Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Intra-Articular Injection of the Selective IB Kinase Inhibitor NEMO-Binding Peptide Ameliorates Collagen Induced Arthritis by Inducing Regulatory T Cells and Alternatively Activated Macrophages.
Min1, Soyoun, Yan1, Mei, Du1, Yong, Arriens1, Cristina, Wu1, Tianfu, Mohan2, Chandra
Nuclear factor (NF)-kB is a transcription factor that is critical in the pathogenesis of various autoimmune disorders including rheumatoid arthritis (RA). To examine whether local NF-kB inhibition had efficacy in reducing inflammation in collagen induced arthritis (CIA) without systemic immune suppression, we tested intra-articular delivery of an IKK inhibitor, NEMO-binding domain peptide (NBP).
NBD peptides were injected intra-articularly into the knee joint of DBA1 mice (N = 6) (150ug/joint) at the onset of disease, while the control mice were administered a scrambled peptide. The severity of arthritis was determined by visual examination of the paws, and the mice were sacrificed 6 weeks after the first immunization. Joint specimens were examined for pathology. Serum levels of anti-collagen antibodies and cytokine production were measured by ELISA. The induction of regulatory T cells and macrophage were assessed by flow cytometry analysis and immunofluorescence staining.
Intra-articular NBD injection ameliorated the severity of arthritis scores (9.0 ± 1.1 vs 5.5 ± 0.7 U, P < 0.01) and reduced bone destruction on histological analysis, compared to vehicle injected mice. The serum concentrations of type-II collagen-specific IgG2a antibodies were significantly lower in NBD-treated mice compared to vehicle-treated mice (0.379 ± 0.05 vs 0.125 ± 0.01 OD units, P < 0.05), whereas the levels of type-II-collagen-specific IgG1 antibodies were mildly increased by NBD treatment. NBD treatment also diminished serum pro-inflammatory cytokines including IFN-g and IL-17 while the regulatory cytokine IL-10 was increased in sera. NBD-treated CIA mice had significantly higher percentages and numbers of CD4+CD25+ cells in dLN compared to the control (4.1 %± 0.3 vs 0.41 %± 0.1, P < 0.01). Furthermore, CD4+ cells from dLN of NBD-treated CIA mice expressed higher levels of Foxp3than those isolated from dLN of control CIA mice. Immunohistochemical analysis of NBD treated mice revealed that Foxp-3 and Ym-1 (a marker of alternatively activated macrophages) were present and adjacent to each other within dLNs, compared to control CIA-subjected mice.
These results indicate that IKK-b-targeted NF-kB blockade using the NBD peptide appears efficacious as a local intra-articular therapy for arthritis, potentially reducing unwanted systemic effects. Together these data demonstrate that NF-kB inhibition promote induction of CD4+CD25+ T reg cells and alternatively activated macrophages, which together may confer therapeutic benefit in inflammatory arthritis.
To cite this abstract, please use the following information:
Min, Soyoun, Yan, Mei, Du, Yong, Arriens, Cristina, Wu, Tianfu, Mohan, Chandra; Intra-Articular Injection of the Selective IB Kinase Inhibitor NEMO-Binding Peptide Ameliorates Collagen Induced Arthritis by Inducing Regulatory T Cells and Alternatively Activated Macrophages. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1638