Hypersensitivity reactions to asparaginase in mice are mediated by anti-asparaginase IgE and IgG and the immunoglobulin receptors FcεRI and FcγRIII.

Abstract

Asparaginase is an important drug for the treatment of leukemias. However, anti-asparaginase antibodies often develop, which can decrease asparaginase drug levels and increase the risk of relapse. The aim of this study is to identify the immunoglobulin isotypes and receptors responsible for asparaginase hypersensitivities. Mice immunized with asparaginase developed anti-asparaginase IgG1 and IgE antibodies, and challenging the sensitized mice with asparaginase induced severe hypersensitivity reactions. Flow cytometry analysis indicated that macrophages/monocytes, neutrophils, and basophils bind asparaginase ex vivo through FcγRIII. In contrast, asparaginase binding to basophils was dependent on FcγRIII and IgE. Consistent with the asparaginase binding data, basophil activation by asparaginase occurred via both IgG/FcγRIII and IgE/FcεRI. Depleting >95% of B cells suppressed IgG but not IgE-dependent hypersensitivity, while depleting CD4+ T cells provided complete protection. Combined treatment with either anti-IgE mAb plus a platelet-activating factor receptor antagonist or anti-FcγRIII mAb plus a H1 receptor antagonist suppressed asparaginase hypersensitivity. The observations indicate that asparaginase hypersensitivity is mediated by antigen-specific IgG and/or IgE through the immunoglobulin receptors FcγRIII and FcεRI, respectively. Provided that these results apply to humans, they emphasize the importance of monitoring both IgE- and IgG-mediated asparaginase hypersensitivities in patients receiving this agent.

• Authors: Sanjay Rathod, Manda Ramsey, Mary V Relling, Fred D Finkelman, Christian A Fernandez
• Journal: Haematologica (Haematologica) Vol. 104 Issue 2 Pg. 319-329 (02 2019) ISSN: 1592-8721 [Electronic] Italy
• PMID: 30237274 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Ferrata Storti Foundation.

Chemical References

• Antineoplastic Agents
• Immunoglobulin G
• Receptors, IgE
• Receptors, IgG
• Immunoglobulin E
• Asparaginase

Topics

• Animals
• Antineoplastic Agents (adverse effects)
• Asparaginase (adverse effects)
• Disease Models, Animal
• Drug Hypersensitivity (diagnosis, immunology, metabolism)
• Female
• Immunization
• Immunoglobulin E (immunology)
• Immunoglobulin G (immunology)
• Leukocyte Count
• Leukocytes (immunology, metabolism)
• Mice
• Protein Binding (immunology)
• Receptors, IgE (metabolism)
• Receptors, IgG (metabolism)