Взаимосвязь содержания Трегуляторных клеток, активности и уровня сывороточных аутоантителу больных системной красной волчанкой на фоне ритуксимабом
Аннотация
Цель. Выявить изменения количества CD+CD25+FoxP3+ T регуляторных клеток (Т рег) у больных СКВ, получающих ритуксимаб, и определить взаимосвязь содержа- ния Т рег с изменением активности заболевания и уровнем сывороточных аутоантител на фоне лечения. Материал и методы. Включены 12 пациенток с доставерной СКВ. ср. возраст больных 30,5±9,8 лет (Me – 31 лет, диапазон от 18 до 49 лет), продолжительность болезни 7-148 мес. Больные обследовались до начала лечения, через 1,3, 6 мес. Активность СКВ оценивали с помощью шкалы SLEDAI 2К. Помимо рутинных лабораторныхисследований определялись антитела к двухспиральной ДНК, количество В лимфоцитов и Трег клеток методом флоуцитометрии. Ритуксимаб вводился еженедельно внутривенно капельно по 500 мг в течение 4-х недель, у 4 больных проведена комбинированная терапия с циклофосфаном. Результаты. Количество Т-рег до начала терапии не было снижено. Не обнаружено корреляции между количеством Т-рег клеток и уровнем антител к ДНК. Корреляционный анализ показал значимую связь динамики маркеров Т-рег (Foxp3+, CD25+, CD4+CD25+), а также значения активности СКВ по SLEDAI 2K после завершения лечения с наличием клинического ответа на терапию ритуксимабом через 3 мес. Модель бинарной логистической регрессии с включением указанных 4 предикторов в совокупности способна корректно предсказать клинический ответ на терапию в 83% случаев. Заключение. Изменение количества СD25+, CD4+CD25+, СD4+CD25+FoxP3+ T клеток сразу после окончания лечения коррелировало с клиническим эффектом терапии ритуксимабом и определяло последующий ответ на анти-В-клеточную терапию больных СКВ.
Список литературы
1. <div><p>Tsokos G.C.,Wong H.K., Enyedy E.J. et al. Immune cell signaling in lupus. Curr. Opin. Rheumatol, 2000, 12, 355–63.</p><p>Shevach E.M., McHugh R.S., Piccirillo C.A., Thornton A.M. Control of T-cell activation by CD4+ CD25+ sup- pressor T cells. Immunol Rev, 2001,182,58-67.</p><p>Hall B.M., Pearce N.W., Gurley K.E. et al. Specific unresponsiveness in rats with prolonged cardiac allograft after treatment with cyclosporine. III. Further characterization of the CD4+ suppressor cell and its mechanisms of action. J. Exp. Med., 1990, 171,141- 57.</p><p>Sakaguchi S., Sakaguchi N., Asano M. et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol., 1995, 155, 1151-64.</p><p>Bluestone J.A., Abbas A.K., Natural versus adap- tive regulatory T cells. Nat. Rev. Immunol., 2003, 3, 253–57.</p><p>Piccirillo C.A., Thornton A.M. Cornerstone of peripheral tolerance: naturally occurring CD4+CD25+ regulatory T cells. Trends Immunol., 2004, 25, 374–80.</p><p>Von Boehmer H. Mechanisms of suppression by suppressor T cells. Nat. Immunol., 2005, 6, 338–44.</p><p>Thompson C.B., Allison J.P. The emerging role of CTLA-4 as an immune attenuator. Immunity, 1997, 7, 445-50.</p><p>Grossman W.J., Verbsky J.W., Barchet W. et al. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity, 2004, 21, 589-601.</p><p>Dieckmann D., Bruett C.H., Ploettner H. et al. Human CD4+CD25+ regulatory, contact-dependent T cells induce IL-10 producing, contact-independent type 1-like regulatory T cells. J. Exp. Med., 2002, 196, 247-53.</p><p>Thornton A.M., Shevach E.M. CD4+CD25+ immuno- regulatory T cells suppress polyclonal T-cell activation in vitro by inhibiting interleukin-2 production. J. Exp. Med., 1998, 188, 287–96.</p><p>Baecher-Allan C., Brown J.A., Freeman G.J. et al. CD4+CD25high regulatory cells in human peripheral blood. J. Immunol., 2001, 167(3), 1245-53.</p><p>Fontenot J.D., Gavin M.A., Rudensky A.Y., Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol., 2003, 4(4), 330-6.</p><p>Hori S., Nomura T., Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science, 2003, 299(5609), 1057-61.</p><p>Bennett C.L., Christie J., Ramsdell F. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet., 2001, 27(1), 20-1.</p><p>Wolf D., Hochegger K., Wolf A.M. et al. CD4+CD25+ regulatory T cells inhibit experimental anti-glomerular basement membrane glomerulonephritis in mice, J. Am. Soc. Nephrol., 16, 2005, 1360–70.</p><p>Liu M.F., Wang C.R., Fung L.L. et al. Decreased CD4+CD25+ T cells in peripheral blood of patients with systemic lupus erythematosus. Scand. J. Immunol., 2004, 59, 198–202.</p><p>Crispin J.C., Martinez A., Alcocer-Varela J. Quantification of regulatory T cells in patients with systemic lupus erythematosus. J. Autoimmun., 2003, 21, 273–6.</p><p>Miyara M., Amoura Z., Parizot C. et al. Global natu- 8 ral regulatory T cell depletion in active systemic lupus erythematosus. J. Immunol., 2005, 175, 8392–400.</p><p>Alvarado-Sanchez B., Hernandez-Castro B., Portales- Perez D. et al. Regulatory T cells in patients with sys- temic lupus erythematosus. J. Autoimmun., 2006, 27, 110-8.</p><p>Suarez A., Lopez P., Gomez J. et al. Enrichment of CD4+CD25high T cell population in SLE patients treated with glucocorticoids. Ann. Rheum. Dis., 2006, 65(11), 1512-7.</p><p>Hochberg M. C. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematotosus. Arthr. Rheum., 1997,40, 1725.</p><p>Vitali C., Bencivelli W., Isenberg D. A. et al. Disease activity in SLE: report of the Consensus Study Group of the European Workshop for Rheumatology Research. II Identification of the variables indicative of disease activity and their use in the development of an activity score. The European Consensus Study Group for Disease Activity in SLE. Clin. Exp. Rheumatol., 1992,10, 541-47.</p><p>Vallerskog T., Gunnarsson I., Widhe M. et al. Treatment with rituximab affects both the cellular and the humoral arm of the immune system in patients with SLE. Clin. Immun., 2007, 122, 62-74.</p><p>Sfikakis P.P., Boletis J.N., Lionaki S. et al. Remission of proliferative lupus nephritis following B cell deple- tion therapy is preceded by down-regulation of the T cell costimulatory molecule CD40 ligand: an open-label trial. Arthritis Rheum., 2005, 52, 501–13.</p><p>Sfikakis P.P., Souliotis V.L., Fragiadaki K.G. et al. Increased expression of the FoxP3 functional marker of regulatory T cells following B cell depletion with rituximab in patients with lupus nephritis. Clin. Immun., 2007, 123, 66-73.</p><p>Vigna-Perez M., Hernandez-Castro B., Paredes-Saharopulos O. et al. Clinical and immunological effects of rituximab in patients with lupus nephritis refractory to conventional therapy: a pilot study. Arthritis Res. Ther., 2006, 8, R83.</p><p>Douek D.C., Vescio R.A., Betts M.R. et al. Assessment of thymic output in adults after hematopoietic stem cell transplantation and prediction of T-cell reconstitution. Lancet, 2000, 355, 1875–81.</p><p>Pawelec G., Barnett Y., Forsey R. et al. Tcells and aging. Front. Biosci., 2002, 7, 1056–183.</p><p>Sfikakis P.P., Gourgoulis G.M., Moulopoulos L.A. et al. Age-related thymic activity in adults following chemotherapy-induced lymphopenia. Eur. J. Clin. Invest., 2005, 35, 380–7.</p><p>Tone M., Tone Y., Adams E. et al. Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells. Proc. Natl. Acad. Sci. USA, 2003, 100, 15059-64.</p><p>Shevach E.M. Regulatory/suppressor T cells in health and disease. Arthritis Rheum., 2004, 50, 2721-4.</p><p>Ehrenstein M.R., Evans J.G., Singh A. et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNF-alpha therapy. J. Exp. Med., 2004, 200, 277-85.</p><p>Monk C.R., Spachidou M., Rovis F. et al. MRL/Mp CD4+, CD25- T cells show reduced sensitivity to suppression by CD4+CD25+ regulatory T cells in vitro: a novel defect of T cell regulation in systemic lupus erythematosus. Arthritis Rheum., 2005, 52, 1180-4.</p><p>Wohlfert E.A., Gorelik L., Mittler R. et al. Deficiency in the E3 ubiquitin ligase Cbl-b results in a multifunc- tional defect in T cell TGF-β sensitivity in vitro and in vivo. J. Immunol., 2006, 176, 1316-20.</p><p>Leandro M.J., Cambridge G., Edwards J.C. et al. B-cell depletion in the treatment of patients with systemic lupus erythematosus: a longitudinal analysis of 24 patients. Rheumatology, 2005, 44, 1542-5.</p><p>Albert D., Dunham J., Khan S. et al. Variability in the biological response to anti-CD20 B-cell depletion in SLE. Ann. Rheum. Dis., 2008, 67(12),1724-31.</p><p>Cambridge G., Leandro M.J., Teodorescu M. et al. B Cell Depletion therapy in systemic lupus erythematosus, effect on autoantibody and antimicrobial antibody profiles. Arthritis Rheum., 2006, 11, 3612-22.</p><p>Tokunaga M., Saito K., Kawabata D. et al. Efficacy of rituximab (anti-CD20) for refractory systemic lupus erythematosus involving the central nervous system. Ann. Rheum. Dis., 2007, 66, 470–5.</p><p>Looney R.J., Anolik J.H., Campbell D., et al. B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab. Arthritis Rheum., 2004, 50, 2580–9</p></div><br />
Для цитирования:
Torgashina A.V. Взаимосвязь содержания Трегуляторных клеток, активности и уровня сывороточных аутоантителу больных системной красной волчанкой на фоне ритуксимабом. Научно-практическая ревматология. 2009;47(2):3-9. https://doi.org/10.14412/1995-4484-2009-452
For citation:
Torgashina A.V. Relationship of T regulatory cells content, activity and serum autoantibodies level in patients with systemic lupus erythematosus receiving rituximab. Rheumatology Science and Practice. 2009;47(2):3-9. (In Russ.) https://doi.org/10.14412/1995-4484-2009-452
Просмотров: 542
Послать статью по эл. почте 
