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Establishment of the Dual Humanized TK-NOG Mouse Model for HIV-associated Liver Pathogenesis
Published on: September 11, 2019
A prototype pathogen bound ex vivo to human erythrocyte complement receptor 1 via bispecific monoclonal antibody
A Nardin1, R Schlimgen, V M Holers
1Department of Biochemistry, University of Virginia School of Medicine, Charlottesville 22908, USA.
Immune complexes (IC) bound to the primate erythrocyte (E) complement receptor (CR1) are cleared from the circulation of primates and localized to the liver. IC can be bound to E CR1 either via C3b opsonization or with cross-linked mAb complexes (heteropolymers, HP) which contain an mAb specific for CR1 and a mAb specific for a prototype pathogen. The long-term goal of our work is to apply the HP to the treatment of human diseases associated with blood-borne pathogens. Therefore we have investigated the feasibility of a non-primate model by studying clearance in mice of bacteriophage phiX174 bound via HP to primate E. E-HP-phiX174 complexes were prepared in vitro and infused into the circulation of mice under conditions allowing short term survival of E in the circulation. By radioimmunoassays and flow cytometry, we found that phiX174 is removed from E and cleared from the circulation coincident with loss of HP and CR1, and that the majority of cleared phiX174 is localized to the liver. Through the use of HP constructed with Fab' fragments, we verified the requirement for the Fc portion of the mAb in clearance; inhibition of C3 activation delayed clearance, suggesting a role for complement. The present findings in the mouse confirm previous observations in the non-human primate model.
Immune complexes (IC) bound to the primate erythrocyte (E) complement receptor (CR1) are cleared from the circulation of primates and localized to the liver. IC can be bound to E CR1 either via C3b opsonization or with cross-linked mAb complexes (heteropolymers, HP) which contain an mAb specific for CR1 and a mAb specific for a prototype pathogen. The long-term goal of our work is to apply the HP to the treatment of human diseases associated with blood-borne pathogens. Therefore we have investigated the feasibility of a non-primate model by studying clearance in mice of bacteriophage phiX174 bound via HP to primate E. E-HP-phiX174 complexes were prepared in vitro and infused into the circulation of mice under conditions allowing short term survival of E in the circulation. By radioimmunoassays and flow cytometry, we found that phiX174 is removed from E and cleared from the circulation coincident with loss of HP and CR1, and that the majority of cleared phiX174 is localized to the liver. Through the use of HP constructed with Fab' fragments, we verified the requirement for the Fc portion of the mAb in clearance; inhibition of C3 activation delayed clearance, suggesting a role for complement. The present findings in the mouse confirm previous observations in the non-human primate model.
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