Domínguez MC, Lorenzo N, Barberá A, Padrón G, Torres AM, Hernández MV, Hernández I, Gil R, Sánchez A, Besada V, González LJ, Garay H, Reyes O, Pérez E, López M, Mazola Y, Cosme K, Ancizar J

Language: English
References: 15
Page: 153-156
PDF size: 193.87 Kb.

ABSTRACT

Induction of immune tolerance as therapeutic approach for autoimmune diseases constitutes a current research focal point. In this sense, two Altered Peptide Ligands (APLs) were evaluated for the induction of peripheral tolerance in patients with Rheumatoid Arthritis (RA). Two novel T cell epitopes from human heat-shock protein 60 (hHsp60), an autoantigen involved in the pathogenesis of RA, were identified by bioinformatics tools and two APLs were designed from these epitopes (APL-1 and APL-2). APL-1 increases the proportions of the CD4+CD25^highFoxP3+ regulatory T cells in ex vivo assays using PBMCs isolated from RA patients. While, APL-2 increased the IL-10 level and suppressed IL-17 secretion, and induces the activation of T cells through his ability to modify cell cycle phase’s distribution of CD4+ T cells from RA patients. Additionally, the therapeutic effect of these APLs in two animal models was evaluated: adjuvant induced arthritis (AA) in Lewis rat and collagen induced arthritis (CIA) in DBA/1 mice. Our approach was compared to metotrexate (MTX), the treatment of reference for RA, in CIA model. Clinical score, TNF-α levels and histopathology were monitored. Both APLs efficiently inhibited the course of AA and CIA, with significant reduction of the clinical and histopathology scores. The therapeutic effect induced by APLs is mediated by different molecular mechanisms, associated with immunologic tolerance. These results indicate a therapeutic potentiality of these APLs and support further investigation for treatment of RA. This study won the Annual Award of the Academy of Sciences of Cuba in 2012.

REFERENCES

1. Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, et al. The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006;54(1):26-37.

2. Kooloos WM, de Jong DJ, Huizinga TW, Guchelaar HJ. Potential role of pharmacogenetics in anti-TNF treatment of rheumatoid arthritis and Crohn’s disease. Drug Discov Today. 2007;12(3-4):125-31.

3. van Vollenhoven RF. Treatment of rheumatoid arthritis: state of the art 2009. Nat Rev Rheumatol. 2009;5(10):531-41.

4. Satpute SR, Durai M, Moudgil KD. Antigen-specifi c tolerogenic and immunomodulatory strategies for the treatment of autoimmune arthritis. Semin Arthritis Rheum. 2008;38(3):195-207.

5. van Eden W, van der Zee R, Prakken B. Heat-shock proteins induce T-cell regulation of chronic inflammation. Nat Rev Immunol. 2005;5(4):318-30.

6. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775-87.

7. Prakken BJ, Roord S, van Kooten PJ, Wagenaar JP, van Eden W, Albani S, et al. Inhibition of adjuvant-induced arthritis by interleukin-10-driven regulatory cells induced via nasal administration of a peptide analog of an arthritis-related heat-shock protein 60 T cell epitope. Arthritis Rheum. 2002;46(7):1937-46.

8. Huurman VA, van der Meide PE, Duinkerken G, Willemen S, Cohen IR, Elias D, et al. Immunological effi cacy of heat shock protein 60 peptide DiaPep277 therapy in clinical type I diabetes. Clin Exp Immunol. 2008;152(3):488-97.

9. Bielekova B, Martin R. Antigen-specifi c immunomodulation via altered peptide ligands. J Mol Med (Berl). 2001;79(10): 552-65.

10. Lin HH, Zhang GL, Tongchusak S, Reinherz EL, Brusic V. Evaluation of MHC-II peptide binding prediction servers: applications for vaccine research. BMC Bioinformatics. 2008;9 Suppl 12:S22.

11. Garrood T, Pitzalis C. Targeting the infl amed synovium: the quest for specifi city. Arthritis Rheum. 2006;54(4):1055-60.

12. van Amelsfort JM, Jacobs KM, Bijlsma JW, Lafeber FP, Taams LS. CD4(+) CD25(+) regulatory T cells in rheumatoid arthritis: differences in the presence, phenotype, and function between peripheral blood and synovial fl uid. Arthritis Rheum. 2004;50(9):2775-85.

13. Choy EH, Panayi GS. Cytokine pathways and joint infl ammation in rheumatoid arthritis. N Engl J Med. 2001; 344(12): 907-16.

14. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, et al. A distinct lineage of CD4 T cells regulates tissue infl ammation by producing interleukin 17. Nat Immunol. 2005;6(11):1133-41.

15. Nakae S, Nambu A, Sudo K, Iwakura Y. Suppression of immune induction of collagen- induced arthritis in IL-17-defi cient mice. J Immunol. 2003;171(11):6173-7.