mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-2017-4-387-400mimmun-1310Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESИНДУКЦИЯ Т-КЛЕТОЧНОГО ИММУННОГО ОТВЕТА У ПАЦИЕНТОВ С ХРОНИЧЕСКИМ ГЕПАТИТОМ С НА ФОНЕ ИММУНОТЕРАПИИ ДЕНДРИТНЫМИ КЛЕТКАМИINDUCTION OF T-CELL IMMUNE RESPONSE IN CHRONIC HCV-INFECTED PATIENTS WITH UNDERLYING DENDRITIC CELL IMMUNOTHERAPYР.Черных Е.ChernykhE. R.

Черных Елена Рэмовна – доктор медицинских наук, профессор, член-корр. РАН, заведующая  лабораторией клеточной иммунотерапии.

630099, Новосибирск, ул. Ядринцевская, 14, тел.: 8 (383) 236-03-29, факс: 8 (383) 222-70-28

PhD, MD (Medicine), Professor, Corresponding Member, Russian Academy of Sciences, Head, Laboratory of Cellular Immunotherapy.

Novosibirsk

ct_lab@mail.ruОлейникЕ. А.OleynikE. A.

Аспирант лаборатории клеточной иммунотерапии.

Новосибирск

Postgraduate Student,  Laboratory of Cellular Immunotherapy.

Novosibirsk

ЛеплинаО. Ю.LeplinaO. Yu.

Доктор медицинских наук, ведущий научный сотрудник лаборатории клеточной иммунотерапии.

Новосибирск

PhD, MD (Medicine), Leading Research Associate, Laboratory of Cellular Immunotherapy.

Novosibirsk

ТихоноваМ. А.TikhonovaM. A.

Кандидат биологических наук,  старший научный сотрудник лаборатории клеточной иммунотерапии.

Новосибирск

PhD (Biology), Senior Research Associate, Laboratory of Cellular Immunotherapy.

Novosibirsk

КурочкинаЮ. Д.KurochkinaYu. D.

Аспирант лаборатории клеточной иммунотерапии, врач-ревматолог клиники иммунопатологии.

Новосибирск

Postgraduate Student,  Laboratory of Cellular Immunotherapy, Physician (Rheumatology), Clinics of Immunopathology.

Novosibirsk

СтаростинаН. М.StarostinaN. M.

Кандидат медицинских наук, заслуженный врач РФ, заведующая  отделением иммунологии  Клиники иммунопатологии.

Новосибирск

PhD (Medicine), Honored Doctor of Russian Federation, Head, Immunology Department, Clinics of Immunopathology.

Novosibirsk

ОстанинА. А.OstaninА. А.

Доктор медицинских наук, профессор, главный научный сотрудник лаборатории клеточной иммунотерапии.

Новосибирск

PhD, MD (Medicine), Professor, Main Research Associate, Laboratory of Cellular Immunotherapy.

Novosibirsk

ФГБНУ «Научно-исследовательский институт фундаментальной и клинической иммунологии»РоссияResearch Institute of Fundamental and Clinical ImmunologyRussian Federation201730082017194387400Copyright © Р. Ч.Е., Олейник Е.А., Леплина О.Ю., Тихонова М.А., Курочкина Ю.Д., Старостина Н.М., Останин А.А., 20172017Р. Ч.Е., Олейник Е.А., Леплина О.Ю., Тихонова М.А., Курочкина Ю.Д., Старостина Н.М., Останин А.А.Chernykh E.R., Oleynik E.A., Leplina O.Y., Tikhonova M.A., Kurochkina Y.D., Starostina N.M., Ostanin А.А.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/1310

Ключевая роль Т-клеток в элиминации вируса и отсутствие сильного Т-клеточного ответа у больных хроническим гепатитом С (ХГС)  позволяет рассматривать активацию антиген-специфических  Т-клеток в качестве перспективного подхода  к повышению эффективности лечения. Учитывая центральную роль  дендритных клеток (ДК) в индукции Т-клеточного ответа,  целью  исследования  явилась оценка влияния иммунотерапии ДК на показатели иммунитета у больных ХГС.  Десять пациентов с хронической HCV-инфекцией (генотип 1) были  вакцинированы ДК,  генерируемыми из моноцитов в присутствии интерферона-α (IFN-ДК) и нагруженными рекомбинантными белками Core (1–120) и NS3 (1192–1457). Вакцинотерапия включала инициирующий (4 вакцинации с недельным  интервалом) и поддерживающий (6 вакцинаций с месячным интервалом) курс с последующим периодом 6-месячного наблюдения. Проведение иммунотерапии ДК  не сопровождалось развитием тяжелых нежелательных явлений, выраженных поствакцинальных реакций или  возрастанием биохимических проявлений активности гепатита. Исследования ex vivo показали, что  иммунотерапия ДК приводила к индукции выраженного устойчивого иммунного ответа  на Core и умеренного ответа на  NS3,  что  проявлялось значимым возрастанием пролиферации и продукции IFNγ при  стимуляции  МНК Core  и усилением продукции IFNγ (при  отсутствии достоверного возрастания пролиферативного ответа) при  стимуляции МНК NS3.  Иммунотерапия ДК  также  приводила к возрастанию до  нормативных значений КонА-индуцированной пролиферации МНК,  свидетельствуя о восстановлении митогенной реактивности Т-клеток. В то же время активация Т-клеточного ответа  не сопровождалась индукцией антиген-специфических Th2-клеток и не приводила к генерации регуляторных СD4+CD25+CD127-Т-клеток. Несмотря на индукцию иммунного ответа,  иммунотерапия ДК не сопровождалась значимым снижением виремии. Тем не менее  преходящее уменьшение вирусной нагрузки у 4 пациентов и стойкое снижение виремии у двух, а также  наличие обратной взаимосвязи между NS3-специфическим пролиферативным ответом и уровнем вирусной нагрузки (Rs = 0,62; p < 0,05) (на момент завершения 6-месячного наблюдения) указывает на способность антиген-специфических Т-клеток ограничивать репликацию вируса.

A key role of T cells in viral elimination and  absence  of strong  T cell responses  in patients with chronic hepatitis C virus (HCV) infection presumes that activation of antigen-specific T cells may be a promising approach to enhance treatment efficacy. Given the central role of dendritic cells (DCs) in the induction of T cell response, the aim of our study was to evaluate  effects of DC immunotherapy upon  immunological parameters in chronic HCV infection. Ten patients with chronic hepatitis C (genotype 1) were vaccinated with monocytederived DCs, generated in presence of IFNα (IFN-DCs) and pulsed with recombinant HCV Core (1–120) and NS3 (1192–1457) proteins. The vaccination protocol included as initiating procedure (one injection per week, ns = 4) and maintaining treatment (one  monthly injection, ns = 6), with subsequent follow up for 6 months. The immunotherapy was not associated with serious adverse events,  significant  post-vaccination reactions, or increased hepatitis C activity, according to biochemical tests. Ex vivo studies have shown that immunotherapy elicited  strong and stable immune response  to Core and moderate response  to NS3 protein, which manifested as a significant  increase  of MNC proliferation and  IFNγ production in response  to Core  and  enhancement of IFNγ production (without higher  proliferation rates),  in response  to NS3.  DC  immunotherapy also led to increase  of ConA-induced MNC proliferation up  to normal levels indicating a recovery  of mitogenic T cell  reactivity. Meanwhile, T cell  activation did  not  elicit  antigen-specific Th2  response  and  expansion of CD4+CD25+CD127  regulatory T cells.  Despite induced immune response, the  immunotherapy with  DCs was not  accompanied by decreased viremia  levels. Nevertheless, a transitory decrease of viral load  in four patients and stable decrease of viremia  in two patients as well as an inverse correlation between  NS3-specific proliferation and viremia  (Rss = 0.62; p < 0.05) by the end of 6-month follow-up indicated that  the antigenspecific T cells may have a potential to control viral replication.

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