Hypersensitivity reactions to asparaginase in mice are mediated by anti-asparaginase IgE and IgG and the immunoglobulin receptors Fc?RI and Fc?RIII.

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 Fc?RIII. In contrast, asparaginase binding to basophils was dependent on Fc?RIII and IgE. Consistent with the asparaginase binding data, basophil activation by asparaginase occurred via both IgG/Fc?RIII and IgE/Fc?RI. 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-Fc?RIII 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 Fc?RIII and Fc?RI, 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.

SUBMITTER: Rathod S 

PROVIDER: S-EPMC6355496 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature