Stem cell therapy in animal models of allergic airway diseases

Kyu-Sup Cho

doi:10.4168/aard.2016.4.3.167

Journal List > Allergy Asthma Respir Dis > v.4(3) > 1059174

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Cho: Stem cell therapy in animal models of allergic airway diseases

Review

Allergy Asthma Respir Dis 2016;4(3):167-173.

Published online: 12 May 2016

DOI: https://doi.org/10.4168/aard.2016.4.3.167

Stem cell therapy in animal models of allergic airway diseases

Kyu-Sup Cho

^¹Department of Otorhinolaryngolgy-Head and Neck Surgery, Pusan National University School of Medicine, Busan, Korea

Correspondence to: Kyu-Sup Cho http://orcid.org/0000-0002-4381-6996 Department of Otorhinolaryngology-Head and Neck Surgery, Pusan National University Hospital, Pusan National University School of Medicine, 179 Gudeok-ro, Seo-gu, Busan 49241, Korea Tel: +82-51-240-7824, Fax: +82-51-246-8668, E-mail: choks@pusan.ac.kr

^* This work was supported by the year 2016 clinical research grant from Pusan National University Hospital.

Received 9 February 2016 Revised 2 March 2016 Accepted 22 March 2016

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Allergic airway diseases are characterized by T-helper type 2 (Th2)-skewed eosinophilic inflammation, mucus hypersecretion, and airway hyperresponsiveness. The excessive activation of Th2 cells due to insufficient suppression of regulatory T cells (Tregs) is thought to play a major role in the initiation and development of allergic airway disease. Several studies have shown that stem cells provide a significant reduction in allergic airway inflammation and improve lung function in animal models. The immunomodulatory effects of stem cells in allergic airway disease may be mediated by the upregulation of Tregs and increases in several soluble factors, such as prostaglandin E2, transforming growth factor-β, interleukin-10, and indoleamine 2, 3-dioxygenase. This review ex-amines the current understanding of the immunomodulatory properties of stem cells and its therapeutic implication in allergic airway disease. Furthermore, we will discuss mechanisms by which stem cells inhibit allergic airway inflammation via immunomodulation from a Th2- to a Th1-biased response.

Keywords: Stem cells, Immunosuppression, Allergic rhinitis, Asthma, Regulatory T lymphocytes

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Fig. 1.

Adipose tissue-derived stem cells labeled with Cell Tracker CM-Dil (red) were more intensively distributed within the lung of asthmatic mice (A) than control mice (B) (magnification, ×200).

Fig. 2.

Schematic illustration of the soluble factors for MSC-mediated immunosuppression. TLR, toll-like receptor; MSC, mesenchymal stem cell; DC, dendritic cells; HGF, hepatocyte growth factor; IL, interleukin; PGE2, prostaglandin E2; IDO, indoleamine 2,3-dioxygenase; NO, nitric oxide; PDL-1, programmed death ligand-1; TGF-β1, transforming growth factor-β1; SDF-1, stem cell derived factor 1; VEGF, vascular endothelial growth factor; IL-1RA, interleukin-1 receptor antagonist; TNF-α, tumor necrosis factor-; IFN-, interferon; Ig, immunoglobulin; NK, natural killer; MAC, macrophage. Adapted from Sueblinvong et al. Transl Res 2010;156:188–205.³³

Fig. 3.

Schematic presentation of possible immunomodulatory mechanisms of stem cells in allergic airway diseases. AR, allergic rhinitis; AHR, airway hyperrespon-siveness; IDO, indoleamine 2,3-dioxygenase; IFN-γ, interferon-γ; Ig, immunoglobulin; IL, interleukin; PGE2, prostaglandin E2; TGF-β, transforming growth factor-β; Tregs, regulatory T cells.

Table 1.

Summary of soluble factors critical for mesenchymal stem cells-medi-ated immunosuppression

Factor	Function
iNOS	Inhibits T-cell proliferation
CCL2	Inhibits CD4⁺ Th17 cells
IDO	Inhibits T-cell proliferation, promotes type II macrophage differentiation, impair NK cell activity
Semaphorin-3A	Inhibits T-cell proliferation
B7-H4	Inhibits T-cell activation and proliferation
HLA-G	Inhibits PBMC response
LIF	Inhibits T-cell proliferation
TSG6	Regulates macrophages, inhibits inflammation
Galectin(S)	Inhibits T-cell proliferation
HO-1	Inhibits T-cell response, induce IL-10⁺ Tr1 and TGF-β⁺ Tregs
IL-6	Inhibit the differentiation of dendritic cells, inhibit T-cell proliferation
TGF-β	Induces Tregs, inhibits NK cell activation and function
IL-10	Inhibits T-cell response, decreases Th17 cell differentiation
PGE2	Induces Foxp3⁺ Tregs, inhibits NK cell function, induces type II macrophages, inhibit DC maturation
PD-L1/2	Inhibits Th17 cells, inhibits T-cell proliferation
FasL	Induces T-cell apoptosis

iNOS, inducible nitric oxide synthase; CCL2, chemokine ligand 2; IDO, indoleamine 2,3-dioxygenase; NK, natural killer; HLA-G, human leukocyte antigen G; LIF, leukemia inhibitory factor; PBMC, peripheral blood mononuclear cells; TSG6, TNF-α stimulated gene/protein 6; HO-1, heme oxygenase-1; TGF-β, transforming growth factor-β; IL, interleukin; PGE2, prostaglandin E2; DC, dendritic cells; PD-L1/2, programmed cell death 1 ligand1/2; FasL, Fas ligand.

Table 2.

Proteins detected in the mesenchymal stem cell secretome

Type	Proteins
Angiogenic factors	Angiogenin
	Angiopoietin
	Vascular endothelial growth factor
Growth and trophic factors	Brain-derived neurotrophic factor
	Epidermal growth factor
	Fibroblast growth factors
	Giant cell line-derived neurotrophic factor
	Hepatocyte growth factor
	Insulin like growth factor I
	Nerve growth factor
	Placental growth factor
	Platelet-derived growth factor
Pro-inflammatory cytokines	Interferon-γ
	Interleukin-12
	Interleukin-1α
	Interleukin-2
	Tumor necrosis factor-α
Anti-inflammatory cytokines	Interleukin-10
	Interleukin-13
	Macrophage migration inhibitory factor
	Transforming growth factor-β

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