mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-PFO-2875mimmun-2875Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESФенотипические свойства дендритных клеток при различных вариантах стимуляции созреванияPhenotypic features of dendritic cells when using different modes of their stimulated maturationФадеевФ. А.FadeyevF. A.

Фадеев Федор Алексеевич – кандидат биологических наук, доцент, заведующий лабораторией клеточных культур.

620026, Екатеринбург, ул. Карла Маркса, 22а

Тел.: 8 (912) 618-24-97, Факс: 8 (343) 355-62-40

Fedor A. Fadeyev - PhD (Biology), Associate Professor, Chief of Laboratory, Institute of Medical Cell Technologies.

22a Carl Marx St Ekaterinburg 620026

Phone: +7 (912) 618-24-97, Fax: +7 (343) 355-62-40

fdf79@mail.ruАлександроваА. Д.AleksandrovaA. D.

Александрова Анастасия Дмитриевна – младший научный сотрудник лаборатории клеточных культур.

Екатеринбург

Anastasia D. Aleksandrova - Junior Research Associate, Institute of Medical Cell Technologies.

Ekaterinburg

anastasia.nikanorova@yandex.ruМогиленскихА. С.MogilenskikhA. S.

Могиленских Анна Сергеевна – научный сотрудник лаборатории клеточных культур.

Екатеринбург

Anna S. Mogilenskikh - Research Associate, Institute of Medical Cell Technologies.

Ekaterinburg

annasajler@yandex.ruГАУЗ СО «Институт медицинских клеточных технологий»РоссияInstitute of Medical Cell TechnologiesRussian Federation202415112023262253262Copyright © Фадеев Ф.А., Александрова А.Д., Могиленских А.С., 20242024Фадеев Ф.А., Александрова А.Д., Могиленских А.С.Fadeyev F.A., Aleksandrova A.D., Mogilenskikh A.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/2875

Дендритные клетки, полученные из моноцитов периферической крови, могут использоваться для клеточной иммунотерапии онкологических заболеваний. Чаще всего для иммунотерапии используют зрелые ДК, сенсибилизированные опухолеассоциированными антигенами. Функциональная активность ДК при иммунотерапии во многом определяется их иммунофенотипом и секреторным профилем, формирующимися после созревания. Целью данной работы являлась оценка фенотипических свойств ДК при стимуляции созревания различными способами.

Стимуляция созревания ДК осуществлялась с использованием провоспалительных цитокинов и их смесей, а также лигандов дендритноклеточных TLRs. Для стимуляции были использованы: TNF, poly I:C, LPS, цитокиновый коктейль (TNF + IL-1 + IL-6 + PGE2), коктейль в смеси с poly I:C, а также лизат клеток меланомы. Через 48 часов после стимуляции созревания оценивали уровень экспрессии ДК-рецепторов, принимающих участие во взаимодействии с Т-лимфоцитами, используя метод проточной цитофлуориметрии. Также оценивали секрецию клетками IL-12 (активатора Т-клеточного иммунного ответа) и IL-10 (ингибитора Т-клеточного иммунного ответа) с помощью ИФА.

Нами было показано, что ДК, полученные после стимуляции цитокиновым коктейлем, демонстрируют наиболее высокий уровень экспрессии рецепторов, необходимых для взаимодействия с Т-лимфоцитами и активации клеточного звена иммунитета: антигенпрезентирующих (HLA-DR), костимулирующих (CD83, CD40, CD86) и рецепторов, контролирующих миграцию ДК в лимфоузлы (CCR7). Кроме того, стимулированные с помощью коктейля ДК активно секретируют как IL-12, так и IL-10. Эффект от применения TNF и poly I:C был умеренным: экспрессия большинства рецепторов была существенно ниже, чем при использовании коктейля; достоверных отличий от контроля (без стимуляции созревания) по уровню секреции IL-12 выявлено не было. LPS и лизат клеток меланомы практически не оказали влияния как на иммунофенотип, так и на секреторный профиль ДК. Добавление к цитокиновому коктейлю poly I:C практически не оказало влияния на рецепторный пейзаж ДК, но привело к значительному увеличению секреции как провоспалительного IL-12, так и противовоспалительного IL-10.

Полученный результат позволяет предварительно рассматривать смесь цитокинового коктейля с poly I:C как наиболее эффективное средство для стимуляции созревания ДК. В то же время требуются дальнейшие эксперименты по сравнению функциональной активности ДК, полученных с использованием разных способов стимуляции созревания.

Monocyte-derived dendritic cells (DCs) can be used for cell immunotherapy of cancer. In most cases, mature DCs, loaded with tumor-associated antigens, are used for immune therapy. The functionality of DCs for immunotherapy substantially depends on their immunophenotype and secretory profile, which are established after DCs maturation. The purpose of this research was to explore the phenotype of DCs after using various approaches for stimulation of their maturation.

Maturation of DCs was stimulated by pro-inflammatory cytokines and their mixtures, or by ligands to the TLRs of DCs. DCs were stimulated by the following means: TNF; poly I:C; LPS; cytokine cocktail (TNF + IL-1 + IL-6 + PGE2); the cocktail mixed with poly I:C; and melanoma cells lysate. Forty-eight hours after stimulation, the expression of DCs’ receptors involved into their interaction with T cells, was evaluated by flow cytometry. Moreover, the secretion of IL-12 (activator of T cell response) and IL-10 (inhibitor of T cell response) was estimated by ELISA technique.

We have shown that, following stimulation with cytokine cocktail, the DCs exhibit highest expression of receptors, which are necessary for interaction with T cells and for activation of T cell mediated immune response, i.e., antigen-presenting receptors (HLA-DR), co-stimulatory receptors (CD83, CD40, CD86), and receptors controlling the migration of DCs to lymph nodes (CCR7). Moreover, the cocktail-stimulated DCs intensively secrete both IL-12 and IL-10. The stimulatory effect of TNF and poly I:C proved to be moderate: the expression of most receptors was significantly lower than after using the cocktail; no significant differences from control (in absence of induced maturation) in IL-12 secretion were detected. LPS and melanoma cell lysate did not affect both expression of receptors and secretory profile of DCs. Addition of poly I:C to the cytokine cocktail did not affect the receptor expression, but significantly increased the secretion of both proinflammatory IL-12 and anti-inflammatory IL-10.

The results of experiments demonstrate that the mixture of cytokine cocktail and poly I:C seems to be the most effective tool for stimulation of DCs maturation. However, further experiments are required to compare the functionality of DCs when using different tools for induced DC maturation.

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