Antibodies targeting the M1 prime domain of human membrane IgE, which could trigger apoptosis and mediate antibody-dependent cell-mediated cytotoxicity of IgE B cells in vitro, inhibited both primary and memory IgE responses in M1 prime Selleck ABT 199 GFP knockin mice [ 12]. When administered during an ongoing IgE response in a mouse model of allergic asthma, these antibodies reduced antigen-specific IgE levels to levels comparable to those in naïve

mice and far below the levels present at the initiation of treatment [ 12]. These antibodies also inhibited human IgE production in immunodeficient mice that were reconstituted with human immune cells [ 12 and 29]. In a different study, anti-IgE antibodies that bound both serum and membrane IgE were engineered for increased

binding to the inhibitory IgG receptor FcγRIIb [ 33]. By binding both membrane IgE and FcγRIIb simultaneously on IgE-switched B cells, these antibodies inhibit membrane IgE signaling. When administered either preventively or during an ongoing IgE response in mice expressing a human FcγRIIb receptor or in immunodeficient mice reconstituted with human immune cells, these antibodies reduced IgE levels by greater than 90%. This in vivo activity required the co-engagement of membrane IgE with FcγRIIb. Interestingly, two groups have reported high expression of membrane IgE on IgE plasma cells in mice [17•• and 18••], and therefore therapies that target membrane IgE-expressing cells may directly target not only IgE-switched B cells, but also IgE plasma cells. However, none Akt targets of the studies discussed above determined the direct effect of the membrane IgE-targeted therapeutics on IgE plasma cells. It

has been difficult to study IgE production in humans due to the low abundance of IgE-switched cells and technical limitations in identifying them. The limited available data on human IgE responses is largely consistent with what has been observed in mice. For instance, significant seasonal increases and decreases in allergen-specific and total IgE levels in allergic individuals, consisting of as much as two-fold changes observed over the course of several months, is reminiscent of the transient Glutathione peroxidase IgE responses observed in mice [38, 39 and 40]. However, reports of long-term helminth-specific IgE [41] or the transfer of allergen-specific IgE to non-atopic recipients of bone marrow transplants [42 and 43] indicate that, in contrast to mice, there may be a significant contribution of long-lived IgE plasma cells to IgE production in humans. In addition, studies of patients with asthma and allergic rhinitis have described significant local IgE production in nasal and bronchial mucosal tissues [44], which has not been reported in mice.