Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement

The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.


Amelioration of Lupus Nephritis with Dendritic Cells Using a NF-KappaB Decoy and Histone H3 Peptide in NZB/W F1 Mice

Hasegawa,  Hitoshi, Inoue,  Atsushi, Kohno,  Masashi, Matsumoto,  Takuya, Yasukawa,  Masaki

Purpose:

The expression of costimulatory molecules on antigen-presenting cells is crucial in determining T-cell immune response and is regulated by nuclear transcriptional factor (NF)-kappa B. The peptide of core histone H3 contains T cell epitopes of NZB/W F1 mice. We investigate the effect of NF-kappaB decoy-treated dendritic cells (DCs) on the lupus nephritis in NZB/W F1 mice reducing the T cell response against Histone H3 peptide.

Method:

DCs propagated from bone marrow cells of NZB/W F1 mice were used. Double-stranded NF-kappaB decoys were generated using equimolar amount of single-stranded sense and antisense phosphorothioate-modified ODN containing NF-kappaB binding sites and were added at the initiation of DC culture of mice. Female 10-week-old NZB/W F1 mice were treated with DCs pulsed with Histone H3 peptide, three times. Phenotypical expression of DC was analysed by flowcytometry. Immune stimulatory activity of DCs was examined in T cell proliferation assay. Proteinuria concentration of NZB/W F1 mice was measured weekly to monitor the development of nephritis. Serum levels of anti-DNA antibodies were measured by ELISA. For assessment of lupus nephritis, NZB/W F1 mice were sacrified at 28 weeks of age and evaluated histologically.

Results:

NF-kappaB decoys suppressed suface expression of costimulatory molecules, including CD80, CD86 and CD40 of DCs, but the expression of MHC was not affected. NF-kappaB decoy-treated DCs significantly suppressed allostimulatory activity and self-antigen specific T-cell proliferative responce. Administration of NF-kappaB decoy-treated DCs reduced significantly proteinuria, anti-DNA antibodies of 28-week-old NZB/W F1 mice compared with control mice. The pathological change in the control mice included mesangial thickening and hypercellularity evolving into sclerosis. The nephritis score in the NF-kappaB decoy DCs-treated mice was significant lower than that in the control mice. This indicates that NF-kappaB DCs pulsed with Histone H3 peptide may suppress or delay renal inflammation in vivo.

Conclusion:

NF-kappaB decoy-treated DCs may promote tolerance induction by reducing the antigen-specific autoimmune response and provide a therapeutic effect to lupus nephritis of NZB/W F1 mice. This strategy may be benefical for the treatment of human autoimmune diseases.

To cite this abstract, please use the following information:
Hasegawa, Hitoshi, Inoue, Atsushi, Kohno, Masashi, Matsumoto, Takuya, Yasukawa, Masaki; Amelioration of Lupus Nephritis with Dendritic Cells Using a NF-KappaB Decoy and Histone H3 Peptide in NZB/W F1 Mice [abstract]. Arthritis Rheum 2009;60 Suppl 10 :1048
DOI: 10.1002/art.26125

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