Ablation of type I hypersensitivity in experimental allergic conjunctivitis by eotaxin-1/CCR3 blockade

Abstract

The immune response is regulated, in part, by effector cells whose activation requires multiple signals. For example, T cells require signals emanating from the T cell antigen receptor and co-stimulatory molecules for full activation. Here, we present evidence indicating that IgE-mediated hypersensitivity reactions in vivo also require cognate signals to activate mast cells. Immediate hypersensitivity reactions in the conjunctiva are ablated in mice deficient in eotaxin-1, despite normal numbers of tissue mast cells and levels of IgE. To further define the co-stimulatory signals mediated by chemokine receptor 3 (CCR3), an eotaxin-1 receptor, effects of CCR3 blockade were tested with an allergic conjunctivitis model and in ex vivo isolated connective tissue-type mast cells. Our results show that CCR3 blockade significantly suppresses allergen-mediated hypersensitivity reactions as well as IgE-mediated mast cell degranulation. We propose that a co-stimulatory axis by CCR3, mainly stimulated by eotaxin-1, is pivotal in mast cell-mediated hypersensitivity reactions.

Blocking Mast Cell–Mediated Type I Hypersensitivity in Experimental Allergic Conjunctivitis by Monocyte Chemoattractant Protein-1/CCR2

“…We recently showed that ablation of eotaxin-1 significantly suppresses allergen-induced signs in the eyes and mast cell degranulation. 8 Thus, both CCR1-and CCR3-mediated signals appear to be necessary for optimal mast cell activation. This implicates that the CC chemokine-receptors may serve as indispensable stimuli for inflamed conjunctiva, although their relative importance needs to be carefully evaluated.…”

“…For example, eotaxin-1, a CC chemokine, is a signature eosinophil mediator 6 but also serves as an allergenprimed mast cell activator. 7,8 MIP-1␣, another CC chemokine, is also necessary for mast cell activation. 9 Thus, the CC chemokines are critically involved in mast cell-mediated acute inflammation, and the allergen-primed mast cell degranulation leads to latephase eosinophilic inflammation.…”

Mechanisms underlying the localisation of mast cells in tissues

“…These data highlight some of the difficulties in the mast cell field, with contrasting observations from in vitro and in vivo experimental systems. For CCL11, these differences may be reconciled with data suggesting that the CCL11ÀCCR3 axis may be more involved with mast cell development, rather than migration [60]. This is highlighted by the finding that immediate hypersensitivity reactions in the conjunctiva are ablated in mice deficient in CCL11, despite normal numbers of tissue mast cells and concentration of IgE.…”

Role of CCL7 in Type I Hypersensitivity Reactions in Murine Experimental Allergic Conjunctivitis

“…We reported that mice deficient for CCL11 or treated with a neutralizing Ab to this chemokine displayed reduced mast cell degranulation and impaired immediate hypersensitivity responses (12). Furthermore, mice deficient for CCR3 showed reductions in early-phase allergic symptoms, vascular leakage, and conjunctival eosinophil recruitment in a mouse model of allergic conjunctivitis (13)(14)(15).…”