The pros and cons of immunomodulatory IL-10 gene therapy with recombinant AAV in a Cftr-/- -dependent allergy mouse model
Gene Therapy Center; Department of Pediatrics
Medical Subject Headings
Animals; Antigens, Fungal; Aspergillosis, Allergic; Bronchopulmonary; Aspergillus fumigatus; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Cytokines; Dependovirus; Disease Models, Animal; Gene Therapy; Immunoglobulin E; Interleukin-10; Lung; Mice; Mice, Inbred C57BL; Mice, Knockout; Splenomegaly; Thrombocytopenia
Allergy and Immunology | Genetics and Genomics | Pediatrics | Respiratory Tract Diseases
Cystic fibrosis (CF) patients have decreased levels of lung epithelial interleukin (IL)-10 and increased levels of proinflammatory cytokines (tumor necrosis factor-alpha, 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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Citation: Gene Ther. 2009 Feb;16(2):172-83. Epub 2008 Sep 25. Link to article on publisher's site