The immunomodulatory effect of inhaled granulocyte-macrophage colony-stimulating factor in cystic fibrosis. A new treatment paradigm

Lars Heslet1, Christiane Bay2, Steen Nepper-Christensen31Serendex ApS, Gentofte, Denmark; 2University of Copenhagen, Medical Faculty, Copenhagen, Denmark; 3Department of Head and Neck Surgery, Otorhinolaryngology, K&oslash;ge Hospital, DenmarkBackground: Patients with cystic fibrosis (CF) ex...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Heslet L, Bay C, Nepper-Christensen S
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2012
Materias:	Pathology RB1-214 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/b069854e66e24ccaaa9bfcfdb38cae8d
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:b069854e66e24ccaaa9bfcfdb38cae8d
record_format	dspace
spelling	oai:doaj.org-article:b069854e66e24ccaaa9bfcfdb38cae8d2021-12-02T00:15:22ZThe immunomodulatory effect of inhaled granulocyte-macrophage colony-stimulating factor in cystic fibrosis. A new treatment paradigm1178-7031https://doaj.org/article/b069854e66e24ccaaa9bfcfdb38cae8d2012-01-01T00:00:00Zhttp://www.dovepress.com/the-immunomodulatory-effect-of-inhaled-granulocyte-macrophage-colony-s-a9101https://doaj.org/toc/1178-7031Lars Heslet1, Christiane Bay2, Steen Nepper-Christensen31Serendex ApS, Gentofte, Denmark; 2University of Copenhagen, Medical Faculty, Copenhagen, Denmark; 3Department of Head and Neck Surgery, Otorhinolaryngology, K&oslash;ge Hospital, DenmarkBackground: Patients with cystic fibrosis (CF) experience recurrent infections and develop chronically infected lungs, which initiates an altered immunological alveolar environment. End-stage pulmonary dysfunction is a result of a long sequence of complex events in CF, progressing to alveolar macrophage dysfunction via a T-helper 2 (TH2) dominated alveolar inflammation with CD20 T-cell activation, induced by the chronic infection and showing a poor prognosis. There is great potential for treatment in transforming the TH2 into the more favorable T-helper 1 (TH1) response.Methods: Current literature in the PubMed database and other sources was reviewed in order to evaluate aspects of the innate alveolar host defense mechanisms and the potential impact on the immunoinflammatory response of inhalation of granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with CF.Results: It seems that the cellular host defense, (ie, the alveolar macrophage and neutrocyte function) and the inhaled GM-CSF interact in such a way that the so-called tolerant alveolar environment dominated by the TH2 response may be transformed into an active TH1 state with a normal pulmonary host defense. The shift of the TH2 to the TH1 subset dominated by specific and unspecific antibodies may be achieved after the inhalation of GM-CSF. A clinical report has shown promising results with inhalation of GM-CSF in a chronically-infected CF patient treated with several antibacterial and antifungal agents. Inhaled GM-CSF transformed the tolerance toward the Gram-negative infection reflected by the so-called TH2 subset into the more acute TH1 response characterized by recruitment of the T-cells CD8 and CD16, a condition related to better-preserved lung function. This indicated a transformation from a state of passive bacterial tolerance toward the Gram-negative infecting and colonizing bacteria. This GM-CSF effect cannot be achieved by administering the drug via the IV route because the drug is water-soluble and too large to penetrate the alveolocapillary membrane.Conclusions: Inhalation of GM-CSF seems to be a novel way to positively modulate the alveolar environment toward an altered immunological state, reflected by a positive change in the pattern of surrogate markers, related to better preservation of pulmonary function and thus improved outcomes in CF patients. It is suggested that future studies examining standard endpoint variables such as number of infections and amount of antibiotics used should be supplemented by surrogate markers, to reveal any positive cellular and cytokine responses reflecting changes in the alveolar compartment after GM-CSF inhalation. The immunological alveolar environment should be monitored by a specific pattern of surrogate markers. Continued research is clearly indicated and the role of inhaled GM-CSF in modulating pulmonary host defense in CF patients should be investigated in a large study.Keywords: cystic fibrosis, granulocyte-macrophage colony-stimulating factor, TH1 response, TH2 subset, surrogate markersHeslet LBay CNepper-Christensen SDove Medical PressarticlePathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol 2012, Iss default, Pp 19-27 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Pathology RB1-214 Therapeutics. Pharmacology RM1-950
spellingShingle	Pathology RB1-214 Therapeutics. Pharmacology RM1-950 Heslet L Bay C Nepper-Christensen S The immunomodulatory effect of inhaled granulocyte-macrophage colony-stimulating factor in cystic fibrosis. A new treatment paradigm
description	Lars Heslet1, Christiane Bay2, Steen Nepper-Christensen31Serendex ApS, Gentofte, Denmark; 2University of Copenhagen, Medical Faculty, Copenhagen, Denmark; 3Department of Head and Neck Surgery, Otorhinolaryngology, K&oslash;ge Hospital, DenmarkBackground: Patients with cystic fibrosis (CF) experience recurrent infections and develop chronically infected lungs, which initiates an altered immunological alveolar environment. End-stage pulmonary dysfunction is a result of a long sequence of complex events in CF, progressing to alveolar macrophage dysfunction via a T-helper 2 (TH2) dominated alveolar inflammation with CD20 T-cell activation, induced by the chronic infection and showing a poor prognosis. There is great potential for treatment in transforming the TH2 into the more favorable T-helper 1 (TH1) response.Methods: Current literature in the PubMed database and other sources was reviewed in order to evaluate aspects of the innate alveolar host defense mechanisms and the potential impact on the immunoinflammatory response of inhalation of granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with CF.Results: It seems that the cellular host defense, (ie, the alveolar macrophage and neutrocyte function) and the inhaled GM-CSF interact in such a way that the so-called tolerant alveolar environment dominated by the TH2 response may be transformed into an active TH1 state with a normal pulmonary host defense. The shift of the TH2 to the TH1 subset dominated by specific and unspecific antibodies may be achieved after the inhalation of GM-CSF. A clinical report has shown promising results with inhalation of GM-CSF in a chronically-infected CF patient treated with several antibacterial and antifungal agents. Inhaled GM-CSF transformed the tolerance toward the Gram-negative infection reflected by the so-called TH2 subset into the more acute TH1 response characterized by recruitment of the T-cells CD8 and CD16, a condition related to better-preserved lung function. This indicated a transformation from a state of passive bacterial tolerance toward the Gram-negative infecting and colonizing bacteria. This GM-CSF effect cannot be achieved by administering the drug via the IV route because the drug is water-soluble and too large to penetrate the alveolocapillary membrane.Conclusions: Inhalation of GM-CSF seems to be a novel way to positively modulate the alveolar environment toward an altered immunological state, reflected by a positive change in the pattern of surrogate markers, related to better preservation of pulmonary function and thus improved outcomes in CF patients. It is suggested that future studies examining standard endpoint variables such as number of infections and amount of antibiotics used should be supplemented by surrogate markers, to reveal any positive cellular and cytokine responses reflecting changes in the alveolar compartment after GM-CSF inhalation. The immunological alveolar environment should be monitored by a specific pattern of surrogate markers. Continued research is clearly indicated and the role of inhaled GM-CSF in modulating pulmonary host defense in CF patients should be investigated in a large study.Keywords: cystic fibrosis, granulocyte-macrophage colony-stimulating factor, TH1 response, TH2 subset, surrogate markers
format	article
author	Heslet L Bay C Nepper-Christensen S
author_facet	Heslet L Bay C Nepper-Christensen S
author_sort	Heslet L
title	The immunomodulatory effect of inhaled granulocyte-macrophage colony-stimulating factor in cystic fibrosis. A new treatment paradigm
title_short	The immunomodulatory effect of inhaled granulocyte-macrophage colony-stimulating factor in cystic fibrosis. A new treatment paradigm
title_full	The immunomodulatory effect of inhaled granulocyte-macrophage colony-stimulating factor in cystic fibrosis. A new treatment paradigm
title_fullStr	The immunomodulatory effect of inhaled granulocyte-macrophage colony-stimulating factor in cystic fibrosis. A new treatment paradigm
title_full_unstemmed	The immunomodulatory effect of inhaled granulocyte-macrophage colony-stimulating factor in cystic fibrosis. A new treatment paradigm
title_sort	immunomodulatory effect of inhaled granulocyte-macrophage colony-stimulating factor in cystic fibrosis. a new treatment paradigm
publisher	Dove Medical Press
publishDate	2012
url	https://doaj.org/article/b069854e66e24ccaaa9bfcfdb38cae8d
work_keys_str_mv	AT hesletl theimmunomodulatoryeffectofinhaledgranulocytemacrophagecolonystimulatingfactorincysticfibrosisanewtreatmentparadigm AT bayc theimmunomodulatoryeffectofinhaledgranulocytemacrophagecolonystimulatingfactorincysticfibrosisanewtreatmentparadigm AT nepperchristensens theimmunomodulatoryeffectofinhaledgranulocytemacrophagecolonystimulatingfactorincysticfibrosisanewtreatmentparadigm AT hesletl immunomodulatoryeffectofinhaledgranulocytemacrophagecolonystimulatingfactorincysticfibrosisanewtreatmentparadigm AT bayc immunomodulatoryeffectofinhaledgranulocytemacrophagecolonystimulatingfactorincysticfibrosisanewtreatmentparadigm AT nepperchristensens immunomodulatoryeffectofinhaledgranulocytemacrophagecolonystimulatingfactorincysticfibrosisanewtreatmentparadigm
_version_	1718403882836557824

The immunomodulatory effect of inhaled granulocyte-macrophage colony-stimulating factor in cystic fibrosis. A new treatment paradigm

Ejemplares similares