Ian P. Lewkowich, PhD

Assistant Professor, UC Department of Pediatrics

Phone 513-636-3999

Email ian.lewkowich@cchmc.org

Immunology; asthma

While Th2 immune responses are central to disease pathology in allergic asthma, there is a growing understanding that the Th2 paradigm is not sufficient to explain the entire spectrum of disease severity. Indeed, there is growing belief that severe disease may be driven by a different process than mild to moderate disease.

Using a mouse model of allergic asthma in which one strain develops a phenotype characteristic of mild asthma (C3H/HeJ), and others develop a phenotype characteristic of severe disease (A/J), we have identified several novel mechanisms through which asthma severity is regulated. We have found that the development of severe allergic asthma is associated with a limited capacity of Tregs to limit pulmonary dendritic cell activity, enhanced capacity for antigen uptake by pulmonary myeloid dendritic cells, and the development of a mixed Th2/Th17 immune response. In contrast, C3H mice demonstrate increased Treg activity, preferential antigen uptake by pulmonary plasmacytoid dendritic cells, and an exclusively Th2-biased immune response. We are presently using the A/J versus C3H/HeJ mouse model of allergic asthma to tease out the mechanisms responsible the development of severe allergic asthma.

PhD: University of Manitoba, Winnipeg, Canada, 2004.

Lewkowich IP, Fox JG Perkins C, Lewis L, Finkelman FD Smith DE, Bryce PJ, Kurt-Jones EA, Wang TC, Sivaprasad U, Hershey GK, Herbert DR. Trefoil factor 2 rapidly induces interleukin 33 to promote type 2 immunity during allergic asthma and hookworm infection. J Exp Med. 2012;209(3):607-22.

Lufti R, Ledford JR, Zhou P, Lewkowich IP, Page K. Dendritic Cell-Derived Tumor Necrosis Factor α Modifies Airway Epithelial Cell Responses. J Innate Immun. 2012;4(5-6):542-52.

Lewkowich IP, Lajoie S, Stoffers SL, Suzuki Y, Richgels PK, Dienger K, Sproles AA, Yagita H, Hamid Q, Wills-Karp M. PD-L2 modulates asthma severity by directly decreasing dendritic cell IL-12 production. Mucosal Immunol. 2012.

Stefater JA, Lewkowich IP, Rao S, Ajima R, Mariggi G, Wills-Karp M, Pollard J, Yamaguchi T, McMahon AP, Ferrara N, Gerhardt H, Lang RA. Microglial Wnt ligands suppress retinal angiogenesis via activation of the VEGF inhibitor Flt1. Nature. 2011;474(7352):511-515.

Lewkowich IP, Day SB, Ledford JR, Zhou P, Dienger K, Wills-Karp M, Page K. Protease-activated receptor 2 activation of myeloid dendritic cells regulates allergic airway inflammation. Respir Res. 2011;(12):122.

Lewkowich IP1, Lajoie S1, Suzuki Y, Clark JR, Sproles AA, Dienger K, Budelsky A, and Wills-Karp M, Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma. Nat Immunol. 2010;(10):928-935.

Chen G, Wan H, Luo F, Zhang L, Xu Y, Lewkowich IP, Wills-Karp M and Whitsett JA. Foxa2 programs Th2 cell-mediated innate immunity in the developing lung. J Immunol. 2010;(184):6133-6141.

Lewkowich IP, Lajoie S, Dienger K, Herman NS, Sproles AA, and Wills-Karp M. Enhanced allergen uptake, activation, and IL-23 production by pulmonary myeloid DCs drives airway hyperresponsiveness in asthma-susceptible mice. PLoS ONE. 2008;(3):e3879.

Köhl J, Baelder R, Lewkowich IP, Pandey MK, Hawlisch H, Wang L, Best J, Herman NS, Sproles AA, Zwirner J, Whitsett JA, Gerard C, Sfyroera G, Lambris JD, and Wills-Karp M. A regulatory role for the C5a anaphylotoxin on type 2 immunity in asthma. J Clin Invest. 2006;(116):783-796.

Lewkowich IP, Herman NS, Schleifer KW, Dance MP, Chen BL, Dienger KM, Sproles AA, Shah JS, Köhl J, Belkaid Y, and Wills-Karp M. CD4+CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function. J Exp Med. 2005;(202):1549-1561.