Effect of immune complexes of Cryptococcus neoformans polysaccharide on the host

Abstract

Cryptococcus neoformans is an encapsulated fungus that causes illness in 6--8% of AIDS patients. The polysaccharide capsule of C. neoformans is primarily composed of glucuronoxylomannan (GXM). GXM is shed during infection and accumulates in the host. GXM has many immunomodulatory effects; consequently its presence in the serum of infected individuals is likely to have adverse consequences. A GXM-specific murine IgG1 antibody will soon enter clinical trials. The therapeutic benefit of this antibody is thought to, at least partially, be due to its ability to mobilize GXM and clear it from the circulation. We studied the following aspects of GXM-mAb immune complexes: (i) fate; (ii) consequences of immune complex formation; (iii) mechanism of toxicity induced by immune complexes.;All isotypes of GXM specific mAb examined enhanced serum GXM clearance and promoted GXM sequestration in the liver and the spleen. MAb-mediated GXM deposition in the liver, but not in the spleen, was Fc receptor-dependent. CD4+ T cells were not necessary for mAb-mediated serum GXM clearance.;In agreement with previous reports we found that passive administration of GXM specific mAb to Swiss Webster mice infected with C. neoformans resulted in acute lethal toxicity (ALT). Toxicity was associated with hemoconcentration and hypotension. Toxicity could be prevented by rat antibody to Fc receptor or GXM-specific IgM before IgG1. Differences existed in the ability of various subtypes of IgG to induce toxicity; IgG1 was toxic and IgG3 was not.;We found greater platelet activating factor (PAF) release in the spleen and liver of infected mice given IgG1 than in mice given IgG3; suggesting that differential release of PAF is likely to account for the differential toxicity observed with these subtypes. We found no evidence that differential regulation of cytokines accounts for the differential ability of IgG1 and IgG3 to induce toxicity. Hence, the mechanism of ALT appears to be fundamentally different from that of cytokine release syndromes.;Our results provide a better understanding of the consequences of immune complex formation in the host and should benefit efforts aimed at further improving mAb therapies.