title: Selective expansion of human regulatory T cells in nasal polyps, and not adjacent tissue microenvironments, in individual patients exposed to steroids.
abstract: Severe forms of chronic rhinosinusitis (CRS), a common upper airway inflammatory disorder, are associated with nasal polyps (NPs). NP disease is ameliorated by glucocorticoid (GC) treatment, whose cellular effects are poorly understood. We therefore assessed the influence of GC therapy on NPs in CRS patients, focusing on regulatory T (Treg) cells. Tregcell populations were analyzed by flow cytometry in NPs and control tissues from GC-treated CRS patients and controls. After GC exposure, selective expansion of Tregcells was seen within NPs, and not blood or adjacent ethmoid tissues. To confirm direct GC effects, NPs from the same patients were biopsied prior to, and following, 1week of oral GC exposure. Direct expansion of Tregs into the same NP bed was detected in 4/4 CRS patients following GC exposure. Tregcell spikes into NPs were secondary to cellular recruitment given limited Ki67 expression within these regulatory cells. Chemokine gene expression profiling identified several chemokines, notably CCL4, induced within NPs upon GC treatment. Neutralization of chemokine receptor/ligand interactions using CCR4 small molecule antagonists reduced Tregmigration towards GC-treated NPs in an ex vivo migration assay. Our findings suggest that the common use of GCs in the treatment of NP disease leads to recruitment of Tregcells from peripheral sites into NP tissues, which may be critical to the anti-inflammatory effect of GCs. Mechanistically Tregexpansion appears to be conferred, in part, by chemokine receptor/ligand interactions induced following corticosteroid therapy.
authors.affiliation: Division of Rhinology, Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Edward
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Mrinmoy
authors.initials: M
authors.lastname: Sanyal
authors.affiliation: Division of Rhinology, Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Le
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Rabin Medical Center, Petah Tikva, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ethan
authors.initials: E
authors.lastname: Soudry
authors.affiliation: Division of Rhinology, Department of Otolaryngology - Head and Neck Surgery, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Vijay R
authors.initials: VR
authors.lastname: Ramakrishnan
authors.affiliation: Division of Rhinology, Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Dawn T
authors.initials: DT
authors.lastname: Bravo
authors.affiliation: Division of Rhinology, Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Nguyen
authors.affiliation: Division of Rhinology, Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: David
authors.initials: D
authors.lastname: Zarabanda
authors.affiliation: Division of Rhinology, Department of Otolaryngology - Head and Neck Surgery, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Todd T
authors.initials: TT
authors.lastname: Kingdom
authors.affiliation: Division of Rhinology, Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Hwang
authors.affiliation: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: C
authors.initials: C
authors.lastname: Garrison Fathman
authors.affiliation: Division of Rhinology, Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: jnayak@stanford.edu.
authors.forename: Jayakar V
authors.initials: JV
authors.lastname: Nayak
mesh_terms: D001706:Biopsy; D018925:Chemokines / Q000235:genetics; D002908:Chronic Disease; D051858:Forkhead Transcription Factors / Q000276:immunology; D020869:Gene Expression Profiling; D005938:Glucocorticoids / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009298:Nasal Polyps / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D011241:Prednisone / Q000494:pharmacology* / Q000627:therapeutic use; D012220:Rhinitis / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D012852:Sinusitis / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
chemical_list: D018925:Chemokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D005938:Glucocorticoids; D011241:Prednisone
keywords: Chemokine; Chronic rhinosinusitis; Flow cytometry; Mucosal immunity; Nasal polyp; Prednisone; Regulatory T cells; Upper airway