mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-2008-1-77-80mimmun-84Research ArticleКРАТКИЕ СООБЩЕНИЯSHORT COMMUNICATIONSВЛИЯНИЕ СТАТИНОВ НА АНТИГЕНСПЕЦИФИЧЕСКУЮ АКТИВАЦИЮ ЛИМФОЦИТОВ БОЛЬНЫХ РЕВМАТОИДНЫМ АРТРИТОМ – ИССЛЕДОВАНИЕ IN VITROEFFECTS OF STATINS UPON ANTIGEN-SPECIFIC LYMPHOCYTE ACTIVATION IN PATIENTS WITH RHEUMATOID ARTHRITIS: AN IN VITRO STUDYШиринскийИ. В.ShirinskyI. V.

Лаборатория клинической иммунофармакологии

ishirinsky@mail.ruШиринскийВ. С.ShirinskyV. S.

Лаборатория клинической иммунофармакологии

 

ishirinsky@mail.ruГосударственное учреждение научно-исследовательский институт клинической иммунологии СО РАМН, г. НовосибирскRussian Federation2008140720141017780Copyright © Ширинский И.В., Ширинский В.С., 20142014Ширинский И.В., Ширинский В.С.Shirinsky I.V., Shirinsky V.S.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.mimmun.ru/mimmun/article/view/84

Резюме. К числу кандидатных аутоантигенов, инициирующих развитие ревматоидного артрита (РА), относится коллаген II типа (CII). Показано, что статины обладают противовоспалительными и иммуномодулирующими свойствами. Механизмы действия статинов на индуцированную аутоантигенами активацию Т-лимфоцитов у больных РА остаются неясными. Целью настоящего исследования была оценка влияния мевастатина на CII и CD3-индуцированную активацию мононуклеаров периферической крови (МНК ПК) больных РА. МНК ПК, выделенные от больных активным (DAS28 – 6,6±0,64) РА, были стимулированы антителами к CD3 (анти-CD3) или CII. В культуры добавлялись мевастатин в различных концентрациях, мевалоновая кислота, геранилгеранил пирофосфат (GGpp) и фарнезил пирофосфат (Fpp). Мевастатин в концентрации 10 μM статистически значимо уменьшал CII-индуцированную пролиферацию МНК ПК и продукцию IFNγ. Эти эффекты мевастатина были частично обратимы при добавлении в культуры мевалоната кислоты, GGpp и Fpp. Мевастатин не оказывал влияния на стимулированную анти-CD3 стимуляцию МНК ПК. Заключается, что мевастатин способен ингибировать антигенспецифическую стимуляцию Т-лимфоцитов у больных РА благодаря снижению синтеза метаболитов мевалоновой кислоты.

Abstract. Collagen type II (Col II) is among the proposed candidate autoantigens initiaiting rheumatoid arthritis (RA). Statins have been shown to have anti-inflammatory and immunomodulating properties. Mechanisms of statin effects upon the autoantigen-induced T lymphocyte activation in RA patients are still unknown. The aim of present study was to evaluate the effects of mevastatin upon Col II- and anti-CD3-induced (PBMC) activation of peripheral blood mononuclear cells (PBMC) from RA patients. PBMC from active RA patients (DAS28 – 6.6±0.64) were stimulated with antibodies specific for either anti-CD3 or anti-Col II. The cultured cells were treated with mevastatin at different concentrations. Mevalonic acid, geranylgeranyl pyrophosphate (GGpp) and farnesyl pyrophosphate (Fpp) were added to cultures. Mevastatin at concentration of 10 μM caused significant reduction of Col II-induced PBMC proliferation and of IFNγ production. These mevastatin effects were partially reversible by addition of mevalonic acid, GGpp, and Fpp. Mevastatin did not influence the anti-CD3 induced PBMC activation. In conclusion, mevastatin is able to suppress antigen-specific T-cell stimulation in RA patients, due to decreased production of mevalonic acid metabolites.

ревматоидный артрит3-гидрокси-3-метилглутарил-КоА-редуктазастатиныin vitrorheumatoid arthritisstatinsin vitroReferencesArnett F.C., Edworthy S.M., Bloch D.A., McShane D.J., Fries J.F., Cooper N.S., Healey L.A., Kaplan S.R., Liang M.H., Luthra H.S., et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis // Arthritis Rheum. – 1988. – Vol. 31. – P. 315-324.Arnett F.C., Edworthy S.M., Bloch D.A., McShane D.J., Fries J.F., Cooper N.S., Healey L.A., Kaplan S.R., Liang M.H., Luthra H.S., et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis // Arthritis Rheum. – 1988. – Vol. 31. – P. 315-324.Boyum A. Isolation of leucocytes from human blood. A two-phase system for removal of red cells with methylcellulose as erythrocyte-aggregating agent // Scand. J. Clin. Lab. Invest. Suppl. – 1968. – Vol. 97. – P. 9-29.Boyum A. Isolation of leucocytes from human blood. A two-phase system for removal of red cells with methylcellulose as erythrocyte-aggregating agent // Scand. J. Clin. Lab. Invest. Suppl. – 1968. – Vol. 97. – P. 9-29.Greenwood J., Steinman L., Zamvil S.S. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation // Nat. Rev. Immunol. – 2006. – Vol. 6. – P. 358-370.Greenwood J., Steinman L., Zamvil S.S. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation // Nat. Rev. Immunol. – 2006. – Vol. 6. – P. 358-370.Kim W.U.,Kim K.J. T cell proliferative response to type II collagen in the inflammatory process and joint damage in patients with rheumatoid arthritis // J. Rheumatol. – 2005. – Vol. 32. – P. 225-230.Kim W.U.,Kim K.J. T cell proliferative response to type II collagen in the inflammatory process and joint damage in patients with rheumatoid arthritis // J. Rheumatol. – 2005. – Vol. 32. – P. 225-230.Koopman W.J., Arthritis and allied conditions: a textbook of rheumatology. – Philadelphia: Lippincot Williams and Wilkins, 2001. – P. 1091-1094.Koopman W.J., Arthritis and allied conditions: a textbook of rheumatology. – Philadelphia: Lippincot Williams and Wilkins, 2001. – P. 1091-1094.Kwak B., Mulhaupt F., Myit S., Mach F. Statins as a newly recognized type of immunomodulator // Nat. Med. – 2000. – Vol. 6. – P. 1399-1402.Kwak B., Mulhaupt F., Myit S., Mach F. Statins as a newly recognized type of immunomodulator // Nat. Med. – 2000. – Vol. 6. – P. 1399-1402.Leung B.P., Sattar N., Crilly A., Prach M., McCarey D.W., Payne H., Madhok R., Campbell C., Gracie J.A., Liew F.Y., McInnes I.B. A novel anti-inflammatory role for simvastatin in inflammatory arthritis // J. Immunol. – 2003. – Vol. 170. – P. 1524-1530.Leung B.P., Sattar N., Crilly A., Prach M., McCarey D.W., Payne H., Madhok R., Campbell C., Gracie J.A., Liew F.Y., McInnes I.B. A novel anti-inflammatory role for simvastatin in inflammatory arthritis // J. Immunol. – 2003. – Vol. 170. – P. 1524-1530.McCarey D.W., McInnes I.B., Madhok R., Hampson R., Scherbakov O., Ford I., Capell H.A., Sattar N. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial // Lancet. – 2004. – Vol. 363. – P. 2015-2021.McCarey D.W., McInnes I.B., Madhok R., Hampson R., Scherbakov O., Ford I., Capell H.A., Sattar N. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial // Lancet. – 2004. – Vol. 363. – P. 2015-2021.Neuhaus O., Strasser-Fuchs S., Fazekas F., Kieseier B.C., Niederwieser G., Hartung H.P., Archelos J.J. Statins as immunomodulators: comparison with interferon-beta 1b in MS // Neurology. – 2002. – Vol. 59. – P. 990-997.Neuhaus O., Strasser-Fuchs S., Fazekas F., Kieseier B.C., Niederwieser G., Hartung H.P., Archelos J.J. Statins as immunomodulators: comparison with interferon-beta 1b in MS // Neurology. – 2002. – Vol. 59. – P. 990-997.Prevoo M.L., van't Hof M.A., Kuper H.H., van Leeuwen M.A., van de Putte L.B., van Riel P.L. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis // Arthritis Rheum. – 1995. – Vol. 38. – P. 44-48.Prevoo M.L., van't Hof M.A., Kuper H.H., van Leeuwen M.A., van de Putte L.B., van Riel P.L. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis // Arthritis Rheum. – 1995. – Vol. 38. – P. 44-48.Veillard N.R., Braunersreuther V., Arnaud C., Burger F., Pelli G., Steffens S., Mach F. Simvastatin modulates chemokine and chemokine receptor expression by geranylgeranyl isoprenoid pathway in human endothelial cells and macrophages // Atherosclerosis. – 2006. – Vol. 188. – P. 51-58.Veillard N.R., Braunersreuther V., Arnaud C., Burger F., Pelli G., Steffens S., Mach F. Simvastatin modulates chemokine and chemokine receptor expression by geranylgeranyl isoprenoid pathway in human endothelial cells and macrophages // Atherosclerosis. – 2006. – Vol. 188. – P. 51-58.Vollmer T., Key L., Durkalski V., Tyor W., Corboy J., Markovic-Plese S., Preiningerova J., Rizzo M., Singh I. Oral simvastatin treatment in relapsing-remitting multiple sclerosis // Lancet. – 2004. – Vol. 363. – P. 1607-1608.Vollmer T., Key L., Durkalski V., Tyor W., Corboy J., Markovic-Plese S., Preiningerova J., Rizzo M., Singh I. Oral simvastatin treatment in relapsing-remitting multiple sclerosis // Lancet. – 2004. – Vol. 363. – P. 1607-1608.Weitz-Schmidt G., Welzenbach K., Brinkmann V., Kamata T., Kallen J., Bruns C., Cottens S., Takada Y., Hommel U. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site // Nat. Med. – 2001. – Vol. 7. – P. 687-692.Weitz-Schmidt G., Welzenbach K., Brinkmann V., Kamata T., Kallen J., Bruns C., Cottens S., Takada Y., Hommel U. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site // Nat. Med. – 2001. – Vol. 7. – P. 687-692.Yokota K., Miyazaki T., Hirano M., Akiyama Y., Mimura T. Simvastatin inhibits production of interleukin 6 (IL-6) and IL-8 and cell proliferation induced by tumor necrosis factor-alpha in fibroblast-like synoviocytes from patients with rheumatoid arthritis // J. Rheumatol. – 2006. – Vol. 33. – P. 463-471.Yokota K., Miyazaki T., Hirano M., Akiyama Y., Mimura T. Simvastatin inhibits production of interleukin 6 (IL-6) and IL-8 and cell proliferation induced by tumor necrosis factor-alpha in fibroblast-like synoviocytes from patients with rheumatoid arthritis // J. Rheumatol. – 2006. – Vol. 33. – P. 463-471.Yoshida M., Tsuji M., Kurosaka D., Kurosaka D., Yasuda J., Ito Y., Nishizawa T., Yamada A. Autoimmunity to citrullinated type II collagen in rheumatoid arthritis // Mod. Rheumatol. – 2006. – Vol. 16. – P. 276-281.Yoshida M., Tsuji M., Kurosaka D., Kurosaka D., Yasuda J., Ito Y., Nishizawa T., Yamada A. Autoimmunity to citrullinated type II collagen in rheumatoid arthritis // Mod. Rheumatol. – 2006. – Vol. 16. – P. 276-281.

The authors declare that there are no conflicts of interest present.