The role of TLR2 and GITR agonists in allergic airways disease

Patel, Manish (2005) The role of TLR2 and GITR agonists in allergic airways disease. PhD thesis, University of Glasgow.

Abstract

Asthma is a chronic inflammatory condition characterised by airway hyperresponsiveness, inflammatory infiltrates in the bronchial wall containing eosinophils, and elevated serum IgE levels to common inhaled allergens. Over the last twenty years, the prevalence of asthma and allergies has increased markedly which cannot be explained by changes in genetic predisposition. A greater understanding of the regulation of the inflammatory responses in asthma will assist in identification of potential targets for therapeutic intervention. In this thesis, I have used a murine model of allergic airways disease to investigate (i) the effects of Toll-Like Receptor 2 (TLR2) activation; and (ii) the role of Glucocorticoid-induced tumour necrosis factor receptor (GITR). Toll-Like Receptors (TLRs) are primary sensors of both innate and adaptive immune systems where they play a pivotal role in the response directed against structurally conserved components of pathogens. Synthetic bacterial lipopeptide Pam3CSK4 (BLP) is a TLR2 agonist capable of modulating Th1 and Th2 responses. I examined the therapeutic effect of Pam3CSK4 on established airways inflammation in a murine model of asthma. In mice previously sensitised and challenged with OVA, Pam3CSK4 given intraperitoneally markedly reduced the total inflammatory cell infiltrate and eosinophilia in bronchoalveolar lavage fluid. Pam3CSK4 therapy was associated with a reduction in OVA-induced IL-4 and IL-5 secretion from thoracic lymph node culture, airway inflammation, bronchial hyperresponsiveness, and serum levels of IgE. Pam3CSK4 therapy was also associated with an increase in OVA-induced IFNgamma, IL-12 and IL-10 production. However, the anti-inflammatory effect of Pam3CSK4 was independent of IL-10 or TGFbeta but critically dependent on IL-12, the production of which by dendritic cells was enhanced by Pam3CSK4 in vitro. The heightened levels of IL-12 in turn enhanced a specific Th1 response and decreased Th2 activity. Glucocorticoid-induced tumour necrosis factor receptor (GITR) is expressed at low levels on resting T cells, B cells, and macrophages but at high levels on regulatory T cells. Although GITR expression is up-regulated on CD4[+] effector cells upon activation, the role of GITR in Th1 and Th2 cell development is unclear. Here I show that activation of GITR signalling by anti-GITR antibody markedly enhanced the induction of both Th1 (IFNgamma) and Th2 (IL-5) cytokine production by naive CD4[+]CD25[-] T cells, but had little or no effect on established Th1 or Th2 cell lines or clones. Consistent with this observation, anti-GITR antibody significantly enhanced the expression of the key Th1 (T-bet) and Th2 (GATA3) transcription factors in vitro. Administration of anti-GITR mAb also markedly exacerbated airway inflammation of a murine OVA model of asthma with elevated production of OVA-specific IFNgamma, IL-2, IL-4, IL-5, and IgE. Furthermore, adoptive transfer of CD4[+]GITR[+] T cells effectively abolished airway inflammation induced in SCID mice reconstituted with CD4[+]GITR[-] T cells. The findings in this thesis provide direct evidence that TLR2 and GITR are important mediators in murine allergic airways disease, suggesting that TLR2 agonists and GITR could represent potential targets for novel therapeutic agents in clinical asthma.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: Eddy Liew
• Keywords: Immunology
• Date of Award: 2005
• Depositing User: Enlighten Team
• Unique ID: glathesis:2005-74072
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 23 Sep 2019 15:33
• Last Modified: 23 Sep 2019 15:33
• URI: https://theses.gla.ac.uk/id/eprint/74072