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Anti-IFNγ and peptide-tolerization therapies inhibit acute lung injury induced by crossreactive influenza-A (IAV)-specific memory T-cells

Viral infections have variable outcomes with severe disease occurring in only few individuals. We hypothesized that this variable outcome could correlate with the nature of responses made to previous microbes. To test this, mice were infected initially with IAV and in memory-phase challenged with LC...

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Published in:The Journal of immunology (1950) 2013-02, Vol.190 (6), p.2736-2746
Main Authors: Wlodarczyk, Myriam F., Kraft, Anke R., Chen, Hong D., Kenney, Laurie L., Selin, Liisa K.
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container_issue 6
container_start_page 2736
container_title The Journal of immunology (1950)
container_volume 190
creator Wlodarczyk, Myriam F.
Kraft, Anke R.
Chen, Hong D.
Kenney, Laurie L.
Selin, Liisa K.
description Viral infections have variable outcomes with severe disease occurring in only few individuals. We hypothesized that this variable outcome could correlate with the nature of responses made to previous microbes. To test this, mice were infected initially with IAV and in memory-phase challenged with LCMV, which we show here to have relatively minor cross-reactivity with IAV. The outcome in genetically identical mice varied from mild pneumonitis to severe acute lung injury with extensive pneumonia and bronchiolization, similar to that observed in patients that died of the 1918 H1N1 pandemic. Lesion expression did not correlate with virus titers. Instead, disease severity directly correlated with and was predicted by the frequency of IAV-PB1 703 - and -PA 224 -specific responses, which crossreacted with LCMV-GP 34 and -GP 276 , respectively. Eradication or functional ablation of these pathogenic memory T-cell populations, using mutant-viral strains, peptide-based tolerization strategies, or short-term anti-IFNγ treatment inhibited severe lesions such as bronchiolization from occurring. Heterologous immunity can shape outcome of infections and likely individual responses to vaccination, and can be manipulated to treat or prevent severe pathology.
doi_str_mv 10.4049/jimmunol.1201936
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title Anti-IFNγ and peptide-tolerization therapies inhibit acute lung injury induced by crossreactive influenza-A (IAV)-specific memory T-cells
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