Monoclonal Antibody–Mediated Toxicity inCryptococcus neoformansInfection: Mechanism and Relationship to Antibody Isotype

Abstract

Antibody reagents represent an alternative for the therapy of human cryptococcosis, and monoclonal antibody 18B7 (IgG1) is a candidate for phase I trial in humans with cryptococcosis. However, antibody administration to mice with established Cryptococcus neoformans infection has been reported to produce acute lethal toxicity (ALT). The present study confirmed this phenomenon and investigated the mechanism of ALT. ALT was associated with hemoconcentration, hypotension, and circulatory collapse; however, toxicity could be prevented by platelet-activating factor inhibitor, rat antibody to Fc receptor, or IgM before IgG1. Significant isotype-specific differences were found in ALT, which can be interpreted as consistent with the hypothesis that there are distinct Fc receptors for murine IgG1 and IgG3. The IgM and IgG3 isotype preference in antibody responses to polysaccharide antigens in mice may translate to a lack of toxicity of antigen-antibody complexes during the course of infections with encapsulated pathogens.

Mechanism for the Isotype Dependence of Antibody-Mediated Toxicity inCryptococcus neoformans-Infected Mice

“…Mice either died within an hour or made a full recovery. ALT results from cardiovascular collapse caused by hypotension and a rapid rise in hematocrit (8). According to the current model, ALT occurs when passively administered mAb binds GXM, forms Ag-Ab complexes, and triggers a capillary leak syndrome that results in hemoconcentration, hyperviscosity, and hypotension (8,11).…”

“…ALT results from cardiovascular collapse caused by hypotension and a rapid rise in hematocrit (8). According to the current model, ALT occurs when passively administered mAb binds GXM, forms Ag-Ab complexes, and triggers a capillary leak syndrome that results in hemoconcentration, hyperviscosity, and hypotension (8,11). The trigger event is thought to be the cross-linking of Fc receptors on phagocytic cells during uptake of GXM-Ab complexes (8,11).…”

“…Acute lethal toxicity (ALT) characterized by an acute onset of listlessness, ataxia, uncontrolled movements, and paralysis of hind limbs was described in mice with C. neoformans infection after administration of mAb to GXM (8,11). Mice either died within an hour or made a full recovery.…”

“…According to the current model, ALT occurs when passively administered mAb binds GXM, forms Ag-Ab complexes, and triggers a capillary leak syndrome that results in hemoconcentration, hyperviscosity, and hypotension (8,11). The trigger event is thought to be the cross-linking of Fc receptors on phagocytic cells during uptake of GXM-Ab complexes (8,11). Fc receptor activation results in the release of platelet-activating factor (PAF) (12)(13)(14)(15) has been implicated in the pathogenesis of ALT because PAF administration causes a similar syndrome (16 -18) and ALT can be prevented by PAF antagonists (9,11).…”

Immunoglobulin M Efficacy AgainstCryptococcus neoformans: Mechanism, Dose Dependence, and Prozone-Like Effects in Passive Protection Experiments

“…A better understanding of IgM efficacy against C. neoformans is important because IgM to GXM is common in human sera (18 -21), can protect against this pathogen (7,8), and does not cause acute lethal toxicity when administered to infected mice (22 …”