Virally Delivered Cytokines Alter the Immune Response to Future Lung Infections

Abstract

Respiratory syncytial virus (RSV) is an important cause of infant morbidity and mortality worldwide and is increasingly recognized to have a role in the development and exacerbation of chronic lung diseases. There is no effective vaccine, and we reasoned that it might be possible to skew the immune system towards beneficial nonpathogenic responses by selectively priming protective T-cell subsets. We therefore tested recombinant RSV ( ؉ T cells were observed after challenge in mice primed with rRSV/IFN-␥. By contrast, rRSV/IL-4-primed mice were protected against weight loss during secondary challenge but showed airway eosinophilia. When rRSV/IL-4-primed mice were challenged with influenza virus, weight loss was attenuated but was again accompanied by marked airway eosinophilia. Thus, immunization directed toward enhancement of Th1 responses reduces viral load but is not necessarily protective against disease. Counter to expectation, Th2-biased responses were more beneficial but also influenced the pathological effects of heterologous viral challenge.

Delivery of Cytokines by Recombinant Virus in Early Life Alters the Immune Response to Adult Lung Infection

“…Importantly, the ability of IFN-␥ to protect in this neonatal model contrasts with the results for adult mice, where RSV/IFN-␥ enhances disease during rechallenge (16). It is therefore necessary to consider the age of first priming in the development of vaccines, since the age at which the vaccine is administered is critical for determining the pattern of immune response that results.…”

“…As described previously (5,16), reduced viral titers were observed following infection with the RSV/IFN-␥ virus compared to RSV/wt and RSV/IL-4. This finding could be due to the insertion of the IFN-␥ cDNA within the RSV genome affecting replication.…”

“…These viruses grow in both human and mouse cell lines with kinetics similar to those of wild-type viruses (data not shown). In adult BALB/c mice, RSV/IL-4 grows at wild-type levels, while RSV/IFN-␥ is attenuated approximately 10-fold (5,6,16). To assess the effect of these viruses on neonates, mice less than 1 week of age were infected with 8 ϫ 10 4 FFU RSV/wt, RSV/IFN-␥, or RSV/IL-4 intranasally (i.n.).…”

“…In contrast, the coexpression of IL-4 by RSV (RSV/IL-4) causes defective T-cell responses but does not affect viral clearance (6). Upon challenge, RSV/IFN-␥-primed adult mice show enhanced CD8 T-cell recruitment, leading to immunopathology, while RSV/ IL-4-primed mice showed enhanced eosinophilia (16). The aim of the current study was to investigate the effects of cytokine modulation on the neonatal immune response to RSV.…”

Protective T cell immunity against respiratory syncytial virus is efficiently induced by recombinant BCG

“…Although symptoms associated with RSV infection usually manifest as rhinitis in adults, in premature infants, the elderly, and immunosuppressed individuals RSV infection frequently leads to severe symptoms and airway obstruction (5,6). Furthermore, it has been proposed that exposure to RSV infection early in life can lead to increased susceptibility to recurrent allergic wheezing and asthma during the following years (7). Considering epidemiological data, RSV is responsible for a health problem that is extremely expensive for individuals, governments, and health care systems.…”