The pros and cons of immunomodulatory IL-10 gene therapy with recombinant AAV in a Cftr-/- -dependent allergy mouse model.
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.
Mueller
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C
Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Braag
S A
SA
Martino
A T
AT
Tang
Q
Q
Campbell-Thompson
M
M
Flotte
T R
TR
D000818:Animals; D000946:Antigens, Fungal / Q000276:immunology; D001229:Aspergillosis, Allergic Bronchopulmonary / Q000150:complications / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D001232:Aspergillus fumigatus / Q000276:immunology; D003550:Cystic Fibrosis / Q000150:complications / Q000276:immunology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000172:deficiency / Q000235:genetics*; D016207:Cytokines / Q000096:biosynthesis; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D007073:Immunoglobulin E / Q000097:blood; D016753:Interleukin-10 / Q000097:blood / Q000235:genetics*; D008168:Lung / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013163:Splenomegaly / Q000209:etiology; D013921:Thrombocytopenia / Q000209:etiology
D000946:Antigens, Fungal; D016207:Cytokines; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D016753:Interleukin-10; D007073:Immunoglobulin E