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: H Atkins, B R Davies, J A Kirby, J D Kelly
• Journal: British journal of cancer (Br J Cancer) Vol. 89 Issue 12 Pg. 2312-9 (Dec 15 2003) ISSN: 0007-0920 [Print] England
• PMID: 14676812 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adjuvants, Immunologic
• Cytokines
• Interleukins
• Lipopolysaccharides
• Membrane Glycoproteins
• Oligonucleotides
• Receptors, Cell Surface
• Toll-Like Receptor 4
• Toll-Like Receptors
• carboxyphenylglycine
• Glycine

Topics

• Adjuvants, Immunologic (administration & dosage)
• Administration, Intravesical
• Animals
• Carcinoma, Transitional Cell (drug therapy, immunology)
• Cytokines (immunology)
• Dendritic Cells (immunology)
• Female
• Glycine (analogs & derivatives, immunology)
• Immunotherapy (methods)
• Interleukins (immunology)
• Lipopolysaccharides (immunology)
• Membrane Glycoproteins (immunology)
• Mice
• Mice, Inbred C3H
• Mycobacterium bovis (immunology)
• Oligonucleotides (immunology)
• Receptors, Cell Surface (immunology)
• T-Lymphocytes, Helper-Inducer (immunology)
• Toll-Like Receptor 4
• Toll-Like Receptors
• Urinary Bladder Neoplasms (drug therapy, immunology)