Modulation of exaggerated-IgE allergic responses by gene transfer-mediated antagonism of IL-13 and IL-17e.
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.
Mueller
Christian
C
Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. chris.mueller@umassmed.edu
Keeler
Allison
A
Braag
Sofia
S
Menz
Timothy
T
Tang
Qiushi
Q
Flotte
Terence R
TR
D000818:Animals; D039481:CD11b Antigen / Q000096:biosynthesis; D015704:CD4 Antigens / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005434:Flow Cytometry / Q000379:methods; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006967:Hypersensitivity / Q000235:genetics* / Q000628:therapy; D007107:Immune System; D007073:Immunoglobulin E / Q000235:genetics / Q000378:metabolism*; D018793:Interleukin-13 / Q000235:genetics*; D020381:Interleukin-17 / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D018418:Th2 Cells / Q000378:metabolism
D039481:CD11b Antigen; D015704:CD4 Antigens; D018793:Interleukin-13; D020381:Interleukin-17; D007073:Immunoglobulin E