Bacterial motif DNA as an adjuvant for the breakdown of immune self-tolerance to pyruvate dehydrogenase complex.
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 (CFA), the standard adjuvant used for induction of Th1 responses in murine autoimmune and infectious 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.
Jones
David E J
DE
Centre for Liver Research, University of Newcastle, Framlington Place, Newcastle-upon-Tyne, England. D.E.J.Jones@ncl.ac.uk
Palmer
Jeremy M
JM
Burt
Alastair D
AD
Walker
Claire
C
Robe
Amanda J
AJ
Kirby
John A
JA
D000276:Adjuvants, Immunologic / Q000235:genetics*; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D018899:CpG Islands / Q000276:immunology; D004269:DNA, Bacterial / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008105:Liver Cirrhosis, Biliary / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D011768:Pyruvate Dehydrogenase Complex / Q000276:immunology*; D017634:Self Tolerance / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014612:Vaccines / Q000276:immunology
D000276:Adjuvants, Immunologic; D004269:DNA, Bacterial; D007376:Interleukin-2; D011768:Pyruvate Dehydrogenase Complex; D014612:Vaccines; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma