title: Polarisation of a T-helper cell immune response by activation of dendritic cells with CpG-containing oligonucleotides: a potential therapeutic regime for bladder cancer immunotherapy.
abstract: Intravesical bacillus Calmette-Guerin (BCG) is a treatment for transitional cell carcinoma (TCC) and carcinoma in situ (cis) of the urinary bladder, but some patients remain refractory. The mechanism of cancer clearance is not known, but T cells are thought to play a contributory role. Tissue dendritic cells (DCs) are known to initiate antigen-specific immune responses following activation of receptors, which recognise molecular patterns on the surface of microorganisms. A family of these receptors, the toll-like receptors (TLRs), are also crucial for activating DC to produce cytokines that polarise the T-cell response towards a T helper (Th)1 or Th2 phenotype. This study compared the potential of intact BCG to activate DC with that of the defined TLR4 ligand lipopolysaccharide (LPS) and the TLR9 ligand CpG-oligonucleotide. It was found that all three stimuli efficiently activated normal DC, but cells expressing a mutant TLR4 responded poorly to stimulation with LPS. Importantly, stimulation with BCG induced both IL-12 and IL-10, suggesting subsequent development of a poorly focused T-cell immune response containing both Th1 and Th2 immune function. By contrast, LPS- and CpG-oligonucleotides induced only IL-12, indicating the potential to produce a Th1 response, which is likely to clear cancer most efficiently. Given the toxicity of LPS, our data suggest that CpG-oligonucleotides may be beneficial for intravesical therapy of bladder cancer.
authors.affiliation: Northern Institute for Cancer Research, School of Surgical and Reproductive Sciences, Faculty of Medical Sciences, University of Newcastle, Framlington Place, Newcastle-Upon-Tyne NE2 4HH, UK.
authors.forename: H
authors.initials: H
authors.lastname: Atkins
authors.forename: B R
authors.initials: BR
authors.lastname: Davies
authors.forename: J A
authors.initials: JA
authors.lastname: Kirby
authors.forename: J D
authors.initials: JD
authors.lastname: Kelly
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000283:Administration, Intravesical; D000818:Animals; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000276:immunology*; D007167:Immunotherapy / Q000379:methods; D007378:Interleukins / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D009163:Mycobacterium bovis / Q000276:immunology; D009841:Oligonucleotides / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D007378:Interleukins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D009841:Oligonucleotides; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C453101:carboxyphenylglycine; D005998:Glycine