GSBS Student Publications

Title

Modulation of Exaggerated-IgE Allergic Responses by Gene Transfer-mediated Antagonism of IL-13 and IL-17e.

Student Author(s)

Allison M. Keeler

UMMS Affiliation

Gene Therapy Center; Department of Pediatrics

Date

3-24-2010

Document Type

Article

Medical Subject Headings

Immunoglobulin E; Hypersensitivity, Immediate; Interleukin-13; Interleukin-17; Receptors, IgE

Disciplines

Allergy and Immunology | Genetics and Genomics | Immunology and Infectious Disease | Life Sciences | Medicine and Health Sciences

Abstract

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.

Rights and Permissions

Mol Ther. 2010 Mar;18(3):511-8. Epub 2009 Nov 24. Link to article on publisher's website

DOI of Published Version

10.1038/mt.2009.264

Comments

Medical student Timothy Menz participated in this study as part of the Senior Scholars research program at the University of Massachusetts Medical School.

Related Resources

Link to article in PubMed

Journal Title

Molecular therapy : the journal of the American Society of Gene Therapy

PubMed ID

19935781