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Bacterial motif DNA as an adjuvant for the breakdown of immune self-tolerance to pyruvate dehydrogenase complex

Lookup NU author(s): Professor David Jones, Dr Jeremy Palmer, Professor Alastair Burt, Dr Amanda Robe, Professor John Kirby

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Abstract

Bacterial DNA containing unmethylated CpG dinucleotide motifs is immunostimulatory to mammals, skewing CD4(+) T-cell responses toward the Th1 phenotype. Autoreactive T-cell responses seen in primary biliary cirrhosis (PBC) are typically of the Th1 phenotype, raising the possibility that bacterial DNA might play a role in the generation of pathologic autoimmunity. We therefore studied the effects of CpG motif-containing oligodeoxynucleotides (ODN) on responses to pyruvate dehydrogenase complex (PDC, the autoantigen in PBC) in a murine model. Sensitization of SJL/J mice with non-self-PDC has been shown to result in induction of autoreactive T-cell responses to PDC sharing characteristics with those seen in patients with PBC. Administration of CpG ODN to SJL/J mice at the time of sensitization with PDC resulted in a significant skewing of splenic T-cell response to self-PDC, with significant augmentation of the Th1 cytokine response (interleukin [IL] 2 and interferon [IFN] gamma) and reduction of the Th2 response (IL-4 and IL-10). In fact, CpG ODN seemed to be more effective at biasing the response phenotype and as effective at inducing liver histologic change as complete Freund's adjuvant (CIA), the standard adjuvant used for induction of Th1 responses in murine autoimmune and infections immunity models. In conclusion, our findings raise the possibility that bacteria play a role in the development of autoimmunity (in PBC at least) through the potential of their DNA to shift the T-cell responses toward the phenotype associated with autoimmune damage. Moreover, this study suggests caution in the therapeutic use of CpG ODN as vaccine adjuvants.


Publication metadata

Author(s): Jones DEJ, Palmer JM, Burt AD, Walker C, Robe AJ, Kirby JA

Publication type: Article

Publication status: Published

Journal: Hepatology

Year: 2002

Volume: 36

Issue: 3

Pages: 679-686

ISSN (print): 0270-9139

ISSN (electronic): 1527-3350

Publisher: John Wiley & Sons, Inc.

URL: http://dx.doi.org/10.1053/jhep.2002.35067

DOI: 10.1053/jhep.2002.35067


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