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1.
Clin Immunol ; 179: 66-76, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28279811

RESUMEN

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. Treg cell populations were analyzed by flow cytometry in NPs and control tissues from GC-treated CRS patients and controls. After GC exposure, selective expansion of Treg cells 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. Treg cell 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 Treg migration 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 Treg cells from peripheral sites into NP tissues, which may be critical to the anti-inflammatory effect of GCs. Mechanistically Treg expansion appears to be conferred, in part, by chemokine receptor/ligand interactions induced following corticosteroid therapy.


Asunto(s)
Glucocorticoides/farmacología , Pólipos Nasales/inmunología , Prednisona/farmacología , Rinitis/inmunología , Sinusitis/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Biopsia , Quimiocinas/genética , Enfermedad Crónica , Factores de Transcripción Forkhead/inmunología , Perfilación de la Expresión Génica , Glucocorticoides/uso terapéutico , Humanos , Pólipos Nasales/tratamiento farmacológico , Pólipos Nasales/genética , Pólipos Nasales/patología , Prednisona/uso terapéutico , Rinitis/tratamiento farmacológico , Rinitis/genética , Rinitis/patología , Sinusitis/tratamiento farmacológico , Sinusitis/genética , Sinusitis/patología , Linfocitos T Reguladores/inmunología
2.
Int Forum Allergy Rhinol ; 3(10): 841-7, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23901007

RESUMEN

BACKGROUND: New epithelial cells are generated through the proliferation and differentiation of resident progenitor cells in the nasal cavity. In several upper airway diseases, such as cystic fibrosis and chronic rhinosinusitis, self-renewing progenitor cells may be functionally defective, or compromised in their ability, to regenerate cells that maintain normal mucociliary clearance. Herein, we describe our early work to define and characterize a rare population of human nasal epithelial putative progenitors. METHODS: Single-cell suspensions of human ethmoid sinus tissues were prepared following endoscopic sinus surgery. Cell surface antibodies were analyzed as candidate markers for detecting progenitor cells. A panel of antibodies, including epithelial cell adhesion molecule (EpCAM, epithelial cells), CD45 (hematopoietic cells), nerve growth factor receptor (NGFR/CD271), intercellular adhesion molecule-1 (ICAM1/CD54), and integrin-α6 (ITGA6/CD49f) were used to resolve epithelial progenitor candidates by high-dimensional flow cytometry and the gating technique of fluorescence minus one (FMO) controls. RESULTS: A rare population of approximately 0.06% of total ethmoid cells was discriminated as EpCAM(-) CD45(-) NGFR(+) ICAM1(+) by surface markers. Use of ITGA6 was excluded based on FMO control analysis. This lineage-negative population was purified to 99% homogeneity by cell sorting and analyzed by immunofluorescence microscopy. Sorted cells were subsequently confirmed to uniformly express the transcription factor p63. Upon in vitro culture, lineage-negative clonal cells were confirmed to spontaneously differentiate into epithelial lineage-positive cells. CONCLUSION: Using the NGFR and ICAM1 cellular coordinates, we have identified a promising population of native human nasal epithelial progenitor cells that require more formal investigation for their role in upper airway regeneration.


Asunto(s)
Células Epiteliales/citología , Senos Etmoidales/citología , Mucosa Respiratoria/citología , Células Madre/citología , Antígenos de Neoplasias/metabolismo , Biomarcadores/metabolismo , Moléculas de Adhesión Celular/metabolismo , Células Cultivadas , Molécula de Adhesión Celular Epitelial , Células Epiteliales/clasificación , Citometría de Flujo , Humanos , Integrina alfa6/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Receptores de Factor de Crecimiento Nervioso/metabolismo , Células Madre/clasificación , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo
3.
Int Forum Allergy Rhinol ; 3(11): 866-76, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24106221

RESUMEN

BACKGROUND: Nasal polyps (NPs) are hallmark inflammatory lesions of sinusitis. Despite the spectrum of NP conditions, cellular differences between NPs from patients with chronic rhinosinusitis with NPs (CRSwNP) and aspirin-exacerbated respiratory disease (AERD) are poorly understood. NPs are associated with abundant eosinophils; the contributions of neutrophil and basophil granulocytes are less defined. We therefore sought to assess granulocyte subpopulations, and differential effects following prednisone pretreatment, within NPs of CRSwNP and AERD patients. METHODS: NPs, adjacent ethmoid sinus tissue, and peripheral blood mononuclear cells (PBMCs) were obtained from patients undergoing endoscopic sinus surgery. Samples from 5 cohorts: CRSwNP ± prednisone (n = 6 each), AERD ± prednisone (n = 6 each), and controls (n = 9), were analyzed by high-dimensional flow cytometry to gate granulocyte populations. Specimens were also assessed using immunohistochemistry (IHC) staining. RESULTS: Systemic prednisone administration was associated with a lower frequency of eosinophils (p < 0.0001, n = 6) in NPs in both CRSwNP and AERD patients, whereas a decrease in neutrophils (p = 0.0070, n = 6) in NPs was only observed in CRSwNP patients after prednisone treatment. In contrast, steroids do not alter basophil proportions (p = 0.48, n = 6) within NPs from either group. No significant shift in granulocyte subsets after steroid treatment was identified in the adjacent ethmoid mucosa or PBMCs from the same patients. Immunohistochemistry (IHC) staining supported these findings. CONCLUSION: Granulocyte subpopulations are focally affected within NPs by systemic steroid exposure, without notable granulocyte alterations in the surrounding regional tissues. These data provide direct insights into the cellular effects of routine prednisone exposure in CRS patients, and highlight a unique microenvironment present within NP lesions.


Asunto(s)
Glucocorticoides/farmacología , Granulocitos/efectos de los fármacos , Pólipos Nasales/tratamiento farmacológico , Prednisona/farmacología , Adulto , Anciano , Aspirina/efectos adversos , Enfermedad Crónica , Senos Etmoidales/patología , Femenino , Citometría de Flujo/métodos , Granulocitos/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Mucosa Nasal/patología , Pólipos Nasales/complicaciones , Pólipos Nasales/metabolismo , Enfermedades Respiratorias/inducido químicamente , Enfermedades Respiratorias/complicaciones , Rinitis/complicaciones , Sinusitis/complicaciones , Resultado del Tratamiento , Adulto Joven
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