Simultaneous Disruption of Interleukin (IL)-4 and IL-13 Defines Individual Roles in T Helper Cell Type 2–mediated Responses

Abstract

Using a single vector targeting strategy, we have generated mice with a combined deficiency of interleukin (IL)-4 and IL-13 to clarify their roles in T helper type 2 (Th2) cell responses. Using immunological challenges normally characterized by a Th2-like response, we have compared the responses of the double-deficient mice with those generated by wild-type, IL-4–deficient, and IL-13–deficient mice. Using a pulmonary granuloma model, induced with Schistosoma mansoni eggs, we demonstrate that although eosinophil infiltration, immunoglobulin E, and IL-5 production are reduced in the IL-4–deficient mice and IL-13–deficient mice, they are abolished only in the combined absence of both cytokines. Furthermore, IL-4/13–deficient animals are severely impaired in their ability to expel the gastrointestinal nematode Nippostrongylus brasiliensis. Unexpectedly, N. brasiliensis–infected IL-4/13–deficient mice developed elevated IL-5 and eosinophilia, indicating that compensatory mechanisms exist for the expression of IL-5, although serum IgE remained undetectable. IL-4/13–deficient mice default to a Th1-like phenotype characterized by the expression of interferon γ and the production of IgG2a and IgG2b. We conclude that IL-4 and IL-13 cooperate to initiate rapid Th2 cell–driven responses, and that although their functions overlap, they perform additive roles.

Critical Role for T Cells in Sephadex-Induced Airway Inflammation: Pharmacological and Immunological Characterization and Molecular Biomarker Identification

“…Specifically, AHR, eosinophilic inflammation, and IgE production, normally seen after local Ag challenge, do not develop in mice in which the gene for IL-4 or IL-13 is disrupted or in animals in which the cytokine or its receptor are blocked in vivo (40, 50 -58). Likewise, it was recently shown in a pulmonary granuloma model, induced with Schistosoma mansoni eggs, that although eosinophil infiltration, IgE, and IL-5 production are reduced in the IL-4-deficient mice and IL-13-deficient mice, they are abolished only in the combined absence of both cytokines (51). It was shown recently that IL-13-transgenic mice with targeted pulmonary overexpression of IL-13 have significant numbers of eosinophils in the airways, associated with epithelial cell hypertrophy, mucous cell metaplasia, subepithelial airway fibrosis, airways obstruction, and nonspecific AHR (59).…”

Surfactant protein D inhibits TNF-α production by macrophages and dendritic cells in mice

“…For the in vitro type II cell culture studies, adult (200 g) Sprague-Dawley rats (Charles River Laboratories, Wilmington, Mass) were used, as previously described. 15,39 BALB/c mice were sensitized and challenged with Aspergillus fumigatus, as described previously, 38 and studied 0 (not challenged), 1, 6, 12, 24, 48, and 72 hours later. In brief, mice were sensitized intraperitoneally with 20 μg of A fumigatus (Hollister-Stier, Spokane, Wash) together with 20 mg of alum (Imject Alum; Pierce, Rockford, Ill) in 100 μL of PBS at days 0 and 14, followed by intranasal challenge on day 28 with 25 μL of A fumigatus extract in glycerol-PBS.…”

“…38 Briefly, lavage was carried out once with 0.7 mL and twice with 1 mL of sterile PBS. BAL fluid was centrifuged at 4°C for 10 minutes at 400g, and the pellet was resuspended in 1 mL of PBS.…”

Differences in Expression, Affinity, and Function of Soluble (s)IL-4Rα and sIL-13Rα2 Suggest Opposite Effects on Allergic Responses

“…IL-13-deficient mice and IL-4/IL-13-double deficient mice (48) were a gift from Dr. A. McKenzie (Medical Research Council Laboratory of Molecular Biology, Cambridge, U.K.). IL-13R␣2-deficient mice (49) and Stat6-deficient mice (C.129S2-Stat6 tm1Gru/J ) (18) were a gift from M. Grusby (Harvard University, Boston, MA).…”