Effect of humoral immune mechanisms on the pharmacokinetics, organ distribution and tissue localization of an immunologically active fungal polysaccharide antigen

Many encapsulated pathogens release capsular polysaccharide (CP) antigens into host tissues but little is known about the clearance mechanisms of these antigens. Cryptococcus neoformans is an opportunistic encapsulated fungal pathogen which causes chronic infections accompanied by high serum and tissue levels of CP antigen. Two methods were used to study the fate of CP in mice: measurement of radioactivity after administration of ¹²⁵I-labelled C. neoformans CP and measurement of CP tissue content by ELISA. The results of both methods were consistent, and indicated that CP is cleared from the serum by deposition in the spleen and liver. To investigate the role and relative efficacy of monoclonal antibodies (mAbs) in GXM clearance, we measured GXM organ distribution in mice after administration of IgM, IgG3, IgG1, IgG2a, and IgA mAbs. The experimental system consisted of intravenous GXM administration followed by intraperitoneal mAb administration. Our results indicate: i) a relative efficacy of IgG1,IgM > IgG2a > IgG3 > IgA in mAb-mediated serum GXM clearance; ii) mAbs of each isotype mediated liver and spleen GXM deposition; iii) mAb-mediated GXM deposition in liver, but not spleen is Fc-dependent; iv) complement enhances IgM-mediated GXM deposition in liver but not spleen; and v) even in CD4 -/- mice mAb mediates serum GXM clearance and GXM deposition in liver and spleen. The results indicate a requirement for intact mAbs in the therapy of cryptococcosis and suggest guidelines for choosing empiric doses of mAb in the upcoming clinical trial.