In these studies, it was calculated that the IgE memory B cells contributed to the majority of the IgE memory response. By contrast, studies of mice with monoclonal T cells and B cells [17•• and 19] have identified IgG1 memory B cells as the major source of IgE memory responses. In these Transmembrane Transproters inhibitor studies, however, IgE and IgG1 memory B cells were not purified and compared directly, and therefore it is possible that the contributions of IgE memory B cells were not fully accounted for due to their low frequency in the mixed cell populations that were

examined. Overall, the understanding of the sources of IgE memory is limited and remains controversial. Taken together, the studies in mice have delineated a pathway of IgE production and memory that results in primarily transient, short-lived IgE antibody responses and limited IgE memory (Figure 2). This model for IgE production and memory suggests that a significant proportion of IgE antibody is generated from ongoing naïve and/or memory B cell activation and differentiation into IgE-producing plasma cells and implies that IgE antibody levels could be significantly reduced by inhibiting new IgE production, such as by targeting the cytokines IL-4 and IL-13 to inhibit IgE class switch GSK1120212 in vitro recombination or by targeting IgE-switched B cells directly. In addition, this model also implies that a significant proportion of long-term IgE memory could

be eliminated by targeting IgE-switched memory B cells, although the IgG1 memory B cells that contribute to IgE memory would not be affected by this approach. Studies in mice and monkeys have shown that deficiency or neutralization of IL-4, IL-13, or the receptor IL-4Rα that is shared by both IL-4 and IL-13,

inhibits IgE production [24, 25, 26 and 27], but only a few studies have assessed the effect of neutralization of IL-4/IL-13 during an ongoing or established IgE response [28]. A study in a cynomolgus monkey model of IgE responses to Ascaris suum antigen showed that treatment with anti-IL-13 antibodies over an 8-week period that included an Ascaris challenge resulted in a reduction in Ascaris-specific IgE titers below pre-treatment levels, although no significant changes in total IgE levels were observed [ 25]. Multiple groups have directly targeted IgE-switched B cells using antibodies that bind PDK4 either specifically to the membrane IgE BCR or to both membrane and secreted IgE [12, 29, 30, 31, 32, 33, 34, 35, 36 and 37], with several groups demonstrating in vivo activity of these antibodies [ 12, 33, 34, 35, 36 and 37]. Early studies showed that polyclonal and monoclonal anti-mouse IgE antibodies could inhibit primary and memory IgE responses, but did not prevent the development of IgE memory [ 35 and 36]. More recently, an antibody specific for mouse membrane IgE, which could trigger apoptosis of IgE B cells in vitro, inhibited IgE production when administered to mice preventively, but not when administered during an ongoing IgE response [ 34].