Food allergies are a significant public health concern and their prevalence in the US is on the rise. The CDC estimates that food allergies affect approximately 6% of children under age three and 4% of the overall population, representing 12 million Americans. Peanut and tree nut allergies develop during childhood and are usually life-long. In the US alone, approximately three million people report allergies to peanuts and tree nuts and a study showed that the number of children with peanut allergy doubled between 1997 and 2002. The public health and economic impact of food allergies is further highlighted by reports indicating that food allergy episodes are the most common ER visit for anaphylaxis and that 50% of food allergy patients will have accidental exposure leading to allergy within a two year period. Despite the continued rise in the prevalence of food allergies in industrialized countries, there have been no new treatments developed. The design and delivery of new prophylactic and therapeutic agents require a better understanding of the basic immunological processes that control allergic reactions in intestine. This proposal will employ new genetic and immunologic tools to gain novel insights into the molecular and cellular events that underlie the pathogenesis of food allergy. Food allergies are thought to be the result of a loss of tolerance to food antigens. Current models suggest that food allergies are caused by the development of MHC CII (MHC CII)-dependent activation of antigen-specific CD4+ Th2 cells that promote the production of IgE and subsequent mast cell-dependent allergic inflammation in the intestine. Our preliminary studies suggest a previously unrecognized role for intestinal epithelial cells (IECs) in the development of food allergy. Specifically, two new preliminary observations form the foundations of this proposal. First, we generated mice bearing an IEC-specific deletion of MHC class II (MHC-CII?IEC mice) to examine the influence of IEC-intrinsic MHC CII in the development of Th2 cytokine responses. In preliminary studies, we identified a significant defect in Th2 cytokine-dependent immunity in these mice, suggesting MHC CII expression on IECs may play a critical role in the initiation or propagation of type 2 inflammation in the intestine. Second, we have found that IEC-produced TSLP is required for the establishment of type 2 inflammatory responses in the skin and lung. In a model of food allergy, we also have found that TSLP is required for IgE production, implicating TSLP in the response to food antigens. Based on these preliminary data, the focus of this proposal is to test the role of IECs in the pathogenesis of food allergy. Specifically, we will delineate the functions of IEC-intrinsic MHC CII or IEC-secreted TSLP in a murine model of IgE-dependent food allergy to provide insight for the future design of therapeutic agents to treat and/or prevent food allergies. Food allergies are a significant public health concern and their prevalence in the US is on the rise. The CDC estimates that food allergies affect approximately 6% of children under age three and 4% of the overall population, representing 12 million Americans. Despite their increasing prevalence, the underlying processes that cause food allergy are poorly defined. The goals of this research proposal are to provide new insights into how the body's immune system becomes dysregulated during food allergy and to contribute this knowledge to the design of new drugs for treatment and prevention of these diseases.
Food allergies are a significant public health concern and their prevalence in the US is on the rise. The CDC estimates that food allergies affect approximately 6% of children under age three and 4% of the overall population, representing 12 million Americans. Despite their increasing prevalence, the underlying processes that cause food allergy are poorly defined. The goals of this research proposal are to provide new insights into how the body's immune system becomes dysregulated during food allergy and to contribute this knowledge to the design of new drugs for treatment and prevention of these diseases.
| Veiga-Fernandes, Henrique; Artis, David (2018) Neuronal-immune system cross-talk in homeostasis. Science 359:1465-1466 |
| Meisel, Jacquelyn S; Sfyroera, Georgia; Bartow-McKenney, Casey et al. (2018) Commensal microbiota modulate gene expression in the skin. Microbiome 6:20 |
| Moriyama, Saya; Brestoff, Jonathan R; Flamar, Anne-Laure et al. (2018) ?2-adrenergic receptor-mediated negative regulation of group 2 innate lymphoid cell responses. Science 359:1056-1061 |
| Klose, Christoph S N; Mahlakõiv, Tanel; Moeller, Jesper B et al. (2017) The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation. Nature 549:282-286 |
| Blander, J Magarian; Longman, Randy S; Iliev, Iliyan D et al. (2017) Regulation of inflammation by microbiota interactions with the host. Nat Immunol 18:851-860 |
| Wallrapp, Antonia; Riesenfeld, Samantha J; Burkett, Patrick R et al. (2017) The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. Nature 549:351-356 |
| Monticelli, Laurel A; Buck, Michael D; Flamar, Anne-Laure et al. (2016) Arginase 1 is an innate lymphoid-cell-intrinsic metabolic checkpoint controlling type 2 inflammation. Nat Immunol 17:656-65 |
| Alex, Aneesh; Tait Wojno, Elia D; Artis, David et al. (2016) Label-Free Imaging of Eosinophilic Esophagitis Mouse Models Using Optical Coherence Tomography. Methods Mol Biol 1422:127-36 |
| Rak, Gregory D; Osborne, Lisa C; Siracusa, Mark C et al. (2016) IL-33-Dependent Group 2 Innate Lymphoid Cells Promote Cutaneous Wound Healing. J Invest Dermatol 136:487-496 |
| Tait Wojno, Elia D; Artis, David (2016) Emerging concepts and future challenges in innate lymphoid cell biology. J Exp Med 213:2229-2248 |
Showing the most recent 10 out of 47 publications
