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The pros and cons of immunomodulatory IL-10 gene therapy with recombinant AAV in a Cftr−/−-dependent allergy mouse model

Abstract

Cystic fibrosis (CF) patients have decreased levels of lung epithelial interleukin (IL)-10 and increased levels of proinflammatory cytokines (tumor necrosis factor-α, IL-4, IL-8 and IL-6). This has also been documented in Cftr (cystic fibrosis transmembrane conductance regulator)-deficient mice (Cftr 489X−/−, FABP-hCFTR+/+). Our laboratory has recently characterized a peculiar hyper-IgE phenotype in these mice, in response to Aspergillus fumigatus crude protein extract (Af-cpe). Thus, we hypothesized that sustained systemic circulating IL-10 levels achieved through skeletal muscle transduction with recombinant adeno-associated vectors expressing IL-10 (rAAV1-IL-10) would serve to downregulate Th1 and Th2 cytokine production. This in turn would dampen the allergic response in the Cftr−/−-dependent mouse model of allergic bronchopulmonary aspergillosis. After Af-cpe sensitization and airway challenge, mice treated with rAAV1-IL-10 had markedly lower IgE levels when compared to the control-treated rAAV1-GFP group. This was accompanied by a significant reduction in the levels of IL-5, IL-4 and IL-13 in the lung compartment. The lower lung cytokine profiles resulted in a near absence of eosinophil recruitment in the lung and a lower inflammatory response in the lung tissue of mice receiving rAAV1-IL-10. Unfortunately, sustained secretion of IL-10 from transduced muscle did lead to thrombocytopenia and splenomegaly in mice injected with rAAV1-IL-10. These results highlight that while IL-10 gene therapy is very effective for treating allergic responses caution must be taken with the prolonged secretion of IL-10.

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Abbreviations

ABPA:

allergic bronchopulmonary aspergillosis

Af-cpe:

Aspergillus fumigatus crude protein extract

CFTR:

cystic fibrosis transmembrane conductance regulator

rAAV:

recombinant adeno-associated virus.

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Acknowledgements

We thank Mark Atkinson, Clive Wasserfall and Todd Brusko for their helpful comments and insights. This study was supported by grants for NHLBI (HL51811) and the Cystic Fibrosis Foundation.

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Mueller, C., Braag, S., Martino, A. et al. The pros and cons of immunomodulatory IL-10 gene therapy with recombinant AAV in a Cftr−/−-dependent allergy mouse model. Gene Ther 16, 172–183 (2009). https://doi.org/10.1038/gt.2008.156

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Keywords

  • allergy
  • Aspergillus
  • Cystic fibrosis
  • IL-10
  • AAV
  • thrombocytopenia

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