Amelioration of murine immune thrombocytopenia by CD44 antibodies: a potential therapy for ITP?

Crow, Andrew R.; Song, Seng; Suppa, Sara J; Ma, Shuhua; Reilly, Michael P.; André, Pierrette; McKenzie, Steven E.; Lazarus, Alan H.

doi:10.1182/blood-2010-05-280115

Cited by 21 publications

(33 citation statements)

References 23 publications

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“…Deglycosylated IM7 (which more minimally depletes platelets) does have anti-inflammatory effects in ITP (A. Amash and A.H. Lazarus, unpublished data). More interestingly, we have also shown that other CD44 mAbs such as KM114, KM81, and KM201 are able to ameliorate ITP (50). The lack of direct inhibition of phagocytosis with these other Abs that ameliorate ITP demonstrates that these Abs may work by an indirect mechanism in ITP, or that platelet phagocytosis is distinct from RBC phagocytosis.…”

Section: Discussionmentioning

confidence: 61%

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CD44 Antibody Inhibition of Macrophage Phagocytosis Targets Fcγ Receptor– and Complement Receptor 3–Dependent Mechanisms

Amash

Wang

et al. 2016

The Journal of Immunology

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Targeting CD44, a major leukocyte adhesion molecule, using specific Abs has been shown beneficial in several models of autoimmune and inflammatory diseases. The mechanisms contributing to the anti-inflammatory effects of CD44 Abs, however, remain poorly understood. Phagocytosis is a key component of immune system function and can play a pivotal role in autoimmune states where CD44 Abs have shown to be effective. In this study, we show that the well-known anti-inflammatory CD44 Ab IM7 can inhibit murine macrophage phagocytosis of RBCs. We assessed three selected macrophage phagocytic receptor systems: Fcγ receptors (FcγRs), complement receptor 3 (CR3), and dectin-1. Treatment of macrophages with IM7 resulted in significant inhibition of FcγR-mediated phagocytosis of IgG-opsonized RBCs. The inhibition of FcγR-mediated phagocytosis was at an early stage in the phagocytic process involving both inhibition of the binding of the target RBC to the macrophages and postbinding events. This CD44 Ab also inhibited CR3-mediated phagocytosis of C3bi-opsonized RBCs, but it did not affect the phagocytosis of zymosan particles, known to be mediated by the C-type lectin dectin-1. Other CD44 Abs known to have less broad anti-inflammatory activity, including KM114, KM81, and KM201, did not inhibit FcγR-mediated phagocytosis of RBCs. Taken together, these findings demonstrate selective inhibition of FcγR and CR3-mediated phagocytosis by IM7 and suggest that this broadly anti-inflammatory CD44 Ab inhibits these selected macrophage phagocytic pathways. The understanding of the immune-regulatory effects of CD44 Abs is important in the development and optimization of therapeutic strategies for the potential treatment of autoimmune conditions.

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Section: Discussionmentioning

confidence: 61%

“…However, we have previously shown that IM7 did not improve platelet counts in a passive model of immune thrombocytopenia (ITP) (50). These seemingly contradictory findings are not due to a lack of anti-inflammatory activity of IM7 in ITP.…”

Section: Discussionmentioning

confidence: 89%

CD44 Antibody Inhibition of Macrophage Phagocytosis Targets Fcγ Receptor– and Complement Receptor 3–Dependent Mechanisms

Amash

Wang

et al. 2016

The Journal of Immunology

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“…Using a murine model of ITP, 19 we first undertook a time course assay to analyze the clearance characteristics of antiplatelet antibody in the presence versus absence of IVIg in C57BL/6 and FcRn-deficient mice. In all mice, all of the antiplatelet IgG was bound to platelets within 10 minutes after antibody administration (assessed by ELISA and flow cytometry, not shown), suggesting that all antiplatelet IgG was quickly bound to the platelets.…”

Section: Resultsmentioning

confidence: 99%

“…19 We next compared the ability of one of these IVIg-mimetic anti-CD44 antibodies (KM114) to ameliorate thrombocytopenia in FcRn-deficient versus C57BL/6 mice. Low-dose KM114 (50 g/ mouse, ϳ 2 mg/kg) was able to effectively ameliorate thrombocytopenia in FcRn-deficient mice to the same extent as control C57BL/6 mice ( Figure 2A).…”

Section: Resultsmentioning

confidence: 99%

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The neonatal Fc receptor (FcRn) is not required for IVIg or anti-CD44 monoclonal antibody–mediated amelioration of murine immune thrombocytopenia

Crow

Suppa

Chen

et al. 2011

Blood

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IVIg‐mediated amelioration of ITP in mice is dependent on sialic acid and SIGNR1

et al. 2012

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Intravenous immunoglobulin G (IVIg) therapy is widely used to treat autoimmune and inflammatory diseases. Recent evidence suggests that in mice, splenic resident cells might be important for the anti-inflammatory activity of IVIg in a model of serum transfer arthritis. Splenectomized human immunothrombocytopenia (ITP) patients, however, still respond to IVIg therapy. To investigate whether the requirement of the spleen is essential for mouse ITP, we used a passive model of induced ITP and demonstrated that IVIg activity was functional in splenectomized animals. Further analysis showed that the IVIgmediated amelioration of platelet phagocytosis was fully dependent on terminal sialic acid residues in the IVIg preparation and could be blocked with a specific ICAM3 grabbing nonintegrin-related 1 (SIGNR1) specific antibody. These results suggest that, similar to the human system, a spleen-independent but sialic acid-and SIGNR1-dependent pathway is responsible for IVIg-mediated suppression of autoantibody-dependent platelet depletion in mice.Supporting Information available online IntroductionIntravenous immunoglobulin G (IVIg) has been used for more than 30 years to treat autoimmune diseases such as immunothrombocytopenia (ITP), Guillain-Barre Syndrome, Kawasaki's disease, and chronic inflammatory demyelinating polyneuropathy (CIDP) [1, 2]. A variety of mechanisms depending either on the IgG variable (Fab fragment) or the constant crystallizable fragment (Fc fragment) have been suggested to be responsible for the anti-inflammatory activity of this IgG preparation [1, 2]. Data from human patients and mouse models of ITP, rheumaCorrespondence: Dr. Falk Nimmerjahn e-mail: fnimmerj@biologie.uni-erlangen.de toid arthritis, and nephrotoxic nephritis indicate that the IgG Fc fragment is important for IVIg activity in these autoimmune diseases in vivo [3][4][5][6][7]. Furthermore, the anti-inflammatory activity of IVIg was abrogated in mice deficient in the inhibitory Fcγ-receptor IIB (FcγRIIB) in a variety of model systems [3,5,[7][8][9][10][11][12][13][14]. A plausible explanation for the role of FcγRIIB was afforded by studies in mice and human patients with CIDP, which showed that FcγRIIB becomes upregulated on innate immune effector cells thereby raising the threshold for cell activation by immune complexes [3,5,7,15]. Further studies revealed that the sugar moiety attached to the IgG Fc fragment and especially terminal sialic acid residues in the Fc-linked but not the Fab-linked sugar moiety of serum IgG are essential for the anti-inflammatory activity [6,[11][12][13]16]. Removal of terminal sialic acid residues strongly impaired the suppressive activity of IVIg or the isolated Fc fragment, whereas enrichment for 2,6-linked sialic acid residues in the Fc-domain or in vitro hypersialylated IgG enhanced the antiinflammatory activity [6,12,13]. Of note, mouse and human antibodies rich in terminal sialic acid residues have a decreased affinity for classical FcγRs and were shown to gain the capacity to bind to mouse SIGNR1 ...

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Amelioration of murine immune thrombocytopenia by CD44 antibodies: a potential therapy for ITP?

Cited by 21 publications

References 23 publications

CD44 Antibody Inhibition of Macrophage Phagocytosis Targets Fcγ Receptor– and Complement Receptor 3–Dependent Mechanisms

CD44 Antibody Inhibition of Macrophage Phagocytosis Targets Fcγ Receptor– and Complement Receptor 3–Dependent Mechanisms

The neonatal Fc receptor (FcRn) is not required for IVIg or anti-CD44 monoclonal antibody–mediated amelioration of murine immune thrombocytopenia

IVIg‐mediated amelioration of ITP in mice is dependent on sialic acid and SIGNR1

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