Food, drug, insect sting allergy, and anaphylaxis
Rapid desensitization of mice with anti-FcγRIIb/FcγRIII mAb safely prevents IgG-mediated anaphylaxis

https://doi.org/10.1016/j.jaci.2013.09.008Get rights and content

Background

Stimulatory IgG receptors (FcγRs) on bone marrow-derived cells contribute to the pathogenesis of several autoimmune and inflammatory disorders. Monoclonal antibodies that block FcγRs might suppress these diseases, but they can induce anaphylaxis.

Objective

We wanted to determine whether a rapid desensitization approach can safely suppress IgG/FcγR-mediated anaphylaxis.

Methods

Mice were injected with serially increasing doses of 2.4G2, a rat mAb that blocks the inhibitory FcγR, FcγRIIb, and the stimulatory receptor, FcγRIII. Rectal temperature was used to detect the development of anaphylaxis. Passive and active IgG-mediated anaphylaxis were evaluated in mice that had been rapidly desensitized with 2.4G2 or mock-desensitized in mice in which monocyte/macrophages, basophils, or neutrophils had been depleted or desensitized and in mice in which FcγRI, FcγRIII, and/or FcγRIV had been deleted or blocked.

Results

Rapid desensitization with 2.4G2 prevented 2.4G2-induced shock and completely suppressed IgG-mediated anaphylaxis. Rapid desensitization of ovalbumin-sensitized mice with 2.4G2 was safer and more effective than rapid desensitization with ovalbumin. 2.4G2 treatment completely blocked FcγRIII and removed most FcγRI and FcγRIV from nucleated peripheral blood cells. Because IgG2a-mediated anaphylaxis was partially FcγRI and FcγRIV dependent, the effects of 2.4G2 on FcγRI and FcγRIV were probably crucial for its complete inhibition of IgG2a-mediated anaphylaxis. IgG2a-mediated anaphylaxis was partially inhibited by depletion or desensitization of monocyte/macrophages, basophils, or neutrophils.

Conclusion

IgG-mediated anaphylaxis can be induced by ligation of FcγRI, FcγRIII, or FcγRIV on monocycte/macrophages, basophils, or neutrophils and can be safely suppressed by rapid desensitization with anti-FcγRII/RIII mAb. A similar approach may safely suppress other FcγR-dependent immunopathology.

Section snippets

Mice

Female BALB/c and C57BL/6 mice were purchased from Taconic (Hudson, NY) and were used at 7 to 12 weeks of age. FcγRIII-deficient and FcγRI-deficient mice on a BALB/c background1, 18 were a gift of Dr Jeffrey Ravetch (Rockefeller University, New York, NY); these mice were bred to each other to generate mice deficient in both FcγRI and FcγRIII. F2 offspring were typed by PCR to identify double-deficient offspring. FcγRIIb-deficient mice on a C57BL/6 background were purchased from the Jackson

Rapid desensitization with anti-FcγRII/RIII mAb (2.4G2) avoids direct toxicity and prevents IgG-mediated anaphylaxis

To determine whether a rapid desensitization approach could prevent the development of anaphylaxis in mice injected with 2.4G2, we first determined the dose of 2.4G2 required to induce shock (hypothermia) in BALB/c mice (Fig 1, A). A significant and substantial decrease in temperature was observed in mice injected with 63 μg or more of this mAb but not in mice injected with 31 μg. In contrast, serial, hourly injections of mice with doubling doses of 2.4G2, starting with a dose of 15 μg and

Discussion

The results of our studies indicate that rapid desensitization with an IgG mAb specific for FcγRIIb and FcγRIII safely allows complete inhibition of IgG-mediated anaphylaxis. Although shock is induced in mice given a single injection of 63 μg of 2.4G2, mice injected hourly with doubling doses of that mAb, starting with a dose of 15 μg, failed to anaphylax in response to 500 μg of 2.4G2, even if pretreated with a long-acting formulation of IL-4 that considerably increases sensitivity to this mAb.

References (60)

  • M. Khodoun et al.

    Peanuts can contribute to anaphylactic shock by activating complement

    J Allergy Clin Immunol

    (2009)
  • Y. Tsujimura et al.

    Basophils play a pivotal role in immunoglobulin-G-mediated but not immunoglobulin-E-mediated systemic anaphylaxis

    Immunity

    (2008)
  • S. Bolland et al.

    Spontaneous autoimmune disease in FcγRIIB-deficient mice results from strain-specific epistasis

    Immunity

    (2000)
  • A. Cheifetz et al.

    The incidence and management of infusion reactions to infliximab: a large center experience

    Am J Gastroenterol

    (2003)
  • P. Domingo et al.

    Associations between Fcγ receptor IIA polymorphisms and the risk and prognosis of meningococcal disease

    Am J Med

    (2002)
  • F. Nimmerjahn et al.

    Fcγ receptors as regulators of immune responses

    Nat Rev Immunol

    (2008)
  • V.C. Huber et al.

    Fc receptor-mediated phagocytosis makes a significant contribution to clearance of influenza virus infections

    J Immunol

    (2001)
  • K.M. Chung et al.

    Antibodies against West Nile Virus nonstructural protein NS1 prevent lethal infection through Fcγ receptor-dependent and -independent mechanisms

    J Virol

    (2006)
  • A. Bergtold et al.

    FcR-bearing myeloid cells are responsible for triggering murine lupus nephritis

    J Immunol

    (2006)
  • J.E. Gessner et al.

    The IgG Fc receptor family

    Ann Hematol

    (1998)
  • T. Hashimoto et al.

    Pathogenesis of epidermolysis bullosa acquisita, an autoimmune subepidermal bullous disease

    J Pathol

    (2012)
  • R.M. Anthony et al.

    Recapitulation of IVIG anti-inflammatory activity with a recombinant IgG Fc

    Science

    (2008)
  • J. Unkeless

    Characterization of a monoclonal antibody directed against mouse macrophage and lymphocyte Fc receptors

    J Exp Med

    (1979)
  • M. Hirano et al.

    IgEb immune complexes activate macrophages through FcγRIV binding

    Nat Immunol

    (2007)
  • M. Khodoun et al.

    Rapid polyclonal desensitization with antibodies to IgE and FcεRIα

    J Allergy Clin Immunol

    (2013)
  • J.V. Ravetch et al.

    IgG Fc receptors

    Annu Rev Immunol

    (2001)
  • D.B. Wilde et al.

    Evidence implicating L3T4 in class II MHC antigen reactivity: monoclonal antibody GK1.5 (anti-L3T4a) blocks class II MHC antigen-specific proliferation, release of lymphokines, and binding by cloned murine helper T lymphocyte lines

    J Immunol

    (1983)
  • T. Springer et al.

    Mac-1: a macrophage differentiation antigen identified by monoclonal antibody

    Eur J Immunol

    (1979)
  • C. Schiller et al.

    Mouse FcγRII is a negative regulator of FcγRIII in IgG immune complex-triggered inflammation but not in autoantibody-induced hemolysis

    Eur J Immunol

    (2000)
  • F.D. Finkelman et al.

    IgD-secreting murine plasmacytomas: identification and partial characterization of two IgD myeloma proteins

    J Immunol

    (1981)
  • Cited by (29)

    • The role of IgG subclasses and platelets in experimental anaphylaxis

      2021, Journal of Allergy and Clinical Immunology
    • Multifaceted roles of basophils in health and disease

      2018, Journal of Allergy and Clinical Immunology
    View all citing articles on Scopus

    Supported by the US Department of Veterans Affairs Merit Award (F.D.F.).

    Disclosure of potential conflict of interest: M. Khodoun, D. Krishnamurthy, and F. Finkelman have a provisional patent, and there is potential that money may be paid to them and their institution. Z. Kucuk has received a grant from the National Institutes of Health. The rest of the authors declare that they have no relevant conflicts of interest.

    These authors contributed equally to this work.

    Durga Krishnamurthy is currently affiliated with the Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.

    View full text