Monoclonal antibody 197 (anti‐FcγRI) infusion in a patient with immune thrombocytopenia purpura (ITP) results in down‐modulation of FcγRI on circulating monocytes

Ericson, Solveig G.; Coleman, Kimberly D.; Wardwell, Kathleen; Baker, Susan C.; Fanger, Michael W.; Guyre, Paul M.; Ely, Pamela

doi:10.1046/j.1365-2141.1996.393931.x

Cited by 50 publications

(28 citation statements)

References 19 publications

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“…In contrast, blocking antibodies for the medium affinity receptor FcγRIV resulted in an impaired platelet clearance. Similar results were obtained in human ITP patients where blocking antibodies to FcγRIIIA, which is the human ortholog of murine FcγRIV [23,42], but not to human FcγRI were very efficient in blocking platelet depletion [43][44][45][46]. Thus, FcγRs are instrumental for IgG-mediated platelet depletion for murine and human ITP and are an attractive target for therapeutic intervention.…”

Section: Effector Pathways Involved In Murine Itpsupporting

confidence: 73%

The role of Fcγ receptors in murine autoimmune thrombocytopenia

et al. 2010

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International audienceImmune thrombocytopenia (ITP) can become a life-threatening condition that requires immediate medical attention. The loss in platelet numbers during ITP can be induced by a variety of triggers. Anti-platelet antibodies of several isotypes and subclasses are a major cause for ITP and are a hallmark of many complex autoimmune diseases such as systemic lupus erythematosus. Mouse models have been important to understand the effector pathways involved in antibody-mediated platelet depletion. Therapeutic interventions based on these results have been proven successful in treating human ITP, thus validating the use of these model systems. One major problem that remains to be answered is which cell populations are crucial for platelet removal. Targeting these cells directly might be a novel therapeutic strategy and will also be important to understand the underlying biological mechanisms

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Section: Effector Pathways Involved In Murine Itpsupporting

confidence: 73%

The role of Fcγ receptors in murine autoimmune thrombocytopenia

et al. 2010

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“…Modulation of Fc␥RI using anti-Fc␥RI Abs has been described for cultured human monocytes (24, 37) and peritoneal exudate macrophages from human Fc␥RI-transgenic mice (17), as well as in vivo in patients with immune thrombocytopenia purpura (22,23). In the present study, our aim was to further investigate the nature of Fc␥RI modulation by a humanized mAb, H22, as well as H22 fusion proteins, using the human myeloid cell lines U937 and its high Fc␥RI-expressing subclone, 10.6, as a model.…”

Section: Discussionmentioning

confidence: 99%

“…Anti-Fc␥RI Abs used as modulators included H22 (7,27); H22 F(abЈ) 2 ; MDX-H210, a bispecific Ab comprised of the FabЈ of mAb H22 and anti-HER2/neu (28); and 197, a mAb which has been shown to cross-link and modulate Fc␥RI (10,22,29) (all kind gifts of Medarex, Bloomsbury, NJ). Also used were two Fc␥RI-targeted eGFP fusion proteins, sFv22xeGFP and wH22xeGFP, constructed from mAb H22 and eGFP (Ref.…”

Section: Abs and Reagentsmentioning

confidence: 99%

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Receptor Modulation by FcγRI-Specific Fusion Proteins Is Dependent on Receptor Number and Modified by IgG

Guyre

Keler²,

Swink³

et al. 2001

The Journal of Immunology

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The high-affinity IgG receptor, FcγRI (CD64), is constitutively expressed exclusively on professional APCs. Human FcγRI binds monomeric IgG with high affinity and is, therefore, saturated in vivo. The binding of IgG to FcγRI causes receptor recycling, while Abs that cross-link FcγRI cause rapid down-modulation of surface FcγRI. Because studies performed in the absence of ligand may not be representative of FcγRI modulation in vivo, we investigated the ability of FcγRI-cross-linking Abs and non-cross-linking derivatives to modulate FcγRI in the presence and absence of ligand. In the absence of ligand mAb H22 and wH22xeGFP, an enhanced green fluorescent protein (eGFP)-labeled fusion protein of H22, cross-linked and rapidly down-modulated surface FcγRI on the human myeloid cell line, U937, and its high FcγRI-expressing subclone, 10.6. This effect was dependent on the concentration of fusion protein and the level of FcγRI expression and correlated with internalization of both wH22xeGFP and FcγRI, itself, as assessed by confocal microscopy. A single-chain Fv version, sFv22xeGFP, which does not cross-link FcγRI, was unable to modulate FcγRI in the absence of IgG. However, if ligand was present, treatment with either monovalent or cross-linking fusion protein led to intracellular receptor accumulation. These findings suggest at least two alternate mechanisms of internalization that are influenced by ligand and demonstrate the physiologic potential of FcγRI to transport a large antigenic load into APCs for processing. These studies may lead to the development of better FcγRI-targeted vaccines, as well as therapies to down-modulate FcR involved in autoimmune diseases.

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“…Furthermore in vivo blockade of FcR on macrophages following treatment of rhesus D1 ITP patients with anti-D antibodies has a similar effect to IVIg [12]. This is also seen with a monoclonal antibody against the FcRIII [13]. Evidence that binding of the Fc to the receptor affects intracellular signalling of B cells and monocytes and thus may indirectly reduce cytokine synthesis and lymphocyte activation.…”

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confidence: 99%