Modulation of Exaggerated-IgE Allergic Responses by Gene Transfer-mediated Antagonism of IL-13 and IL-17e.
Gene Therapy Center; Department of Pediatrics
Allergy and Immunology | Genetics and Genomics | Immunology and Infectious Disease | Life Sciences | Medicine and Health Sciences
Asthma and allergic rhinitis are almost invariable accompanied by elevated levels of immunoglobin E (IgE), and more importantly a genetic link between IgE levels and airway hyper-responsiveness has been established. We hypothesized that expression of soluble receptors directed against interleukin (IL)-13 and IL-17e would prevent the cytokines from engaging the cell-bound receptors and therefore help to attenuate allergic responses in a Cftr(-/-)-dependent mouse model of exaggerated-IgE responses. Cftr(-/-) mice were injected with recombinant adeno-associated virus 1 (rAAV1) intramuscularly expressing soluble receptors to IL-17e (IL-17Rh1fc) or IL-13 (IL-13Ralpha2Fc). Total IgE levels, in mice receiving the IL-17Rh1fc and IL-13Ralpha2Fc therapy, were lower than in the control group. Interestingly Aspergillus fumigatus (Af)-specific IgE levels were undetectable in both the mice receiving the IL-17Rh1fc and IL-13Ralpha2Fc therapies. Further flow cytometry analysis of intracellular gene expression suggests that blocking IL-17e may be interfering with signaling upstream of CD4(+) and CD11b(+) cells and reducing IgE levels by affecting signaling on these cell populations. In contrast it appears that IL-13 blockade acts downstream to reduce IgE levels probably by directly affecting B-cell maturation. These studies demonstrate the feasibility of targeting T helper 2 (Th2) cytokines with rAAV-delivered fusion proteins as a means to treat aberrant immune responses.
DOI of Published Version
Mol Ther. 2010 Mar;18(3):511-8. Epub 2009 Nov 24. Link to article on publisher's website
Molecular therapy : the journal of the American Society of Gene Therapy
Mueller, Christian; Keeler, Allison M.; Braag, Sofia; Menz, Timothy; Tang, Qiushi; and Flotte, Terence R., "Modulation of Exaggerated-IgE Allergic Responses by Gene Transfer-mediated Antagonism of IL-13 and IL-17e." (2010). GSBS Student Publications. 1636.