CCR3 and CXCR3 as Drug Targets for Allergy: Principles and Potential

Abstract

Atopic disorders include a range of conditions such as allergic asthma, -rhinitis, -conjunctivitis, -dermatitis, food and drug allergies and anaphylaxis. Induction of T helper (Th)-2 immune response with consequent IgE dependent eosinophil, basophil and mast cell mediated tissue damage is the characteristic feature of allergies. The mechanism underlying this unique and long appreciated feature of allergy is being elucidated at the molecular level with advances in our knowledge of the chemokine system. Thus, chemokines that target CCR3 in concert with Th2 cytokines appear to play a pathogenic role in allergy. In contrast, chemokines that target CXCR3 in concert with Th1 cytokine appear to play a beneficial role. Accordingly, inhibiting CCR3/Th2 pathway using CCR3 antagonists is viewed as a potentially useful strategy for anti-allergy drug development. In contrast, the idea of using CXCR3 agonists to inhibiting allergic response by promoting CXCR3/Th1 pathway faces serious concerns of their potential pro-inflammatory activities in vivo. In this article we have critically evaluated the literature examining the principle and potential of this anti-allergy drug development strategy including a summary of various compounds that are under investigation.

An Adjuvant-Free Mouse Model of Transdermal Sensitization and Oral Elicitation of Anaphylaxis to Shellfish

“…In general, it is well-known that during allergic responses, the levels of Th2 cytokine tend to increase while the Th1 cytokine levels tend to decrease [31,32]. We found that the levels of both IFN-γ and IL-4 were significantly increased.…”

Predicting anti-allergic activity of 4-oxopyrimido [4,5-b]quinolines: Computational approach using topochemical indices

“…Less commonly, the reaction occurs after a particular food or drug has been taken by mouth. Atopic disorders include a range of conditions such as allergic asthma, rhinitis, conjunctivitis, dermatitis, food and drug allergies, and anaphylaxis (Gangur et al, 2003).…”

Cardiac mMCP-4+ mast cell expansion and elevation of IL-6, and CCR1/3 and CXCR2 signaling chemokines in an adjuvant-free mouse model of tree nut allergy

“…Our analysis suggests marked elevation of a single cytokine in the heart -IL-6 and elevation of a small group of chemokines (CCL9/11/12 and CXCL1/2). It is noteworthy that all these mediators are known to be important mediators in mast cell biology and allergic reactions (Gurish and Austen 2012;Jia et al 1996;Gangur et al 2003;Zhang et al 2007;Tsujino et al 1993). Furthermore, comparing mice that were sensitized vs. those that were sensitized plus oral challenged we noted that elevation of these mediators in the heart tissue was largely in response to oral allergen challenge.…”

“…The chemokine CCL9, an agonist of CCR1 contributes to hypersensitivity reactions (Lean et al 2002). Chemokines CCL11/12 are known to signal the chemokine receptor CCR3 -a critical chemokine receptor in allergic responses and in coordinating cellular traffic in the allergic inflammatory tissues (Kitaura et al 1996;Gangur et al 2003). Thus, the elevation in these mediators in the heart tissue provide molecular evidence for allergic inflammation in the heart.…”