Reovirus type-2 infection in newborn DBA⁄1J mice reduces the development of late allergic asthma

There are several factors, including genetic predispositions and environmental factors, which affect the development of allergic airway inflammation. Airway allergy in humans and animal models is mediated by T helper (Th) 2 immune responses to inhaled environmental allergens in sensitized individuals. This involves a two-phase allergic reaction: early and/or late phases (Skad et al. 1999; Hayashi 2011, 2012). In the early phase, IgE-sensitized mast cells degranulate and release mediators such as histamine and leukotriene, whereas the late phase of the allergic response mainly involves infiltration of eosinophils and Th2 type lymphocytes producing interleukin (IL)-4, IL-5 and IL-13 including IL-17 (Cosmi et al. 2011) and tumour necrosis factor (TNF)-α (Babu et al. 2011) without participation of mast cells and IgE. It has been hypothesized that the increased prevalence of allergic diseases in developed countries may be associated with the decline in some infections shifting the relative predominance between Th2 and Th1 responses. (Strachan 1989; Von Hertzen & Haahtela 2004). In addition, lower prevalence of asthma, hay fever and eczema symptoms in autoimmune diseases such as type 1 diabetes (T1D) patients compared with age-matched controls has been reported (Meerwaldt et al. 2002), whereas pre-existing asthma seems to protect against the development of autoimmune disorders to varying degrees in both men and women (Tirosh et al. 2006). This suggests that there may be induction of mutual reciprocal Th1/Th2 inhibitory effects (Mosmann & Coffman 1989). Reovirus (Reo; serotypes 1, 2 and 3) is an RNA virus classified in the Reoviridae and included in the genus Orthoreovirus. All mammals serve as hosts for Reo infection, but the disease is limited to very young people and manifests as a mild gastroenteritis (Onodera et al. 1990; Tyler et al. 1995; Danthi et al. 2006). However, Reo-2 can induce transient impaired glucose tolerance with mild insulitis peaking at approximately 10 days after infection. In this model the virus was inoculated into one day old newborn genetically autoimmune sensitive DBA/1J mice (H2q haplotype: first chromosome VAS 1 is responsible for autoimmunity; Holmdahl et al. 1990). Most mice recovered from the disease within three weeks after infection (Onodera et al. 1990; Hayashi et al. 1998, 2001). This may be due to the fact that a sufficient number of β-cells were left intact after the destruction, and proliferation accompanied by disappearance of infiltrated cells may occur (Onodera et al. 1990). We have reported previously that Reo-2 infection can induce transient expression of IFN-γ mRNA, but not IL-4 mRNA, from splenic cells both shortly after the infection and during the developmental phase of insulitis when there has been elimination of virus from the mice (Hayashi et al. 1998, 2001). This suggests that infected mice may develop two different types of Th1 responses. In the virus multiplication phase, it has been reported that reoviruses infected cells induce high IFN-α/β (Steele & Hauser 2005; Errington et al. 2008). Also Toll-like receptor-3 on dendritic cells stimulated with reoviruses may induce IFN-α/β, leading to Th1 responses (Errington et al. 2008). Later, in addition, Th1 cells will be induced as a consequence of the development of autoimmune insulitis (Hayashi et al. 1998, 2001). At present the cumulative effects of virus infection and the following autoimmune T1D on the development of airway allergy are not known. To clarify this the effects of Reo-2 infection on the development of late allergic asthma were examined during the recovery phase of Reo-2-triggered insulitis.