lipoteichoic-acid and Asthma

Susceptibility to infections with gram-positive bacteria, which are an important trigger of exacerbations, is increased in COPD and asthma. Unraveling the underlying mechanisms may help developing therapeutic strategies to reduce exacerbation rates. The aim of this study was to evaluate the effects of lipoteichoic acid (LTA), a danger signal from gram-positive bacteria, on T cell cytokines related to bacterial infection defense in COPD and asthma. T cell populations within peripheral blood mononuclear cells (PBMCs) were ex-vivo activated towards T(H)2/T(C)2 subtypes and subsequently stimulated with LTA. IL-2 and IL-5 concentrations in cell culture supernatants were measured by ELISA comparative between non-smokers (NS), current smokers without airflow limitation (S), smokers with moderate to severe COPD and mild to moderate asthmatics (A) (each n=10). IL-2 and IL-5 baseline levels were without differences between the cohorts. After T cell activation, IL-2 and IL-5 releases were increased in all cohorts, however, for IL-2 this increase was significantly higher in S and by trend in COPD compared to the other groups. LTA time-dependently suppressed IL-2 release in NS, S and COPD but not in A. LTA reduced IL-5 release in COPD and A but not in NS and S. Summarized, LTA reduces T(H)2/T(C)2 cytokines indicating immunosuppressive effects, which are dysregulated in COPD and asthma. This implies a misguided response to gram-positive bacterial infections, which might help to explain the increased susceptibility to bacterial infections in COPD and asthma.

Topics: Adult; Aged; Asthma; Case-Control Studies; Disease Susceptibility; Female; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; In Vitro Techniques; Interleukin-2; Interleukin-5; Lipopolysaccharides; Male; Middle Aged; Monocytes; Pulmonary Disease, Chronic Obstructive; T-Lymphocytes; T-Lymphocytes, Cytotoxic; Teichoic Acids; Th2 Cells

Sublingual immunotherapy (SLIT) has been established in humans as a safe and efficacious treatment for type I respiratory allergies.. In this study, we compared three Toll-like receptor (TLR) 2 ligands (Pam3CSK4, Porphyromonas gingivalis lipopolysaccharide and lipoteichoic acid) as potential adjuvants for sublingual allergy vaccines.. These molecules were tested in co-cultures of adjuvant-pre-treated dendritic cells (DCs) with murine naïve CD4(+) T lymphocytes. Patterns of cytokine production, phenotype, proliferation and gene expression were analysed by ELISA, cytofluorometry and quantitative PCR, respectively. TLR2 ligands were subsequently tested in a model of SLIT in BALB/c mice sensitized with ovalbumin (OVA).. Among the three TLR2 ligands tested, the synthetic lipopeptide Pam3CSK4 is the most potent inducer of IL-12p35 and IL-10 gene expression in murine bone marrow-derived DCs, as well as in purified oral myeloid DCs. Only Pam3CSK4-treated DCs induce IFN-gamma and IL-10 secretion by naïve CD4(+) T cells. Sublingual administration of Pam3CSK4 together with the antigen in BALB/c mice sensitized to OVA decreases airway hyperresponsiveness as well as OVA-specific T-helper type 2 (Th2) responses in cervical lymph nodes dramatically.. Pam3CSK4 induces Th1/regulatory T cell responses, and as such, is a valid candidate adjuvant for sublingual allergy vaccines.

Topics: Adjuvants, Immunologic; Administration, Sublingual; Animals; Antigen Presentation; Asthma; Bronchial Hyperreactivity; CD4-Positive T-Lymphocytes; Cytokines; Dendritic Cells; Desensitization, Immunologic; Gene Expression; Humans; Interferon-gamma; Interleukin-10; Lipopeptides; Lipopolysaccharides; Lymph Nodes; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Ovalbumin; Porphyromonas gingivalis; T-Lymphocytes, Helper-Inducer; Teichoic Acids; Toll-Like Receptor 2