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Thymic stromal lymphopoietin–elicited basophil responses promote eosinophilic esophagitis

Abstract

Eosinophilic esophagitis (EoE) is a food allergy–associated inflammatory disease characterized by esophageal eosinophilia. Current management strategies for EoE are nonspecific, and thus there is a need to identify specific immunological pathways that could be targeted to treat this disease. EoE is associated with polymorphisms in the gene that encodes thymic stromal lymphopoietin (TSLP), a cytokine that promotes allergic inflammation, but how TSLP might contribute to EoE disease pathogenesis has been unclear. Here, we describe a new mouse model of EoE-like disease that developed independently of IgE, but was dependent on TSLP and basophils, as targeting TSLP or basophils during the sensitization phase limited disease. Notably, therapeutic TSLP neutralization or basophil depletion also ameliorated established EoE-like disease. In human subjects with EoE, we observed elevated TSLP expression and exaggerated basophil responses in esophageal biopsies, and a gain-of-function TSLP polymorphism was associated with increased basophil responses in patients with EoE. Together, these data suggest that the TSLP-basophil axis contributes to the pathogenesis of EoE and could be therapeutically targeted to treat this disease.

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Figure 1: Experimental mouse model of EoE-like disease.
Figure 2: TSLP-TSLPR interactions are crucial for the pathogenesis of EoE-like disease.
Figure 3: EoE-like disease development is independent of IgE.
Figure 4: Basophils promote EoE-like disease.
Figure 5: Neutralization of TSLP or depletion of basophils ameliorates established EoE-like disease.
Figure 6: The TSLP-basophil axis is active in human subjects with EoE.

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Acknowledgements

We thank members of the Artis laboratory for discussions and critical reading of the manuscript. Research in the Artis lab is supported by the US National Institutes of Health (AI061570, AI087990, AI074878, AI095776, AI102942, AI095466, AI09560 and AI097333 to D.A.), the Swiss National Science Foundation Prospective and Advanced Research Fellowships (PBBEP3_130438 and PA00P3_136468 to M.N.), the US National Institutes of Health (T32-AI060516 and F32-AI098365 to E.D.T.W., T32-AR007465 and KL2-RR024132 to B.S.K., F32-AI085828 to M.C.S., AI091759 to M.G.N. and K08-AI089982 to A.C.), the Australian National Health and Medical Research Council Overseas Biomedical Fellowship (613718 to P.R.G.), the State of Pennsylvania (SAP 4100042728 to P.M.S. and H.H.), the Burroughs Wellcome Fund Investigator in Pathogenesis of Infectious Disease Award (D.A.) and the Crohn's and Colitis Foundation of America (D.A.). This work was supported by the US National Institutes of Health/US National Institute of Diabetes and Digestive and Kidney Diseases P30 Center for Molecular Studies in Digestive and Liver Diseases (P30-DK050306), its pilot grant program and scientific core facilities (Molecular Pathology and Imaging, Molecular Biology, Cell Culture and Mouse) and the Joint Penn-Children's Hospital of Philadelphia Center in Digestive, Liver and Pancreatic Medicine and its pilot grant program. We also thank the Matthew J. Ryan Veterinary Hospital Pathology Lab and the Abramson Cancer Center Flow Cytometry and Cell Sorting Resource Laboratory (partially supported by US National Cancer Institute Comprehensive Cancer Center Support Grant (P30-CA016520)), the Skin Disease Research Center (supported by P30-AR057217) and the Electron Microscopy Resource Laboratory for technical advice and support. J.M.S. and K.R.R. acknowledge support from The Children's Hospital of Philadelphia Institutional Development Fund, and J.M.S. also acknowledges support from the US Department of Defense (A-16809.2). Human tissue samples were obtained by M.-L.W. and A.J.B., funded by Abbot Nutrition (ANUS1013). Research in the Zhou lab is supported by the US National Institutes of Health (R00EB010071) and the Lehigh University start-up fund. The studies described here were supported in part by the Institute for Translational Medicine and Therapeutics Transdisciplinary Program in Translational Medicine and Therapeutics (UL1-RR024134 from the US National Center for Research Resources). The authors also wish to thank P. Just and N. Ruiz at eBioscience for samples of flow cytometry reagents for human basophil panel development, support and invaluable technical advice. CD200R3-specific mAb (clone Ba103) was provided by H. Karasuyama (Tokyo Medical and Dental University Graduate School). The content is solely the responsibility of the authors and does not represent the official views of the US National Center for Research Resources or the US National Institutes of Health.

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M.N., E.D.T.W., B.S.K., M.C.S., P.R.G., M.G.N., A.B.M., A.A., C.Z. and D.A. designed and performed experiments. A.J.B., K.R.R., P.M.-K., A.C., G.W.F., M.-L.W. and J.M.S. obtained human pediatric and adult esophageal biopsies and peripheral blood samples, K.R.C. analyzed pediatric esophageal biopsy histology, and D.A.H. and T.B.-W. coordinated patient care and clinical studies. A.E.M. and Q.J.S. provided CPE, M.K. provided Baso-DTR mice, K.O.-N. and H.K. provided CD200R3-specific mAb, M.R.C. provided TSLPR-deficient mice and TSLP reagents, J.H.Y. and R.d.W.M. performed staining for human TSLP, and P.M.S. and H.H. provided genotype information on pediatric patients with EoE. M.N., E.D.T.W., B.S.K., M.C.S., P.R.G., A.A., C.Z., M.-L.W., J.M.S. and D.A. analyzed the data. M.N., E.D.T.W., M.C.S. and D.A. wrote the manuscript, and all authors critically reviewed the manuscript.

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Correspondence to David Artis.

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M.R.C. is an employee and shareholder of Amgen.

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Noti, M., Wojno, E., Kim, B. et al. Thymic stromal lymphopoietin–elicited basophil responses promote eosinophilic esophagitis. Nat Med 19, 1005–1013 (2013). https://doi.org/10.1038/nm.3281

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