Pathogenesis and management of anaphylaxis: Current status and future challenges

Journal of Allergy and Clinical Immunology (Impact Factor: 11.25). 04/2005; 115(3):571-4. DOI: 10.1016/j.jaci.2004.12.1133
Source: PubMed
  • [Show abstract] [Hide abstract]
    ABSTRACT: Immunotherapy for cancer using antibodies to enhance T cell function has been successful in recent clinical trials. Many molecules which improve activation and effector function of T cells have been investigated as potential new targets for immunomodulatory antibodies, including the tumor necrosis factor receptor (TNFR) superfamily members GITR and OX40. Antibodies engaging GITR or OX40 result in significant tumor protection in preclinical models. In this study, we observed that the GITR agonist antibody DTA-1 causes anaphylaxis in mice upon repeated intraperitoneal dosing. DTA-1-induced anaphylaxis requires GITR, CD4(+) T cells, B cells, and IL-4. Transfer of serum antibodies from DTA-1-treated mice, which contain high levels of DTA-1-specific IgG1, can induce anaphylaxis in naïve mice upon administration of an additional dose of DTA-1, suggesting that anaphylaxis results from anti-DTA-1 antibodies. Depletion of basophils and blockade of platelet activating factor, the key components of the IgG1 pathway of anaphylaxis, rescues the mice from DTA-1-induced anaphylaxis. These results demonstrate a previously undescribed lethal side effect of repetitive doses of an agonist immunomodulatory antibody as well as insight into the mechanism of toxicity, which may offer a means of preventing adverse effects in future clinical trials using anti-GITR or other agonist antibodies as immunotherapies.
    Blood 02/2014; 123(14). DOI:10.1182/blood-2013-12-544742 · 9.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although mast cells have long been known to play a critical role in anaphylaxis and other allergic diseases, they also participate in some innate immune responses and may even have some protective functions. Data from the study of mast cell-deficient mice have facilitated our understanding of some of the molecular mechanisms driving mast cell functions during both innate and adaptive immune responses. This review presents an overview of the biology of mast cells and their potential involvement in various inflammatory diseases. We then discuss some of the current pharmacological approaches used to target mast cells and their products in several diseases associated with mast cell activation.
    Pharmacology [?] Therapeutics 01/2014; DOI:10.1016/j.pharmthera.2014.01.004 · 7.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Anaphylaxis is a systemic hyperacute allergic reaction that develops within minutes following antigen/allergen exposure in humans. Animal models of passive anaphylaxis proposed that anaphylaxis is an IgE-dependent, FcɛRI-dependent, mast cell-dependent, histamine-dependent reaction. Anaphylaxis, however, can be induced by IgG antibodies. For example, IgG1-induced passive systemic anaphylaxis depends on the activating IgG receptor FcγRIIIA and, perhaps, on basophils. Surprisingly, active systemic anaphylaxis in mice required neither IgE, nor FcɛRI, nor mast cells or basophils. We showed recently that active systemic anaphylaxis involves IgG antibodies, activating IgG receptors FcγRIIIA and FcγRIV, platelet-activating factor (PAF), neutrophils and, to a lower extent, basophils. Neutrophil depletion inhibited active, but also passive, systemic anaphylaxis. Importantly, human neutrophils restored anaphylaxis in anaphylaxis-resistant mice, demonstrating that neutrophils are sufficient to induce anaphylaxis and that IgG receptors on human neutrophils may be responsible for anaphylaxis induction. In humans, neutrophils, like mast cells, basophils and eosinophils, do not express FcγRIIIA or FcγRIV, but the activating IgG receptor FcγRIIA. We therefore extended our investigation to the role of human FcγRIIA in systemic anaphylaxis by generating novel FcγRIIA-transgenic mice. We found that in these mice FcγRIIA was sufficient to trigger both active and passive systemic anaphylaxis. We identified monocyte/macrophages and neutrophils to be responsible for FcγRIIA-dependent passive systemic anaphylaxis. Supporting these findings, human monocytes and neutrophils produced anaphylactogenic mediators following FcγRIIA engagement. Our results therefore unravel an unexpected role of IgG, IgG receptors and neutrophils in anaphylaxis and suggest that neutrophils (and monocytes) activated by IgG-induced aggregation of FcγRIIA can contribute to human anaphylaxis.
    Revue Française d'Allergologie 06/2012; 52(4):333–339. DOI:10.1016/j.reval.2012.02.003 · 0.35 Impact Factor