Immunomodulatory effects of CpG oligodeoxynucleotides on established th2 responses.
CpG oligodeoxynucleotides (CpG ODNs) are known to induce type 1 T-helper-cell (Th1) responses. We have previously demonstrated that CpG ODNs administered during sensitization prevent Th2-mediated eosinophilic airway inflammation in vivo. We also reported that key Th1 cytokines, gamma interferon (IFN-gamma) and interleukin 12 (IL-12), are not necessary for this protection. Recent in vivo data suggest that CpG ODNs might also reverse established pulmonary eosinophilia. In order to clarify how CpG ODNs can inhibit established Th2 responses, we evaluated the cytokine production from splenocytes from antigen- and alum-immunized mice. Restimulation with antigen induced IL-5, which was clearly inhibited by coculture with CpG ODNs in a concentration-dependent manner. CpG ODNs also induced IFN-gamma, but in a concentration-independent manner. The inhibition of IL-5 production was not mediated through natural killer cells or via CD8(+) T lymphocytes. Although IFN-gamma plays an important role in inhibition of antigen-induced IL-5 production by CpG ODNs, IFN-gamma was not the sole factor in IL-5 inhibition. CpG ODNs also induced IL-10, and this induction correlated well with IL-5 inhibition. Elimination of IL-10 reduced the anti-IL-5 effect of CpG ODNs, although incompletely. This may be because IFN-gamma, induced by CpG ODNs, is also inhibited by IL-10, serving as a homeostatic mechanism for the Th1-Th2 balance. Overproduction of IFN-gamma was downregulated by CpG ODN-induced IL-10 via modulation of IL-12 production. These data suggest that CpG ODNs may inhibit established Th2 immune responses through IFN-gamma and IL-10 production, the latter serving to regulate excessive Th1 bias. These properties of CpG ODNs might be a useful feature in the development of immunotherapy adjuvants against allergic diseases such as asthma.
Kitagaki
Kunihiko
K
Department of Medicine, Roy J and Lucille Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
Jain
Vipul V
VV
Businga
Thomas R
TR
Hussain
Iftikhar
I
Kline
Joel N
JN
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D007167:Immunotherapy; D016898:Interferon-alpha / Q000502:physiology; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000502:physiology; D015848:Interleukin-5 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000502:physiology
D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D016898:Interferon-alpha; D015848:Interleukin-5; D009838:Oligodeoxyribonucleotides; D016212:Transforming Growth Factor beta; D018664:Interleukin-12; D007371:Interferon-gamma