Depletion of eosinophils in mice through the use of antibodies specific for C-C chemokine receptor 3 (CCR3)

Grimaldi, J. Christopher; Yu, Naichen; Grünig, Gabriele; Seymour, Brian W. P.; Cottrez, Françoise; Robinson, Douglas S.; Hosken, Nancy; Ferlin, Walter; Wu, Xiaoyan; Soto, Hortensia; O’Garra, Anne; Howard, Maureen; Coffman, R. L.

doi:10.1002/jlb.65.6.846

Cited by 94 publications

(65 citation statements)

References 26 publications

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“…In our chronic model of allergic airway disease, we observed impaired allergen-induced recruitment of eosinophils, macrophages, and lymphocytes. Our data showing that murine CCR3 is predominantly expressed by eosinophils are consistent with previous studies (19,20). These observations suggest that leukocyte recruitment in chronic allergic inflammation is orchestrated, at least in part, via CCR3 signaling in eosinophils, although we cannot exclude signal transduction events in other cells such as basophils and epithelial cells, because they have been shown to express low levels of CCR3 at least in the human system (21,22).…”

Section: Discussionsupporting

confidence: 91%

“…To define a causative relationship between the recruitment of eosinophils and the onset or progression of pulmonary pathologies associated with allergic asthma, multiple experimental approaches have been used to deplete animals of eosinophils, including manipulation of cytokine (e.g., IL-5 and eotaxins) levels via gene targeting and neutralizing antibodies and depletion of eosinophils using an anti-CCR3 antibody (19,20,(33)(34)(35). More recently, Lee et al (6) targeted the depletion of eosinophils (these mice are designated as PHIL) using an eosinophil-specific promoter to drive expression of a cytocidal protein, diphtheria toxin A.…”

Section: Discussionmentioning

confidence: 99%

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A central regulatory role for eosinophils and the eotaxin/CCR3 axis in chronic experimental allergic airway inflammation

Fulkerson

Fischetti

McBride

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

192

173

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To clarify the role and regulation of eosinophils, we subjected several key eosinophil-related genetically engineered mice to a chronic model of allergic airway inflammation aiming to identify results that were independent of the genetic targeting strategy. In particular, mice with defects in eosinophil development (⌬dbl-GATA) and eosinophil recruitment [mice deficient in CCR3 (CCR3 knockout) and mice deficient in both eotaxin-1 and eotaxin-2 (eotaxin-1͞2 double knockout)] were subjected to Aspergillus fumigatus-induced allergic airway inflammation. Allergen-induced eosinophil recruitment into the airway was abolished by 98%, 94%, and 99% in eotaxin-1͞2 double knockout, CCR3 knockout, and ⌬dbl-GATA mice, respectively. Importantly, allergen-induced type II T helper lymphocyte cytokine production was impaired in the lungs of eosinophil-and CCR3-deficient mice. The absence of eosinophils correlated with reduction in allergen-induced mucus production. Notably, by using global transcript expression profile analysis, a large subset (29%) of allergen-induced genes was eosinophil-and CCR3-dependent; pathways downstream from eosinophils were identified, including in situ activation of coagulation in the lung. In summary, we present multiple lines of independent evidence that eosinophils via CCR3 have a central role in chronic allergic airway disease.allergy ͉ asthma ͉ chemokine ͉ cytokine

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

A central regulatory role for eosinophils and the eotaxin/CCR3 axis in chronic experimental allergic airway inflammation

Fulkerson

Fischetti

McBride

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

192

173

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“…In a guinea pig model of eosinophil cutaneous recruitment, pretreatment of labeled eosinophils in vitro with a blocking CCR3 antibody inhibited their accumulation in response to eotaxin in vivo (Sabroe et al, 1998). In a model of Nippostrongylus brasiliensis-infected mice, in vivo depletion of CCR3-expressing cells led to a reduction in lung eosinophilia (Grimaldi et al, 1999). In the present study, we show for the first time that in a humanized mouse model of cutaneous allergy, allergen-induced recruitment of eosinophils is also dependent upon CCR3.…”

supporting

confidence: 60%

“…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 al, 1997;Ying et al, 1997), reinforcing the potential role of CCR3 as a major pathway of cell recruitment and therapeutic target in allergic reactions (Bertrand and Ponath, 2000). Hitherto, only two studies have evaluated the effect of CCR3 antagonism in vivo, one on chemokine-induced eosinophil recruitment (Sabroe et al, 1998) and the other in a parasitosis model (Grimaldi et al, 1999). In both cases, an inhibition of eosinophil recruitment was observed.…”

mentioning

confidence: 99%

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

Sénéchal

Fahy

Gentina

et al. 2002

Laboratory Investigation

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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 ...

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“…20,21 In the mouse system, CCR3 expression is almost exclusively detected on eosinophils. 22,23 Importantly, recent studies have demonstrated that CCR3 disruption impaired eosin-ophil recruitment in acute models of experimental asthma. 24 -26 In addition to regulating eosinophil trafficking into mucosal tissues, the eotaxins activate the respiratory burst apparatus, induce degranulation, and up-regulate adhesion molecule expression.…”

mentioning

confidence: 99%

Eosinophils and CCR3 Regulate Interleukin-13 Transgene-Induced Pulmonary Remodeling

Fulkerson

Fischetti

Rothenberg

2006

The American Journal of Pathology

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Interleukin (IL)-13 transgene overexpression in the lung induces features of chronic inflammatory lung disorders, including an eosinophil-rich inflammatory cell infiltration, airway hyper-reactivity, and remodeling of the airway (eg, subepithelial fibrosis, goblet cell metaplasia, and smooth muscle hypertrophy and hyperplasia). Here, we aimed to define the role of eosinophils and eosinophil signaling molecules [eg, eotaxins and CC chemokine receptor (CCR) 3] in IL-13-mediated airway disease. To accomplish this, we mated IL-13-inducible lung transgenic mice with mice deficient in eosinophil chemoattractant molecules (eotaxin-1, eotaxin-2, and their receptor CCR3) and with mice genetically deficient in eosinophils (⌬dbl-GATA). We report that in the absence of eotaxin-2 or CCR3, there was a profound reduction in IL-13-induced eosinophil recruitment into the lung lumen. In contrast, in the absence of eotaxin-1, there was a fourfold increase in IL-13-mediated eosinophil recruitment into the airway. IL-13 transgenic mice deficient in CCR3 had a 98% reduction in lung eosinophils. Furthermore, the reduction in pulmonary eosinophils correlated with attenuation in IL-13-induced mucus cell metaplasia and collagen deposition. Mechanistic analysis identified alterations in pulmonary protease and transforming growth factor-␤ 1 expression in eosinophil-deficient mice. Taken together , these data definitively identify a functional contribution by eosinophils on the effects of chronic IL-13 expression in the lung. Asthma, one of the most common serious chronic diseases of childhood, is an inflammatory lung disease characterized by airway wall remodeling and reduced respiratory function. The chronic inflammatory process, with an airway infiltrate composed primarily of CD4 ϩ lymphocytes and eosinophils, contributes to airway remodeling, defined as altered lung structural changes.1 These structural changes in the airway include mucus cell metaplasia and increased deposition of collagen, proteoglycans, and other matrix proteins in the subepithelial layer.2 Importantly, these structural changes are implicated, at least partially, in the clinical manifestations of asthma.

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Depletion of eosinophils in mice through the use of antibodies specific for C-C chemokine receptor 3 (CCR3)

Cited by 94 publications

References 26 publications

A central regulatory role for eosinophils and the eotaxin/CCR3 axis in chronic experimental allergic airway inflammation

A central regulatory role for eosinophils and the eotaxin/CCR3 axis in chronic experimental allergic airway inflammation

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

Eosinophils and CCR3 Regulate Interleukin-13 Transgene-Induced Pulmonary Remodeling

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