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

Figures & data

Figure 1 Pathogenesis of the complex series of events in cystic fibrosis (CF) progressing to alveolar macrophage dysfunction via a T_H2 dominated alveolar inflammation. (A) Denotes the interaction between the defective cystic fibrosis transmembrane conductance regulator (CFTR)^−/− macrophages in respect to intracellular acidification and Gram-negative infection, an interaction involving a T-cell switch (B) to an alveolar T-helper 2 response with induction of B-cell activation with antibody formation, transforming CF into an immunological allergic disease characterized by increased systemic immunoglobulin formation (IgG and IgE). The T_H2 response has been connected with an unfavorable accelerated declined spirometry. The end stage of the altered alveolar environment (C) with alveolar macrophage dysfunction, reflected by (i) reduced antigen (Ag) presentation, (ii) enhanced tolerance toward lipopolysaccharide (LPS) and finally (iii) reduced expression of recognition receptors, the so-called toll-like receptors (TLR) where TLR-4, which recognizes Gram-negatives, is decreased. In the end, remodeling of peripheral airways will take place producing a reduced alveolar host defense.

Table 1 Comparison of two subsets T_H1 and T_H2 each consisting of T-cells and a corresponding cytokine pattern

Subset	Characterization	Clinical response	Surrogate variables*	References
TH1	Acute inflammatory response orchestrated by the AM*** after GM-CSF activation	T-cell recruitment from systemic cellular pool via macrophage antigen presentation	T-cells: CD8 and 16 TH1 cytokines: IL-12 and IFN-γ	Brazova et al^Citation10 Eksioglu et al^Citation19 Gonzalez-Juarrero et al^Citation20 Moser et al^Citation18 Trapnell et al^Citation21
TH2	Chronic host response LPS tolerance Allergic response	Inflammatory response related to chronic infection/colonization Antibody producing cells via CD20 cells	T-cells: CD20 + antibodies IgE** TH2 cytokines: ILs 4 and 10	Brazova et al^Citation10 Greenberger^Citation4 Knutsen et al^Citation22 Meneghin and Hogaboam^Citation23 Spellberg and Edwards^Citation17

* Notes: Measurements performed in Bronchoalveolar lavage fluid (BALF);

** Specific or unspecific antibodies measured in plasma;

Abbreviations: AM, alveolar macrophage, which after inhaled GM-CSF is transformed by the inhaled GM-CSF into an immune inflammatory competent dendritic cell; GM-CSF, granulocyte-macrophage colony-stimulating factor.

Table 2 Overview of potential surrogate markers in relation to monitoring the efficacy of inhaled GM-CSF

Overall	Variable	Sampling
Inflammation	NO exhaled Eosinophilic toxin	Expiratory air sampling Urine concentration of eosinophilic degradation products
Cytokines	IL-2, 4, 5, 10 og 12, IFN-γ, TNF	Blood
Antibodies	IgE, IgG	Blood
Cells	Recruited from BAL fluid	FACS analysis
Biofilm formation	QS and CFU threshold in relation to biofilm formation monitored by sputum alginate	QS, in vitro test Alginate in sputum ELISA-test

Abbreviations: QS, Quorum sensing; CFU, colony forming unit; BAL, bronchoalveolar lavage; ELISA, enzyme-linked immunosorbent assay; FACS, fluorescence activated cell sorting.

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