Bim-Bcl-2 homology 3 mimetic therapy is effective at suppressing inflammatory arthritis through the activation of myeloid cell apoptosis.
Scatizzi, John C. 1; Hutcheson, Jack 1; Pope, Richard M. 2; Firestein, Gary S. 3; Koch, Alisa E. 4; Mavers, Melissa 1; Smason, Avraham 1; Agrawal, Hemant 2; Haines, Kenneth G. III 5; Chandel, Navdeep S. 2; Hotchkiss, Richard S. 6; Perlman, Harris 7
[Miscellaneous Article]
Arthritis & Rheumatism.
62(2):441-451, February 2010.
(Format: HTML, PDF)
Objective: Rheumatoid arthritis (RA) is a destructive autoimmune disease characterized by an increased inflammation in the joint. Therapies that activate the apoptotic cascade may have potential for use in RA; however, few therapeutic agents fit this category. The purpose of this study was to examine the potential of Bim, an agent that mimics the action of Bcl-2 homology 3 (BH3) domain-only proteins that have shown success in preclinical studies of cancer, in the treatment of autoimmune disease.
Methods: Synovial tissues from RA and osteoarthritis patients were analyzed for the expression of Bim and CD68 using immunohistochemistry. Macrophages from Bim-/- mice were examined for their response to lipopolysaccharide (LPS) using flow cytometry, real-time polymerase chain reaction analysis, enzyme-linked immunosorbent assay, and immunoblotting. Bim-/- mice were stimulated with thioglycollate or LPS and examined for macrophage activation and cytokine production. Experimental arthritis was induced using the K/BxN serum-transfer model. A mimetic peptide corresponding to the BH3 domain of Bim (TAT-BH3) was administered as a prophylactic agent and as a therapeutic agent. Edema of the ankles and histopathologic analysis of ankle tissue sections were used to determine the severity of arthritis, its cellular composition, and the degree of apoptosis.
Results: The expression of Bim was reduced in RA synovial tissue as compared with controls, particularly in macrophages. Bim-/- macrophages displayed elevated expression of markers of inflammation and secreted more interleukin-1[beta] following stimulation with LPS or thioglycollate. TAT-BH3 ameliorated arthritis development, reduced the number of myeloid cells in the joint, and enhanced apoptosis without inducing cytotoxicity.
Conclusion: These data demonstrate that BH3 mimetic therapy may have significant potential for the treatment of RA.
(C) 2010, American College of Rheumatology