diseases through interaction with a high-affinity receptor (FcεRI). We established that Fab fragments of anti-IgE antibodies (HMK-12 Fab) rapidly dissociate preformed IgE-FcεRI complexes in a temperature-dependent manner and inhibit IgE-mediated anaphylactic reactions, even after allergen challenge. X-ray crystallographic studies revealed that HMK-12 Fab interacts with each of two equivalent epitopes on the Cε2 homodimer domain involved in IgE F(ab')2.

The Fab fragment of anti-IgE Cε2 domain prevents allergic reactions through interacting with IgE-FcεRIα complex on rat mast cells.

Immunoglobulin E (IgE) plays a central role in the pathogenesis of Type I hypersensitivity through interaction with a high-affinity receptor (FcεRIα). For therapeutic applications, substantial attention has been focused recently on the blockade of the IgE interaction with FcεRIα. While exploring better options for preventing allergic diseases, we found that the Fab fragment of the rat anti-murine IgE antibody (Fab-6HD5) strongly inhibited passive cutaneous anaphylaxis (PCA) in vivo, as well as spleen tyrosine kinase (Syk) activity and β-hexosaminidase release from basophilic leukemia cells in vitro.

Breast-feeding regulates immune system development via transforming growth factor-β in mice pups.

Background: Breast milk contains important nutrients and immunoregulatory factors that are essential for newborn infants. Recently, epidemiological studies suggested that breast-feeding prevents a wide range of infectious diseases and lowers the incidence of infant allergic diseases.

Methods: To examine the effects of breast milk on immunological development in infancy, we established an artificial rearing system for hand-feeding mice and compared mouse pups fed with either breast milk or milk substitute.

Notch2 activation ameliorates nephrosis.

Activation of Notch1 and Notch2 has been recently implicated in human glomerular diseases. Here we show that Notch2 prevents podocyte loss and nephrosis. Administration of a Notch2 agonistic monoclonal antibody ameliorates proteinuria and glomerulosclerosis in a mouse model of nephrosis and focal segmental glomerulosclerosis.

Differential regulation of osteoclastogenesis by Notch2/Delta-like 1 and Notch1/Jagged1 axes.

Introduction: Osteoclastogenesis plays an important role in the bone erosion of rheumatoid arthritis (RA). Recently, Notch receptors have been implicated in the development of osteoclasts. However, the responsible Notch ligands have not been identified yet.

Expression of Notch receptors and ligands on immature and mature T cells.

Notch plays multiple roles in T cell development in the thymus and T cell differentiation in the periphery. In order to systematically examine the role of Notch in T cell biology, we determined the cell surface expression of all Notch receptors and ligands on various populations of T cells by using a panel of specific monoclonal antibodies we recently established. Notch1 and Notch3 were upregulated at double-negative (DN) 2-DN4 stages of immature thymocytes, then downregulated on mature single-positive thymocytes and peripheral T cells, but were rapidly upregulated again upon activation.

Regulation of experimental autoimmune uveoretinitis by anti-delta-like ligand 4 monoclonal antibody.

Purpose: To investigate the involvement of δ-like ligand (Dll)4 in the development of experimental autoimmune uveoretinitis (EAU) in B10.RIII mice.

Methods: B10.

Notch1-mediated signaling induces MHC class II expression through activation of class II transactivator promoter III in mast cells.

Mast cells constitutively express Notch1 and Notch2 on the cell surface. Notch ligand Dll1 (Delta-like 1) stimulation induces MHC class II expression in mast cells and renders them as antigen-presenting cells. However, nothing is known about the mechanism by which Notch signaling induces MHC class II expression in mast cells.

Notch2 signaling is required for potent antitumor immunity in vivo.

CD8(+) T cells play a central role in cancer immunosurveillance, and the efficient induction of CTLs against tumor Ags is required for successful immunotherapy for cancer patients. Notch signaling directly regulates the transcription of effector molecules in CTLs. However, it remains unclear whether Notch signaling in CD8(+) T cells is required for antitumor CTL responses and whether modulation of Notch signaling can augment antitumor CTL responses.

Development of monoclonal antibodies for analyzing immune and hematopoietic systems of common marmoset.

Objective: Common marmosets are considered experimental animals of primates useful for medical research. We developed several monoclonal antibodies (mAbs) directed to CD molecules to gain initial insight into the immune and hematopoietic systems of this organism, and analyzed the basic cellularity and characters of marmoset lymphocytes.

Materials And Methods: Anti-marmoset CD antigen mAbs were prepared using marmoset antigen-expressing transfectants and used for flow cytometric analyses and cell fractionation.

Eotaxin-1, -2, and -3 immunoreactivity and protein concentration in the nasal polyps of eosinophilic chronic rhinosinusitis patients.

Objectives/hypothesis: Eosinophilic chronic rhinosinusitis (CRS) is characterized by the accumulation of numerous eosinophils in the sinus mucosa and nasal polyps, which are frequently difficult to control, even with surgery. The present study was designed to evaluate the expression and localization of eotaxins, which are well known to be potent and selective chemoattractants for eosinophils in CRS.

Study Design: Randomized study.

Role of ephrinB2 in nonproductive angiogenesis induced by Delta-like 4 blockade.

Delta-like 4 (DLL4) is one of the Notch ligands and plays an important role in vascular development. DLL4 blockade inhibits tumor growth by promoting nonproductive angiogenesis, which is characterized by an increase in vascular density and decrease in tissue perfusion. However, a detailed mechanism remains unclear.

Differential regulation of splenic CD8- dendritic cells and marginal zone B cells by Notch ligands.

The importance of Notch signaling to maintain CD8- dendritic cells (DCs) in the spleen has recently been revealed. However, the ligand responsible for this Notch signaling has not been determined yet. In this study, we demonstrated that blocking of Delta-like (Dll) 1 alone had no significant effect on the maintenance of CD8- DCs while marginal zone (MZ) B cells were significantly reduced in the spleen of mice.

Notch signaling confers antigen-presenting cell functions on mast cells.

Background: Notch signaling is involved in cell fate determination along with the development of the immune system. However, very little is known about the role for Notch signaling in mast cells.

Objective: We investigated the role of Notch signaling in mast cell functions.

Notch ligand Delta-like4 inhibits the development of murine experimental allergic conjunctivitis.

Background: To investigate the involvement of Notch ligands in the development of experimental allergic conjunctivitis (EC) in mice.

Methods: To induce EC, wild-type (WT) or IFN-gamma-deficient (GKO) BALB/c mice were immunized with ragweed (RW) in alum followed by RW challenge in eye drops. Twenty-four hours after RW challenge, the conjunctivas, spleens and blood were harvested to evaluate conjunctival eosinophil infiltration, RW-specific cytokine production and serum Ig levels, respectively.

Highly efficient and feeder-free production of subculturable vascular endothelial cells from primate embryonic stem cells.

The vascular endothelial cell (VEC) differentiation from primate embryonic stem (ES) cells has critical problems: low differentiation efficiencies (<2%) and/or subculture incapability. We report a novel feeder-free culture method for high efficiency production of subculturable VECs from cynomolgus monkey ES cells. Spheres, which were generated from ES cells in the presence of cytokine cocktail, were cultured on gelatin-coated plates.

Dendritic cell-mediated NK cell activation is controlled by Jagged2-Notch interaction.

Natural killer (NK) cells regulate various immune responses by exerting cytotoxic activity or secreting cytokines. The interaction of NK cells with dendritic cells (DC) contributes to NK cell-mediated antitumor or antimicrobial responses. However, the cellular and molecular mechanisms for controlling this interaction are largely unknown.

Delta-like 1 is essential for the maintenance of marginal zone B cells in normal mice but not in autoimmune mice.

Notch2 and Delta-like 1 (Dll1) have been implicated in the development of marginal zone B (MZB) cells. In the present study, we characterized the expression and function of mouse Notch receptors and ligands in the spleen by using newly generated mAbs. Although Notch2 was expressed on both B and T cells in the spleen, the highest expression was observed on precursors of marginal zone B and MZB cells.

Involvement of TNF-like weak inducer of apoptosis in the pathogenesis of collagen-induced arthritis.

TNF-like weak inducer of apoptosis (TWEAK) is a type II membrane protein belonging to the TNF family that regulates apoptotic cell death, cellular proliferation, angiogenesis, and inflammation. However, the role of TWEAK in the pathogenesis of rheumatoid arthritis (RA) remains unclear. In this study, we have investigated the effect of neutralizing anti-TWEAK mAb on the development of collagen-induced arthritis (CIA), a well-established murine model of RA.

Blockade of B7-H1 on macrophages suppresses CD4+ T cell proliferation by augmenting IFN-gamma-induced nitric oxide production.

PD-1 is an immunoinhibitory receptor that belongs to the CD28/CTLA-4 family. B7-H1 (PD-L1) and B7-DC (PD-L2), which belong to the B7 family, have been identified as ligands for PD-1. Paradoxically, it has been reported that both B7-H1 and B7-DC co-stimulate or inhibit T cell proliferation and cytokine production.

Regulation of murine chronic colitis by CD4+CD25- programmed death-1+ T cells.

Naturally arising CD4(+)CD25(+) regulatory T (T(R)) cells are engaged in the maintenance of self tolerance and prevention of autoimmune diseases. However, accumulating evidence suggests that a fraction of peripheral CD4(+)CD25(-) T cells also possesses regulatory activity. Programmed death-1 (PD-1) is a new member of the CD28/CTLA-4 family, which has been implicated in the maintenance of peripheral self tolerance.