Mechanism for the isotype dependence of antibody-mediated toxicity in Cryptococcus neoformans-infected mice

Ab-based therapies have undergone a renaissance in recent years, but infusi on-related reactions are a significant clinical problem, Administration of certain mAbs to Swiss Webster mice infected with Cryptococcus neoformans ca n result in acute lethal toxicity (ALT) characterized by cardiovascular col lapse. 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 i n mice given C, neoformans glucuronoxylomannan (GXM) followed by specific A b of IgG1 or IgG3 isotype. We found no evidence to suggest that the differe nces in IgG1 and IgG3 toxicity mere due to differences in chemokine or cyto kine response. In contrast, liver and spleen tissue PAF content was signifi cantly greater in mice IgG1. Furthermore, our results show differences in t he response to IgG1- and IgG3-GXM complexes regarding: 1) macrophage-inflam matory protein-1 alpha and monocyte chemoattractant protein-1 regulation, 2 ) splenic and hepatic PAF content, and 3) hepatic PAF content in infected m ice. IgG1-associated ALT appears to be the result of greater production of PAF in response to IgG1-GXM complex formation. The results are consistent w ith the view that IgG1 and IgG3 interact,vith different Fe receptors. Our f indings strongly suggest that the mechanism for Ab-mediated ALT is differen t from the cytokine release syndrome described after administration of othe r therapeutic mAbs.