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• W2004252024 abstract "Since their discovery, much data have been accumulated on eosinophil differentiation, morphology, trafficking, and anatomical location(s) in health and disease. Although “classic” activation pathways (such as cytokines, chemokines, proinflammatory components, and adhesion molecules) regulating eosinophil activation have been widely explored, the presence of other activation molecules that might be disease specific is limited. Furthermore, the expression and function of inhibitory receptors on eosinophils have received scant attention. The need to identify new pathways that regulate eosinophil activation is a crucial goal as it can expand our knowledge on this peculiar cell and provide insights into important queries regarding the physiologic function of eosinophils. Over the past several years, it has become increasingly apparent that eosinophils express several receptors belonging to the immunoglobulin superfamily. In this review, we summarize the current knowledge on the expression and function of new pathways that govern eosinophil activation. In addition, we will propose some hypotheses regarding the ability to use these pathways as a future therapeutic approach. In conclusion, we assume that targeting inhibitory receptors on eosinophils may provide opportunities for immunoregulatory therapy in the near future. Since their discovery, much data have been accumulated on eosinophil differentiation, morphology, trafficking, and anatomical location(s) in health and disease. Although “classic” activation pathways (such as cytokines, chemokines, proinflammatory components, and adhesion molecules) regulating eosinophil activation have been widely explored, the presence of other activation molecules that might be disease specific is limited. Furthermore, the expression and function of inhibitory receptors on eosinophils have received scant attention. The need to identify new pathways that regulate eosinophil activation is a crucial goal as it can expand our knowledge on this peculiar cell and provide insights into important queries regarding the physiologic function of eosinophils. Over the past several years, it has become increasingly apparent that eosinophils express several receptors belonging to the immunoglobulin superfamily. In this review, we summarize the current knowledge on the expression and function of new pathways that govern eosinophil activation. In addition, we will propose some hypotheses regarding the ability to use these pathways as a future therapeutic approach. In conclusion, we assume that targeting inhibitory receptors on eosinophils may provide opportunities for immunoregulatory therapy in the near future. Achilles, the son of Thetis and Peleus, was the bravest hero in the Trojan War, according to Greek mythology. In an attempt to make Achilles immortal, his mother dipped him in the river Styx when he was born. As she immersed him, she held him by 1 heel and forgot to dip him a second time. Therefore, the place where she held him remained untouched by the magic water and that part stayed vulnerable. Many attempts have been made to identify an Achilles heel for eosinophils that may be used for targeting these cells in various diseases. In this review, we will summarize the current knowledge on the expression and function of inhibitory receptors on these cells and highlight their potential role as future targets for therapeutic agents. Over the past several years it has become increasingly apparent that inhibitory receptors constitute a major self-regulatory pathway in which activation signals can be counterbalanced and tuned.1Ravetch J.V. Lanier L.L. Immune inhibitory receptors.Science. 2000; 290: 84-89Crossref PubMed Scopus (1046) Google Scholar Certainly, gene-targeted mice with loss of inhibitory receptors display marked autoreactivity and/or inflammation,2Clynes R. Maizes J.S. Guinamard R. Ono M. Takai T. Ravetch J.V. Modulation of immune complex-induced inflammation in vivo by the coordinate expression of activation and inhibitory Fc receptors.J Exp Med. 1999; 189: 179-185Crossref PubMed Scopus (337) Google Scholar, 3O'Keefe T.L. Williams G.T. Batista F.D. Neuberger M.S. Deficiency in CD22, a B cell-specific inhibitory receptor, is sufficient to predispose to development of high affinity autoantibodies.J Exp Med. 1999; 189: 1307-1313Crossref PubMed Scopus (279) Google Scholar which thus highlights a fundamental role for these pathways in immune regulation. Early studies, primarily on natural killer (NK) cells, indicated that inhibitory receptors mainly recognize MHC class I molecules. This recognition could explain the tolerance to normal cells expressing MHC class I molecules and the execution of transformed or virally infected cells that either lose MHC class I expression or express “non-self” MHC class molecules.4Kumar V. McNerney M.E. A new self: MHC-class-I-independent natural-killer-cell self-tolerance.Nat Rev Immunol. 2005; 5: 363-374Crossref PubMed Scopus (144) Google Scholar However, substantial evidence now exists that inhibitory receptors can recognize diverse ligands other than MHC class I molecules.4Kumar V. McNerney M.E. A new self: MHC-class-I-independent natural-killer-cell self-tolerance.Nat Rev Immunol. 2005; 5: 363-374Crossref PubMed Scopus (144) Google Scholar Although these observations can explain how NK cell tolerance is maintained in MHC class I–deficient individuals, they also highlight the ability of these receptors to regulate the functions of other cell types and in settings that are not confined to viral infections and cancer. Inhibitory receptors can be broadly divided into 2 groups, belonging either to the immunoglobulin receptor superfamily, characterized by a single V-type Ig-like domain in the extracellular portion such as killer cell immunoglobulin-like receptors, leukocyte Ig-like receptors (LIRs)/Ig-like transcripts (ILTs), leukocyte-associated Ig-like receptors, gp49B1, inhibitory receptor protein 60 (CD300a) (IRp60)/CD300a and sialic acid-binding Ig-like lectins (Siglec-8s), or to the C-type (calcium-dependent) lectin superfamily, such as mast cell function–associated antigen or CD94/NKG2A.5Katz H.R. Inhibitory receptors and allergy.Curr Opin Immunol. 2002; 14: 698-704Crossref PubMed Scopus (80) Google Scholar The prototype immune inhibitory receptor can be identified by a consensus amino acid sequence, the immunoreceptor tyrosine-based inhibitory motif (ITIM), which is present in the cytoplasmic domain of these molecules. The ITIM sequence is composed of 6 amino acids (Ile/Val/Leu/Ser)-X-Tyr-X-X-(Leu/Val), where X represents any amino acid.1Ravetch J.V. Lanier L.L. Immune inhibitory receptors.Science. 2000; 290: 84-89Crossref PubMed Scopus (1046) Google Scholar, 5Katz H.R. Inhibitory receptors and allergy.Curr Opin Immunol. 2002; 14: 698-704Crossref PubMed Scopus (80) Google Scholar Importantly, inhibitory receptors can express either 1 or several ITIM domains. Upon activation, these inhibitory receptors undergo tyrosine phosphorylation, often by a Src family kinase, which provides a docking site for the recruitment of cytoplasmic phosphatases having a Src homology 2 (SH2) domain such as SH2-containing inositol phosphatase (SHP)-1 and SHP-2 and SH2-containing protein tyrosine phosphatase (SHIP)-1 and SHIP-2.1Ravetch J.V. Lanier L.L. Immune inhibitory receptors.Science. 2000; 290: 84-89Crossref PubMed Scopus (1046) Google Scholar, 5Katz H.R. Inhibitory receptors and allergy.Curr Opin Immunol. 2002; 14: 698-704Crossref PubMed Scopus (80) Google Scholar Conversely, recent reports suggest that intracellular motifs other than ITIMs such as immunoreceptor tyrosine-based switch motifs (ITSMs) or NPXY motifs can also initiate cellular inhibition by binding cytoplasmic phosphatases as well.6Eissmann P. Beauchamp L. Wooters J. Tilton J.C. Long E.O. Watzl C. Molecular basis for positive and negative signaling by the natural killer cell receptor 2B4 (CD244).Blood. 2005; 105: 4722-4729Crossref PubMed Scopus (162) Google Scholar, 7Zhang S. Phillips J.H. Identification of tyrosine residues crucial for CD200R-mediated inhibition of mast cell activation.J Leukoc Biol. 2006; 79: 363-368Crossref PubMed Scopus (47) Google Scholar However, as this will be discussed, the exact mechanism of ITSM-dependent inhibition in eosinophil is yet to be clarified. It is important to note that the classic dichotomy differentiating between inhibitory signals delivered by a phosphorylated ITIM as opposed to the activation signals mediated by immunoreceptor tyrosine-based activatory motifs (ITAMs) has been recently suggested to be much more complex and ambiguous.8Barrow A.D. Trowsdale J. You say ITAM and I say ITIM, let's call the whole thing off: the ambiguity of immunoreceptor signalling.Eur J Immunol. 2006; 36: 1646-1653Crossref PubMed Scopus (186) Google Scholar For instance, in certain circumstances, ITIMs can mediate activation and ITAMs can propagate inhibition signals.9Pasquier B. Launay P. Kanamaru Y. Moura I.C. Pfirsch S. Ruffie C. et al.Identification of FcalphaRI as an inhibitory receptor that controls inflammation: dual role of FcRgamma ITAM.Immunity. 2005; 22: 31-42Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar, 10Barrow A.D. Astoul E. Floto A. Brooke G. Relou I.A. Jennings N.S. et al.Cutting edge: TREM-like transcript-1, a platelet immunoreceptor tyrosine-based inhibition motif encoding costimulatory immunoreceptor that enhances, rather than inhibits, calcium signaling via SHP-2.J Immunol. 2004; 172: 5838-5842Crossref PubMed Scopus (78) Google Scholar However, as this topic is a fresh avenue in eosinophil biology, we will use in this review the established paradigm (Fig 1) of ITIM-ITAM interactions.1Ravetch J.V. Lanier L.L. Immune inhibitory receptors.Science. 2000; 290: 84-89Crossref PubMed Scopus (1046) Google Scholar Although much data have accumulated on pathways regulating eosinophil activation,11Rothenberg M.E. Hogan S.P. The eosinophil.Annu Rev Immunol. 2006; 24: 147-174Crossref PubMed Scopus (1194) Google Scholar the expression and function of inhibitory receptors on eosinophils have received scant attention. As illustrated in Fig 2, eosinophils were shown to express the inhibitory receptors FcγRIIB, ILT5/LIR3, CD33, p75/adhesion inhibitory receptor molecule, Siglec-8, Siglec-10, p140, and IRp60/CD300a.12Munitz A. Bachelet I. Eliashar R. Moretta A. Moretta L. Levi-Schaffer F. The inhibitory receptor IRp60 (CD300a) suppresses the effects of IL-5, GM-CSF, and eotaxin on human peripheral blood eosinophils.Blood. 2006; 107: 1996-2003Crossref PubMed Scopus (115) Google Scholar, 13Tedla N. Bandeira-Melo C. Tassinari P. Sloane D.E. Samplaski M. Cosman D. et al.Activation of human eosinophils through leukocyte immunoglobulin-like receptor 7.Proc Natl Acad Sci U S A. 2003; 100: 1174-1179Crossref PubMed Scopus (76) Google Scholar, 14Munday J. Kerr S. Ni J. Cornish A.L. Zhang J.Q. Nicoll G. et al.Identification, characterization and leucocyte expression of Siglec-10, a novel human sialic acid-binding receptor.Biochem J. 2001; 355: 489-497Crossref PubMed Scopus (98) Google Scholar Activation of human eosinophils by Siglec-8 inhibits their survival by inducing apoptosis and initiating mitochondrial injury, reactive oxygen species generation and rapid cleavage of caspase-3, -8, and -9.15Nutku E. Hudson S.A. Bochner B.S. Mechanism of Siglec-8-induced human eosinophil apoptosis: role of caspases and mitochondrial injury.Biochem Biophys Res Commun. 2005; 336: 918-924Crossref PubMed Scopus (87) Google Scholar Interestingly, Siglec-8 was capable of inducing eosinophil apoptosis even in the presence of IL-5, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF), the hallmark “eosinophil survival cytokines.”16Nutku E. Aizawa H. Hudson S.A. Bochner B.S. Ligation of Siglec-8: a selective mechanism for induction of human eosinophil apoptosis.Blood. 2003; 101: 5014-5020Crossref PubMed Scopus (262) Google Scholar In addition, Bochner et al17Bochner B.S. Alvarez R.A. Mehta P. Bovin N.V. Blixt O. White J.R. et al.Glycan array screening reveals a candidate ligand for Siglec-8.J Biol Chem. 2005; 280: 4307-4312Crossref PubMed Scopus (219) Google Scholar undertook an elegant screening approach using a glycan array identifying 6'-sulfo-sLEX, which is a unique sugar structure that is a potential ligand for Siglec-8. Yet, the biological relevance of these findings has yet to be determined. Recent data indicate that engagement of p75/AIRM or CD33 can inhibit proliferation and/or differentiation of CD34+ myeloid precursors induced by stem cell factor and GM-CSF.18Mingari M.C. Vitale C. Romagnani C. Falco M. Moretta L. p75/AIRM1 and CD33, two sialoadhesin receptors that regulate the proliferation or the survival of normal and leukemic myeloid cells.Immunol Rev. 2001; 181: 260-268Crossref PubMed Scopus (45) Google Scholar, 19Vitale C. Romagnani C. Falco M. Ponte M. Vitale M. Moretta A. et al.Engagement of p75/AIRM1 or CD33 inhibits the proliferation of normal or leukemic myeloid cells.Proc Natl Acad Sci U S A. 1999; 96: 15091-15096Crossref PubMed Scopus (126) Google Scholar Interestingly, CD33 seems to act via the induction of apoptosis similar to Siglec-8, whereas p75/AIRM blocks cell proliferation without induction of apoptosis.19Vitale C. Romagnani C. Falco M. Ponte M. Vitale M. Moretta A. et al.Engagement of p75/AIRM1 or CD33 inhibits the proliferation of normal or leukemic myeloid cells.Proc Natl Acad Sci U S A. 1999; 96: 15091-15096Crossref PubMed Scopus (126) Google Scholar Importantly, we have recently established that eosinophils express p75/AIRM.12Munitz A. Bachelet I. Eliashar R. Moretta A. Moretta L. Levi-Schaffer F. The inhibitory receptor IRp60 (CD300a) suppresses the effects of IL-5, GM-CSF, and eotaxin on human peripheral blood eosinophils.Blood. 2006; 107: 1996-2003Crossref PubMed Scopus (115) Google Scholar Thus, p75/AIRM may regulate eosinophil differentiation as well. Nevertheless, the function of this receptor on eosinophils is yet unknown. In addition, although CD33 and p75/AIRM could inhibit proliferation of myeloid cell precursors, CD300a/IRp60, an additional inhibitory receptor, could not suppress this feature, which suggests distinct functions for various inhibitory receptors.18Mingari M.C. Vitale C. Romagnani C. Falco M. Moretta L. p75/AIRM1 and CD33, two sialoadhesin receptors that regulate the proliferation or the survival of normal and leukemic myeloid cells.Immunol Rev. 2001; 181: 260-268Crossref PubMed Scopus (45) Google Scholar Recently we demonstrated that CD300a/IRp60 can also inhibit eosinophil survival.12Munitz A. Bachelet I. Eliashar R. Moretta A. Moretta L. Levi-Schaffer F. The inhibitory receptor IRp60 (CD300a) suppresses the effects of IL-5, GM-CSF, and eotaxin on human peripheral blood eosinophils.Blood. 2006; 107: 1996-2003Crossref PubMed Scopus (115) Google Scholar In contrast to Siglec-8, which induces eosinophil apoptosis, IRp60/CD300a inhibits survival signals delivered to eosinophils via the IL-3/IL-5/GM-CSF receptor βc.12Munitz A. Bachelet I. Eliashar R. Moretta A. Moretta L. Levi-Schaffer F. The inhibitory receptor IRp60 (CD300a) suppresses the effects of IL-5, GM-CSF, and eotaxin on human peripheral blood eosinophils.Blood. 2006; 107: 1996-2003Crossref PubMed Scopus (115) Google Scholar Cross-linking experiments have revealed that upon IRp60/CD300a activation, JAK2, p38, and extracellular signal-regulated kinase 1/2 phosphorylation are inhibited, probably from the recruitment of SHP-1 and not SHP-2. Furthermore, IRp60/CD300a activation could inhibit eosinophil chemotaxis (in response to eotaxin and LTB4) and activation (in response to IL-5 and GM-CSF). Nevertheless, although IRp60/CD300a regulates several eosinophil checkpoints (Fig 3), its role(s) in eosinophil maturation, adhesion, and eosinophil-related diseases is yet to be determined. Interestingly, IRp60/CD300a and Siglec-8 share a unique property regarding eosinophil inhibition. It seems that the presence of eosinophil survival cytokines prime the responses elicited by these 2 inhibitory receptors. Therefore, activation of Siglec-8 in the presence of these factors ablates the requirement for an additional cross-linking antibody. In addition, the ability of IRp60/CD300a to inhibit eosinophil survival was enhanced upon increasing concentrations of IL-5 and GM-CSF. These findings are important becausee they highlight a potential cross-talk between eosinophil activation pathways and inhibitory ones, which may be further exploited therapeutically. The different outcome of Siglec-8 activation (induction of apoptosis) as opposed to IRp60/CD300 activation (inhibition of survival signals) may be partially explained by the fact that Siglec-8 contains both ITIM and ITSM motifs. ITSM motifs may recruit either inhibitory phosphatases such as SHP-1 and/or SHP-2 or activatory molecules such as slam-associated protein (SAP) and/or 2-Ewing's sarcoma-FLI activated transcript 2 (EAT-2).4Kumar V. McNerney M.E. A new self: MHC-class-I-independent natural-killer-cell self-tolerance.Nat Rev Immunol. 2005; 5: 363-374Crossref PubMed Scopus (144) Google Scholar, 6Eissmann P. Beauchamp L. Wooters J. Tilton J.C. Long E.O. Watzl C. Molecular basis for positive and negative signaling by the natural killer cell receptor 2B4 (CD244).Blood. 2005; 105: 4722-4729Crossref PubMed Scopus (162) Google Scholar Therefore, the interaction between these intracellular components may tune the outcome of Siglec-8 activation on human eosinophils directing it toward apoptosis. Alternatively, ITSM motifs may not be functional in eosinophils, but it is not likely becausee eosinophils express several receptors belonging to the SLAM-subfamily that have been described to recruit SAP and/or EAT-220Munitz A. Bachelet I. Fraenkel S. Katz G. Mandelboim O. Simon H.U. et al.2B4 (CD244) is expressed and functional on human eosinophils.J Immunol. 2005; 174: 110-118Crossref PubMed Scopus (80) Google Scholar (Fig 4). Interestingly, a novel role for monokine induced by IFN-γ (or CXCL9) (Mig) in inhibition of murine eosinophil recruitment was recently demonstrated.21Fulkerson P.C. Zimmermann N. Brandt E.B. Muntel E.E. Doepker M.P. Kavanaugh J.L. et al.Negative regulation of eosinophil recruitment to the lung by the chemokine monokine induced by IFN-gamma (Mig, CXCL9).Proc Natl Acad Sci U S A. 2004; 101: 1987-1992Crossref PubMed Scopus (88) Google Scholar In their study, Fulkerson et al22Fulkerson P.C. Zhu H. Williams D.A. Zimmermann N. Rothenberg M.E. CXCL9 inhibits eosinophil responses by a CCR3- and Rac2-dependent mechanism.Blood. 2005; 106: 436-443Crossref PubMed Scopus (36) Google Scholar reported that the binding of Mig to CCR3, which is a hallmark eosinophil chemokine receptor, activates an inhibitory cascade (yet to be defined). Although this study was not conducted on a classic ITIM-bearing receptor, it suggests that different chemokines and perhaps other agonists can use CCR3 to inhibit eosinophil functions. Mechanistically, these findings could imply that a substantial cross-talk occurs between inhibitory receptors and “eosinophil-specific” cytokine receptors such as CCR3. Supporting such an hypothesis are the findings that abnormal chemotactic responses to stromal cell-derived factor 1 were observed in SHP-1–deficient mice (viable motheaten mice).23Kim C.H. Qu C.K. Hangoc G. Cooper S. Anzai N. Feng G.S. et al.Abnormal chemokine-induced responses of immature and mature hematopoietic cells from motheaten mice implicate the protein tyrosine phosphatase SHP-1 in chemokine responses.J Exp Med. 1999; 190: 681-690Crossref PubMed Scopus (81) Google Scholar Furthermore, the inhibitory receptor paired immunoglobulin-like receptor B has been shown to regulate neutrophil chemotaxis in a Hck-Fgr–dependent fashion, which indicates a functional link between chemokine receptors and inhibitory ones.24Zhang H. Meng F. Chu C.L. Takai T. Lowell C.A. The Src family kinases Hck and Fgr negatively regulate neutrophil and dendritic cell chemokine signaling via PIR-B.Immunity. 2005; 22: 235-246Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar An additional non–classic inhibitory receptor expressed on eosinophils is CD52. CD52 is a glycosilphosphatidilinositol-linked protein that is expressed on various cell types but not on neutrophils.25Elsner J. Hochstetter R. Spiekermann K. Kapp A. Surface and mRNA expression of the CD52 antigen by human eosinophils but not by neutrophils.Blood. 1996; 88: 4684-4693Crossref PubMed Google Scholar Antibody cross-linking of CD52 resulted in inhibition of C5a, platelet activating factor, and GM-CSF–induced production of reactive oxygen species in eosinophils.25Elsner J. Hochstetter R. Spiekermann K. Kapp A. Surface and mRNA expression of the CD52 antigen by human eosinophils but not by neutrophils.Blood. 1996; 88: 4684-4693Crossref PubMed Google Scholar Although the mechanism for this inhibitory effect has not been addressed, it suggests that lipid rafts in eosinophils may be a cellular compartment for eosinophil regulation. In recent years, antibody therapy has become a new treatment modality for a vast array of diseases, including allergy, cancer, and malaria.26Sanz L. Blanco B. Alvarez-Vallina L. Antibodies and gene therapy: teaching old ‘magic bullets’ new tricks.Trends Immunol. 2004; 25: 85-91Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 27Yoshida S. Kobayashi T. Matsuoka H. Seki C. Gosnell W.L. Chang S.P. et al.T-cell activation and cytokine production via a bispecific single-chain antibody fragment targeted to blood-stage malaria parasites.Blood. 2003; 101: 2300-2306Crossref PubMed Scopus (17) Google Scholar Despite this fact, it is widely agreed that the antibody therapeutical approach requires further improvement. Bispecific antibodies are proteins that have 2 different binding specificities usually designed to recognize 2 separate antigens on 2 different cells. This technology has been studied in the context of immune regulation mostly in cancer and parasitic diseases.26Sanz L. Blanco B. Alvarez-Vallina L. Antibodies and gene therapy: teaching old ‘magic bullets’ new tricks.Trends Immunol. 2004; 25: 85-91Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 27Yoshida S. Kobayashi T. Matsuoka H. Seki C. Gosnell W.L. Chang S.P. et al.T-cell activation and cytokine production via a bispecific single-chain antibody fragment targeted to blood-stage malaria parasites.Blood. 2003; 101: 2300-2306Crossref PubMed Scopus (17) Google Scholar Thus, 1 binding site is specific for an antigen on the target cell (that is, infected or cancer cell), whereas the other binding site recognizes specifically an antigen on the immune effector cell. Accordingly, the effector cell mechanisms will be exerted upon the target cell leading to an appropriate immune response. To date, most bispecific antibodies have been designed for cancer settings. It is noteworthy to mention that products representative of all these technologies are currently under clinical trials such as the 2B1 antibody (quadroma-based bispecific antibodies, that is, somatic fusion of 2 different hybridoma cell lines)28Weiner L.M. Clark J.I. Davey M. Li W.S. Garcia de Palazzo I. Ring D.B. et al.Phase I trial of 2B1, a bispecific monoclonal antibody targeting c-erbB-2 and Fc gamma RIII.Cancer Res. 1995; 55: 4586-4593PubMed Google Scholar, 29Weiner L.M. Clark J.I. Ring D.B. Alpaugh R.K. Clinical development of 2B1, a bispecific murine monoclonal antibody targeting c-erbB-2 and Fc gamma RIII.J Hematother. 1995; 4: 453-456Crossref PubMed Scopus (50) Google Scholar and the MDX-H210 (bispecific F(ab′)2 chemically conjugated).30James N.D. Atherton P.J. Jones J. Howie A.J. Tchekmedyian S. Curnow R.T. A phase II study of the bispecific antibody MDX-H210 (anti-HER2 x CD64) with GM-CSF in HER2+ advanced prostate cancer.Br J Cancer. 2001; 85: 152-156Crossref PubMed Scopus (79) Google Scholar, 31Repp R. van Ojik H.H. Valerius T. Groenewegen G. Wieland G. Oetzel C. et al.Phase I clinical trial of the bispecific antibody MDX-H210 (anti-FcgammaRI x anti-HER-2/neu) in combination with Filgrastim (G-CSF) for treatment of advanced breast cancer.Br J Cancer. 2003; 89: 2234-2243Crossref PubMed Scopus (72) Google Scholar, 32van Ojik H.H. Repp R. Groenewegen G. Valerius T. van de Winkel J.G. Clinical evaluation of the bispecific antibody MDX-H210 (anti-Fc gamma RI x anti-HER-2/neu) in combination with granulocyte-colony-stimulating factor (filgrastim) for treatment of advanced breast cancer.Cancer Immunol Immunother. 1997; 45: 207-209Crossref PubMed Scopus (30) Google Scholar Several groups including ours have used inhibitory receptors for anti-allergic treatment. Tom et al33Tam S.W. Demissie S. Thomas D. Daeron M. A bispecific antibody against human IgE and human FcgammaRII that inhibits antigen-induced histamine release by human mast cells and basophils.Allergy. 2004; 59: 772-780Crossref PubMed Scopus (67) Google Scholar have designed a bispecific antibody against IgE and FcγRIIB that inhibits antigen-induced histamine release by human mast cells and basophils in vitro. In addition, Zhu et al34Zhu D. Kepley C.L. Zhang M. Zhang K. Saxon A. A novel human immunoglobulin Fc gamma Fc epsilon bifunctional fusion protein inhibits Fc epsilon RI-mediated degranulation.Nat Med. 2002; 8: 518-521Crossref PubMed Scopus (179) Google Scholar have generated a fusion protein that inhibits FcɛRI-mediated responses by cross-linking it to FcγRIIB and have shown promising results in vivo. Notably, the latter studies did not attempt to target inhibitory receptors on eosinophils. As our data demonstrated that cross-linking of CD300a/IRp60 in the presence of eotaxin or IL-5/GM-CSF inhibits eosinophil chemotaxis, survival, and signaling cascades,12Munitz A. Bachelet I. Eliashar R. Moretta A. Moretta L. Levi-Schaffer F. The inhibitory receptor IRp60 (CD300a) suppresses the effects of IL-5, GM-CSF, and eotaxin on human peripheral blood eosinophils.Blood. 2006; 107: 1996-2003Crossref PubMed Scopus (115) Google Scholar we attempted to inhibit these functions of the eosinophils using a bispecific antibody fragment capable of recognizing CCR3 and CD300a/IRp60. Intranasal administration of the antibody fragment in a murine chronic model of established allergic eosinophilic airway inflammation, reversed the inflammatory process, and inhibits remodeling.35Zhu D. Kepley C.L. Zhang K. Terada T. Yamada T. Saxon A. A chimeric human-cat fusion protein blocks cat-induced allergy.Nat Med. 2005; 11: 446-449Crossref PubMed Scopus (179) Google Scholar, 36Munitz A. Bachelet I. Levi-Schaffer F. Daeron M. Reversal of airway inflammation and remodeling in asthma by a bispecific antibody fragment linking CCR3 to CD300a.J Allergy Clin Immunol. 2006; 118: 1082-1089Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar Although this antibody fragment is not entirely eosinophil specific, and binds to some extent mast cells and basophils, it clearly has an inhibitory function on these cells, and collectively, this highlights a route to target these inhibitory pathways in vivo and perhaps in clinical settings. Immune system homeostasis, as with other physiological systems, is a tightly regulated process governed by an intricate balance between inhibitory and stimulatory signals toward diverse stimuli.1Ravetch J.V. Lanier L.L. Immune inhibitory receptors.Science. 2000; 290: 84-89Crossref PubMed Scopus (1046) Google Scholar, 4Kumar V. McNerney M.E. A new self: MHC-class-I-independent natural-killer-cell self-tolerance.Nat Rev Immunol. 2005; 5: 363-374Crossref PubMed Scopus (144) Google Scholar, 11Rothenberg M.E. Hogan S.P. The eosinophil.Annu Rev Immunol. 2006; 24: 147-174Crossref PubMed Scopus (1194) Google Scholar The best described paradigm of this immune “yin-yan” comes from the NK cell. Although the eosinophil is still a mysterious cell,37Rosenberg H.F. Domachowske J.B. Eosinophils, eosinophil ribonucleases, and their role in host defense against respiratory virus pathogens.J Leukoc Biol. 2001; 70: 691-698PubMed Google Scholar undoubtedly the eosinophil effector functions may have detrimental consequences. Accordingly, there is a need to define pathways capable of inhibiting their functions. Definition of these routes and the potential ligands that interact with such inhibitory pathways will enable us to:1.Gain insight into the molecular mechanisms involved in eosinophil cellular inhibition/activation.2.Provide us with an opportunity to inhibit eosinophil functions in different experimental settings, thus expanding our knowledge on their function in the examined disorder(s).3.Provide us with novel tools to combat detrimental eosinophil functions in disease states." @default.
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• W2004252024 date "2007-06-01" @default.
• W2004252024 modified "2023-09-27" @default.
• W2004252024 title "Inhibitory receptors on eosinophils: A direct hit to a possible Achilles heel?" @default.
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• W2004252024 doi "https://doi.org/10.1016/j.jaci.2007.01.031" @default.
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