Topical application of human-derived Ig isotypes for the control of acute respiratory infection evaluated in a human CD89-expressing mouse model

Abstract

Recurrent and persistent airway infections remain prevalent in patients with primary immunodeficiency (PID), despite restoration of serum immunoglobulin levels by intravenous or subcutaneous plasma-derived IgG. We investigated the effectiveness of different human Ig isotype preparations to protect mice against influenza when delivered directly to the respiratory mucosa. Four polyvalent Ig preparations from pooled plasma were compared: IgG, monomeric IgA (mIgA), polymeric IgA-containing IgM (IgAM) and IgAM associated with the secretory component (SIgAM). To evaluate these preparations, a transgenic mouse expressing human FcαRI/ CD89 within the myeloid lineage was created. CD89 was expressed on all myeloid cells in the lung and blood except eosinophils, reflecting human CD89 expression. Intranasal administration of IgA-containing preparations was less effective than IgG in reducing pulmonary viral titres after infection of mice with A/California/7/09 (Cal7) or the antigenically distant A/Puerto Rico/8/34 (PR8) viruses. However, IgA reduced weight loss and inflammatory mediator expression. Both IgG and IgA protected mice from a lethal dose of PR8 virus and for mIgA, this effect was partially CD89 dependent. Our data support the beneficial effect of topically applied Ig purified from pooled human plasma for controlling circulating and non-circulating influenza virus infections. This may be important for reducing morbidity in PID patients.

IgA: Structure, Function, and Developability

“…As that point approaches, interest will undoubtedly turn to options for delivery to mucosal sites. Progress with topical application of nebulised Igs in the lungs of experimental animals [214,215] suggest that suitable strategies for mucosal delivery of mAbs in humans may appear, and we can anticipate that IgA-based mAbs will emerge as an important new arm of the arsenal of therapeutic mAbs.…”

Neutrophils and Influenza: A Thin Line between Helpful and Harmful

“…[32]. Similarly, in mice with the FcαRI transgene, despite producing the anticipated expression pattern in neutrophils, the FcαRI expression levels in monocytes were only reflected in a subpopulation of peripheral monocytes [25,27].…”

“…Over the past two decades, many mouse models have been developed in an attempt to recapitulate human conditions. Relevant models include hFcαRI tg [25][26][27]; hFcγRI tg [28], hFcγRIIA tg [29], hFcγRIIB tg [30], and hFcγRIIIB tg [31]. Nevertheless, some transgenic mouse models are limited in ways and can only partially mimic human conditions.…”

A new hope? Possibilities of therapeutic IgA antibodies in the treatment of inflammatory lung diseases

“…The immunoglobulins reduced mucosal infection and protected the animals from lethal bacterial and viral infection. In contrast to the in vitro data, coupling of the SC to IgA/M was not beneficial and IVIg was more efficient in vivo (195,197,202). As part of one study, the immunoglobulins were nebulized and administered via oral inhalation to rats and non-human primates.…”

“…The direct application of therapeutic IgA antibodies onto the lung offers a great opportunity compared to systemic delivery as it can support the respiratory immune defense before pathogens enter the circulation, which was shown in several animal models (195)(196)(197)(198)(199)(200)(201)(202), or protect the lung tissue by anti-inflammatory effects as shown in mice (106,197,203,204). Inhalation ensures a rapid and high amount of drug directly delivered to the site of action in the lung, which is not achieved with other administration forms.…”