title: Mechanism for the isotype dependence of antibody-mediated toxicity in Cryptococcus neoformans-infected mice.
abstract: Ab-based therapies have undergone a renaissance in recent years, but infusion-related reactions are a significant clinical problem. Administration of certain mAbs to Swiss Webster mice infected with Cryptococcus neoformans can result in acute lethal toxicity (ALT) characterized by cardiovascular collapse. The ability of a mAb to produce ALT is isotype dependent and occurs with IgG1 but not IgG3. To investigate this phenomenon, we measured spleen and liver cytokine responses and platelet-activating factor (PAF) content in mice given C. neoformans glucuronoxylomannan (GXM) followed by specific Ab of IgG1 or IgG3 isotype. We found no evidence to suggest that the differences in IgG1 and IgG3 toxicity were due to differences in chemokine or cytokine response. In contrast, liver and spleen tissue PAF content was significantly greater in mice IgG1. Furthermore, our results show differences in the response to IgG1- and IgG3-GXM complexes regarding: 1) macrophage-inflammatory protein-1alpha and monocyte chemoattractant protein-1 regulation, 2) splenic and hepatic PAF content, and 3) hepatic PAF content in infected mice. IgG1-associated ALT appears to be the result of greater production of PAF in response to IgG1-GXM complex formation. The results are consistent with the view that IgG1 and IgG3 interact with different Fc receptors. Our findings strongly suggest that the mechanism for Ab-mediated ALT is different from the cytokine release syndrome described after administration of other therapeutic mAbs.
authors.affiliation: Departments of Microbiology and Immunology and Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: N
authors.initials: N
authors.lastname: Lendvai
authors.forename: X W
authors.initials: XW
authors.lastname: Qu
authors.forename: W
authors.initials: W
authors.lastname: Hsueh
authors.forename: A
authors.initials: A
authors.lastname: Casadevall
mesh_terms: D000818:Animals; D000908:Antibodies, Fungal / Q000008:administration & dosage / Q000633:toxicity*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000633:toxicity*; D000918:Antibody Specificity; D000946:Antigens, Fungal / Q000008:administration & dosage / Q000276:immunology; D018932:Chemokine CCL2 / Q000032:analysis; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D018925:Chemokines / Q000032:analysis; D003453:Cryptococcosis / Q000276:immunology* / Q000401:mortality; D003455:Cryptococcus neoformans / Q000276:immunology*; D016207:Cytokines / Q000235:genetics; D005260:Female; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000502:physiology / Q000633:toxicity*; D007132:Immunoglobulin Isotypes / Q000008:administration & dosage / Q000502:physiology* / Q000633:toxicity; D007275:Injections, Intravenous; D007375:Interleukin-1 / Q000032:analysis; D015850:Interleukin-6 / Q000032:analysis; D019402:Macrophage Inflammatory Proteins / Q000032:analysis; D051379:Mice; D010972:Platelet Activating Factor / Q000032:analysis; D011134:Polysaccharides / Q000008:administration & dosage / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D000908:Antibodies, Fungal; D000911:Antibodies, Monoclonal; D000946:Antigens, Fungal; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D016207:Cytokines; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D007375:Interleukin-1; D015850:Interleukin-6; D019402:Macrophage Inflammatory Proteins; D010972:Platelet Activating Factor; D011134:Polysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C027478:glucuronoxylomannan