CCR3-Blocking Antibody Inhibits Allergen-Induced Eosinophil Recruitment in Human Skin Xenografts from Allergic Patients

Abstract

SUMMARY:Eosinophil, basophil, and T helper 2 (TH2) cell recruitment into tissues is a characteristic feature of allergic diseases.These cells have in common the expression of the chemokine receptor CCR3, which may represent a specific pathway for their accumulation in vivo. Although animal models of allergic reactions are available, findings cannot always be extrapolated to man. To overcome these limitations, we have developed a humanized mouse model of allergic cutaneous reaction using severe combined immunodeficiency mice engrafted with skin and autologous peripheral blood mononuclear cells from allergic donors. Intradermal injection of the relevant allergen into human skin xenografts from allergic individuals induced a significant recruitment of human CD4 ϩ T cells, basophils, and TH2-type cytokine mRNA-expressing cells, as well as murine eosinophils. Human skin xenografts, atopic status, and autologous peripheral blood mononuclear cell reconstitution were all mandatory to induce the allergic reaction. Next, we addressed the role of CCR3 in the endogenous mechanisms involved in the inflammatory cell recruitment in this experimental model of allergic cutaneous reaction. In vivo administration of an anti-human CCR3-blocking antibody selectively reduced accumulation of eosinophils but not that of CD4 ϩ cells, basophils, or cells expressing mRNA for TH2-type cytokines. These findings establish a new in vivo model of humanized allergic reaction and suggest that eosinophil migration is mediated mainly through CCR3. Finally, these results suggest that this model might be useful to test human-specific antiallergic modulators. (Lab Invest 2002, 82:929 -939).A llergic diseases are characterized by a tissue infiltration of eosinophils, basophils and T helper 2 (TH2) cells, which is thought to be related to the severity and chronicity of the allergic reaction. This preferential cell accumulation in tissue suggests that there are specific pathways used for their accumulation in vivo. Understanding these mechanisms could aid in developing pharmacologic therapies that would block their recruitment. This recruitment is orchestrated in part by chemokines that act through specialized surface receptors. The chemokine receptor CCR3 is of particular interest in the context of allergic reactions, because it is expressed by TH2 lymphocytes (Sallusto et al, 1997), eosinophils (Ponath et al, 1996), basophils (Uguccioni et al, 1997), and mast cells (Ochi et al, 1999;Romagnani et al, 1999), all of which are found at sites of allergen-induced latephase response (LPR) (Frew and Kay, 1988;Gaga et al, 1991;Irani et al, 1998). The CCR3 receptor is a Gprotein-coupled seven-transmembrane receptor that mediates the action of several chemokines, including eotaxin (CCL11), RANTES (CCL5), MCP-3 (CCL7), and MCP-4 (CCL13) (Ponath et al, 1996;Stellato et al, 1997). All these ligands have been shown to be overexpressed in human allergen-induced cutaneous LPR (Ying et al, 1999), in atopic dermatitis (Yawalkar et al, 1999) and in asthma (Lamkhioued et ...

Establishment of monoclonal antibodies against a novel eosinophil-specific cell surface molecule, major facilitator super family domain containing 10

“…These findings indicate the possibility that M2 is useful also as a neutralizing antibody against eosinophils. It has been reported that antibodies against CCR3 as well as Siglec-F could diminish allergic eosinophilic inflammation at least in its mouse models [6][7][8]. We also confirmed that an anti-Siglec-F antibody exactly suppressed the infiltration of eosinophils ( Supplementary Fig.…”

“…Among them, neutralization of CCR3, Siglec-F and IL-5 receptor alpha, and/or their corresponding ligands successfully suppressed the recruitment of eosinophils [6][7][8][9]. However, the specificity of these molecules on eosinophils is not fully elucidated.…”

ICAM-1-dependent pathways regulate colonic eosinophilic inflammation

“…*, P Ͻ 0.05, as compared with matched control. [ [41][42][43][44][45]. It is notable that ϳ70% of ␤ 2 -integrin ϩ cells were CCR3 ϩ , suggesting that colonic eosinophils expressed ␤ 2 -integrin (results not shown).…”

“…To determine whether ␤ 2 -integrin ϩ cells were eosinophils, we examined the CCR3 expression on ␤ 2 -integrin ϩ cells. In contrast to humans, CCR3 has been localized specifically to eosinophils in the mouse, and only one study has reported CCR3 on murine mast cells [ [41][42][43][44][45]. It is notable that ϳ70% of ␤ 2 -integrin ϩ cells were CCR3 ϩ , suggesting that colonic eosinophils expressed ␤ 2integrin (results not shown).…”

Pulmonary CCL18 Recruits Human Regulatory T Cells

“…Skin grafting was performed as described previously (29,30). In brief, after anesthesia, 6-to 8-wk-old mice were prepared for grafting by shaving the hair from a 5-cm 2 area on each side of the lateral abdominal region.…”