Deciphering Fc-mediated Antiviral Antibody Functions in Animal Models

Schmaljohn, Alan L.; Orlandi, Chiara; Lewis, George K.

Overwhelmingly, immunological data in non-human species have come from mouse models, where inbred mouse strains and myriad research reagents allow complex cell and Ab transfers. In virology, however, mice tend to be wholly or partially resistant to infection and disease caused by human pathogens of greatest interest; a compromise is sometimes found by serial passage of virus in mice to achieve some semblance of human disease and protection. For many years, even when there was a palatable model of viral disease in mice, and early data suggested an important role for Fc in Ab-mediated resistance to certain of those viruses (4), data were generally unconvincing in assigning clear relevance to Fc because of technical limits, to wit: the necessary panels of virus-specific monoclonal antibodies (MAbs) having identical paratopes (Ag combining sites) but different Fc moieties were then unachievable. Consequently, a preponderance of evidence that murine MAbs of IgG2a subtype were generally most protective (especially for CTAbs) were less than definitive; Fab and F(ab) 2 fragments of Abs were almost exclusively non-protective (or poorly so) but were not directly comparable to intact Ab because the fragments (neutralizing in vitro or not) had short half-lives in vivo; attempts to deplete FcR-bearing cells in vivo were confounded by the overall toxicity and secondary effects of such depletions, so that truly appropriate controls were lacking; complement (C') depletion of mice typically left the protective capacity of whole Abs intact, but redundant mechanisms (ADCC as well as CMC) and incomplete C' depletion remained possibilities. Moreover, when cross-species transfers of Abs were made (e.g., human Abs into mice or non-human primates [NHP], mouse Abs into guinea pigs or NHP), positive protective results (e.g. Ab-mediated protection) were useful but negative results were fraught [not only do anti-Abs arise in a few days to eliminate xeno-Abs, but also the Fc-FcR interactions across species are problematic at best (26) ].