Virus-neutralizing antibodies of immunoglobulin G (IgG) but not of IgM or IgA isotypes can cure influenza virus pneumonia in SCID mice

Abstract

The ability of monoclonal antibodies (MAbs) to passively cure an influenza virus pneumonia in the absence of endogenous T-and B-cell responses was investigated by treating C.B-17 mice, homozygous for the severe combined immunodeficiency (SCID) mutation, with individual monoclonal antiviral antibodies 1 day after pulmonary infection with influenza virus PR8 [A/PR/8/34(H1N1)]. Less than 10% of untreated SCID mice survived the infection. By contrast, 100% of infected SCID mice that had been treated with a single intraperitoneal inoculation of at least 175 g of a pool of virus-neutralizing (VN ؉) antihemagglutinin (anti-HA) MAbs survived, even if antibody treatment was delayed up to 7 days after infection. The use of individual MAbs showed that recovery could be achieved by VN ؉ anti-HA MAbs of the immunoglobulin G1 (IgG1), IgG2a, IgG2b, and IgG3 isotypes but not by VN ؉ anti-HA MAbs of the IgA and IgM isotypes, even if the latter were used in a chronic treatment protocol to compensate for their shorter half-lives in vivo. Both IgA and IgM, although ineffective therapeutically, protected against infection when given prophylactically, i.e., before exposure to virus. An Fc␥-specific effector mechanism was not an absolute requirement for antibody-mediated recovery, as F(ab) 2 preparations of IgGs could cure the disease, although with lesser efficacy, than intact IgG. An anti-M2 MAb of the IgG1 isotype, which was VN ؊ but bound well to infected cells and inhibited virus growth in vitro, failed to cure. These observations are consistent with the idea that MAbs of the IgG isotype cure the disease by neutralizing all progeny virus until all productively infected host cells have died. VN ؉ MAbs of the IgA and IgM isotypes may be ineffective therapeutically because they do not have sufficient access to all tissue sites in which virus is produced during influenza virus pneumonia.

Avian Influenza Virus (H5N1): a Threat to Human Health

“…Considering the potential role of cytokine dysregulation in the pathogenesis of influenza H5N1 virus, benefits of immunomodulatory therapy could also be hypothesized. Finally, passive immunotherapy using convalescent-phase serum is believed to have conferred clinical benefit in the 1918 pandemic (140), and neutralizing monoclonal antibodies have shown therapeutic efficacy in influenza A virus infection in mice with severe combined immunodeficiency (167). Thus, passive immunotherapy also remains a possible consideration for the management of human H5N1 disease (75).…”

Current and future antiviral therapy of severe seasonal and avian influenza

“…More recently, Lu et al (2006) showed that a single injection of purified F(ab ) 2 fragments derived from immunoglobulin of hyperimmunized horses protected mice against a lethal H5N1 virus challenge. A murine monoclonal antibody (mab) targeting a conserved site on the HA of H1 and H2 viruses protected mice against both agents (Okuno et al, 1994), and mabs to H1, given either intact or as Fab fragments, prevented lethal H1N1 infection in SCID mice (Mozdzanowska et al, 2003;Palladino et al, 1995). Humanized mabs also prevented death when given to mice up to 3 days after an otherwise lethal H5N1 virus challenge (Hanson et al, 2006).…”

Avian influenza A (H5N1)

“…Considering the observed cytokine dysregulation in H5N1-infected animals and humans, a beneficial effect of immunomodulating agents could be hypothesized and perhaps requires further study. Finally, neutralizing monoclonal antibodies have been shown effective in treating established influenza A virus infection in mice with severe combined immunodeficiency (Palladino et al, 1995). Although mice are not men, this strategy deserves attention in the treatment of a severe illness such as influenza H5N1.…”