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

University of Texas, Southwestern Medical Center at Dallas, Dallas, TX
University of Texas Southwestern Medical Center, Dallas, TX

Background/Purpose:

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).

Methods:

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.

Results:

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.

Conclusion:

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
DOI:

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