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Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22908
We are developing a potential therapeutic approach for removing
pathogens from the circulation of primates in which the pathogen is
bound to the complement receptor (CR1) on E using a bispecific mAb
complex, a heteropolymer (HP). We have used mAb this approach to
demonstrate that cleared prototype pathogens are localized to,
phagocytosed in, and destroyed in the liver. Extension of this work to
a clinical setting will require a detailed understanding of the
mechanism by which the E-bound immune complex substrates are
transferred to fixed tissue macrophages in the liver, the transfer
reaction. Therefore, we examined an in vitro system to study this
process using bacteriophage 
X174 as a model pathogen. E containing
X174 (bound via an anti-CR1/anti-X174 HP) were incubated
with P388D1 murine macrophages, and the two cell types were
separated by centrifugation through Ficoll. Both E and macrophages were
then probed and analyzed by RIA or flow cytometry. The results indicate
that all three components of the E-bound IC (X174, HP, and CR1) were
removed from the E and internalized by the macrophages. We found that
transfer requires the Fc portion of IgG, because little transfer of
X174 occurs when it is bound to E CR1 using a HP containing only Fab
fragments. These findings, taken in the context of other studies,
suggest a general mechanism for the transfer reaction in which Fc
receptors facilitate close juxtaposition of the macrophage to the
E-bound IC which then allows a macrophage-associated protease to cleave
CR1. The released IC are then internalized and processed by the
macrophages.
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