Basic structures for anti-allergy vaccine development. this topic will be considered last because today this strategy usually involves monoclonal antibodies rather than cell permeant small-molecules. In addition, one theme of this review will be how to approach acute vs. chronic treatments for allergic diseases and monoclonal antibody vs. small-molecule strategies may be differentiated by their value for chronic and acute treatments, respectively. The starting point for considering small-molecule approaches will be the earliest steps in the signal transduction reaction that is initiated in mast cells and basophils following their exposure to allergens. This review will also focus on approaches in which the target is well-defined rather than explore the very wide Sophocarpine range of compounds, both synthetic (so-called mast cell stabilizers) and natural NF2 (e.g., plant-derived compounds), that have been demonstrated to inhibit mast cell secretion. Several decades of study have provided biochemists with several interesting targets. As with any therapeutic approach, the question that remains unknown until actual clinical testing is whether any chosen therapeutic target is effectively localized to mast cells/basophils. The last decade or so of study has not been encouraging if one expects to find an FcRI-specific target. All of the FcRI-associated signaling elements that have been identified have also been identified as central participants in other immune cells crucial for a proper immune response. Early steps in FcRI-dependent signaling Working inward from FcRI, the first step in signaling involves src-family kinases. There remains some confusion about the precise number of src-family members that are crucial for signaling, and the final answer may be subtle, with variations among mast cell subtypes or basophils. However, there is general agreement Sophocarpine that lyn kinase is necessary for initiating the reaction [1C4]. Currently, lyn kinase would not be a therapeutic target because this enzyme also participates in the termination of the activation cascade. Studies in both mice and humans have shown that less than maximal inhibition of src-family kinases, and lyn in particular, results in enhanced IgE-mediated functions [5, 6]. The src-family kinases fyn and hck have also been implicated in the IgE-mediated reaction [2, 7], and their roles appear to be restricted to reaction cascades that promote secretion from mast cells. However, the role of fyn and hck in IgE-mediated secretion from human mast cells or basophils has not been explored. Considerable effort has been made to target the next step in the signaling cascade, the activation of syk, a ZAP-70 family member. Although lyn initiates phosphorylation of FcRI, which allows syk Sophocarpine to be recruited, a very broad range of activation signaling cascades start with the activity of syk [8]. This characteristic motivated the development of syk inhibitors for both atopic and other inflammatory diseases, such as rheumatoid arthritis (RA). Effective inhibition of syk, either through genetic means in mice or pharmacological means in humans completely ablates FcRI-mediated secretion and essentially any other pro-inflammatory function that has been studied in mast cells/basophils [9, 10]. Recent syk inhibitors show both high potency and selectivity. Surprisingly, limited testing of syk inhibitors has not resulted in remarkable suppression of allergic symptoms [11]. It is speculated that local metabolism blunts the effectiveness of the drugs, although the precise answer is not known. However, even if syk inhibitors are found to be highly selective and efficacious, syk is Sophocarpine often involved in signaling in immunoreceptor-bearing cells and all leukocytes (including T cells at early stages of development); all these cells use syk in the earliest steps of signal transduction for some of their functions. Syk knockout mice show perinatal mortality. Some cancer cells show heightened proliferation when syk is down-regulated [12]. So development of these inhibitors for atopic diseases has been put on hold except when it is possible to use them topically. Nevertheless, because these inhibitors are being explored for other chronic inflammatory conditions such as RA (e.g., R-788 has completed phase II trials, [13, 14]) some experience with their use in patients with coincident atopy may happen. Downstream of syk activation are two other important signaling enzymes whose function might be considered crucial for mast cell or.
