Treatment with a Toll-like receptor inhibitory GpG oligonucleotide delays and attenuates lupus nephritis in NZB/W mice

Abstract

Activation of the innate immune system by DNA containing hypomethylated CpG motifs has been implicated in the pathogenesis of systemic lupus erythematosus (SLE). Here, we examined the consequences of immunostimulatory CpG-oligodeoxynucleotide (ODN) and inhibitory GpG-ODN treatment in the NZB × NZW F1 (NZB/W) murine model of SLE. Beginning at 5 months of age, we administered CpG-ODN or GpG-ODN at regular intervals to female NZB/W animals. We also determined the effects of ODN administration on NZB/W mouse lymphocyte function, and the specificity of ODN binding to Toll-like receptors (TLRs) other than TLR-9. While CpG-ODN treatment did not appear to have a major impact on disease severity, GpG-ODN treatment significantly delayed the onset of proteinuria in NZB/W mice. Interestingly, short-term GpG-ODN treatment promoted Th2-type T and B cell responses, and inhibited B lymphocyte proliferation in vitro. On the other hand, extended GpG-ODN treatment did not result in sustained Th2 responses or significantly reduced renal disease. Moreover, the binding of CpG-ODN and GpG-ODN was not restricted to TLR-9 as both ODNs also interacted with TLR-3, TLR-7, and TLR-8. Taken together, the data indicate that the protective mechanism of GpG-ODN treatment in the NZB/W model of lupus nephritis involves modulating T cell cytokine profiles and B lymphocyte activation through the inhibition of several TLRs, including TLR-7 and TLR-9.

Keywords::

• Systemic lupus erythematosus
• Toll-like receptors
• inhibitory oligos
• therapy
• Th2

Acknowledgements

We thank Pearline Teo for technical support on unpublished data and Michael Leviten for critical scientific discussions. K.L.G. is supported by a NIH NRSA fellowship AI10663-02. L.S. is supported by NIH and National Multiple Sclerosis Society grants. P.J.U. is the recipient of a Donald E. and Delia B. Baxter Foundation Career Development Award, and was supported by the Dana Foundation, the Floren Family Trust, the Northern California Chapter of the Arthritis Foundation, NIH Grants DK61934, AI50854, AI50865, AR49328, and NHLBI Proteomics Contract N01-HV-28183. P.P.H. is the recipient of an Arthritis Foundation Northern California Chapter Grant. K.L.G. and P.P.H. conceived of the study, participated in its design and coordination, participated in the acquisition, analysis and interpretation of the data, and helped with the draft of the manuscript. L.Y.L. participated in the acquisition, analysis and interpretation of the data. J.P.H. participated in the analysis and interpretation of the data. L.S. and P.J.U. conceived of the study, participated in the analysis and interpretation of the data, and helped with the draft of the manuscript.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.