Effects of human exogenous DNA on production of perforin-containing CD8+ cytotoxic lymphocytes in laboratory setting and clinical practice

Alyamkina, E. A.; Леплина, О. Ю.; Останин, А. А.; Черных, Е. Р.; Николин, В. П.; Попова, Н. А.; Proskurina, Anastasia S.; Gvozdeva, Tatiana S.; Долгова, Е. В.; Orishchenko, Кonstantin E.; Рогачев, В. А.; Sidorov, S. V.; Вараксин, Н. А.; Ryabicheva, T. G.; Богачев, С. С.; Shurdov, Mikhail A.

doi:10.1016/j.cellimm.2012.04.004

Cited by 11 publications

(9 citation statements)

References 32 publications

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“…DNA-based immunomodulators have been shown to display synergistic effects with standard cytostatic drugs used in the clinics [ 4 , 54 , 55 ]. Consistently, we also reported that human dsDNA-based medication has a pronounced anti-cancer effect when combined with doxorubicin and cyclophosphamide [ 8 , 12 , 13 ].…”

Section: Resultssupporting

confidence: 64%

“…When fragmented dsDNA was injected in tumor-engrafted mice following cyclophosphamide or cyclophosphamide and doxorubicin administration, significant antitumor activity was observed [ 13 ]. We speculate that the most likely scenario describing suppression of tumor growth in these in vivo experiments involves activation of key immune system components, namely that of adaptive immunity, which is primarily characterized by production of CD8 + perforin + cytotoxic T cells [ 8 ]. We can not formally exclude yet another option, i.e.…”

Section: Resultsmentioning

confidence: 99%

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Results of multicenter double-blind placebo-controlled phase II clinical trial of Panagen preparation to evaluate its leukostimulatory activity and formation of the adaptive immune response in patients with stage II-IV breast cancer

et al. 2015

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BackgroundWe performed a multicenter, double-blind, placebo-controlled, phase II clinical trial of human dsDNA-based preparation Panagen in a tablet form. In total, 80 female patients with stage II-IV breast cancer were recruited.MethodsPatients received three consecutive FAC (5-fluorouracil, doxorubicin and cyclophosphamide) or AC (doxorubicin and cyclophosphamide) adjuvant chemotherapies (3 weeks per course) and 6 tablets of 5 mg Panagen or placebo daily (one tablet every 2–3 hours, 30 mg/day) for 18 days during each chemotherapy course. Statistical analysis was performed using Statistica 6.0 software, and non-parametric analyses, namely Wilcoxon-Mann–Whitney and paired Wilcoxon tests. To describe the results, the following parameters were used: number of observations (n), median, interquartile range, and minimum-maximum range.ResultsPanagen displayed pronounced leukostimulatory and leukoprotective effects when combined with chemotherapy. In an ancillary protocol, anticancer effects of a tablet form of Panagen were analyzed. We show that Panagen helps maintain the pre-therapeutic activity level of innate antitumor immunity and induces formation of a peripheral pool of cytotoxic CD8+ perforin + T-cells. Our 3-year follow-up analysis demonstrates that 24% of patients who received Panagen relapsed or died after the therapy, as compared to 45% in the placebo cohort.ConclusionsThe data collected in this trial set Panagen as a multi-faceted “all-in-one” medicine that is capable of simultaneously sustaining hematopoiesis, sparing the innate immune cells from adverse effects of three consecutive rounds of chemotherapy and boosting individual adaptive immunity. Its unique feature is that it is delivered via gastrointestinal tract and acts through the lymphoid system of intestinal mucosa. Taken together, maintenance of the initial levels of innate immunity, development of adaptive cytotoxic immune response and significantly reduced incidence of relapses 3 years after the therapy argue for the anticancer activity of Panagen.Trial registrationClinicalTrials.gov NCT02115984 from 04/07/2014.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1142-z) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 64%

Section: Resultsmentioning

confidence: 99%

Results of multicenter double-blind placebo-controlled phase II clinical trial of Panagen preparation to evaluate its leukostimulatory activity and formation of the adaptive immune response in patients with stage II-IV breast cancer

et al. 2015

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“…Our earlier studies of how extracellular exogenous dsDNA contributes to the activation of professional properties of antigen-presenting dendritic cells and establishment of anticancer CD8 + −mediated antitumor immunity reported a number of puzzling effects unrelated to the development of immune response. Namely, we observed significantly suppressed proliferation of tumors grafts in either solid or ascites forms [ 49 - 54 ]. We found that upon consecutive treatment with CP and dsDNA, there is a short period of time after CP injection when administration of dsDNA causes direct toxicity to the cells of engrafted tumor.…”

Section: Resultsmentioning

confidence: 99%

Combination of cyclophosphamide and double-stranded DNA demonstrates synergistic toxicity against established xenografts

et al. 2015

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BackgroundExtracellular double-stranded DNA participates in various processes in an organism. Here we report the suppressive effects of fragmented human double-stranded DNA along or in combination with cyclophosphamide on solid and ascites grafts of mouse Krebs-2 tumor cells and DNA preparation on human breast adenocarcinoma cell line MCF-7.MethodsApoptosis and necrosis were assayed by electrophoretic analysis (DNA nucleosomal fragmentation) and by measurements of LDH levels in ascitic fluid, respectively. DNA internalization into MCF-7 was analyzed by flow cytometry and fluorescence microscopy.ResultsDirect cytotoxic activity of double-stranded DNA (along or in combination with cyclophosphamide) on a solid transplant was demonstrated. This resulted in delayed solid tumor proliferation and partial tumor lysis due to necrosis of the tumor and adjacent tissues. In the case of ascites form of tumor, extensive apoptosis and secondary necrosis were observed. Similarly, MCF-7 cells showed induction of massive apoptosis (up to 45%) as a result of treatments with double-stranded DNA preparation.ConclusionsDouble-stranded DNA (along or in combination with cyclophosphamide) induces massive apoptosis of Krebs-2 ascite cells and MCF-7 cell line (DNA only). In treated mice it reduces the integrity of gut wall cells and contributes to the development of systemic inflammatory reaction.Electronic supplementary materialThe online version of this article (doi:10.1186/s12935-015-0180-6) contains supplementary material, which is available to authorized users.

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“…Проведенное нами сравнительное исследо-вание показало, что получаемые в различных протоколах IL-4-ДК и IFN-ДК не различают-ся между собой по ключевым функциональным характеристикам, а именно -по способности 1) стимулировать пролиферацию Т-клеток на ал-лоантигены и 2) индуцировать генерацию Treg 3) экспрессируют молекулы B7-H1 и TRAIL [3] и отличаются более выраженной прямой ци-тотоксической активностью против клеток опу-холевой линии Jurkat [13]; 4) сохраняют функциональную стабильность и способны эффективно индуцировать реак-ции клеточного и гуморального иммунитета, поскольку активно секретируют Тh1/провос-палительные (IFNγ, IL 8) характеризуются способностью к акти-вации цитотоксических CD8 + Т-лимфоцитов, экспрессирующих внутриклеточно перфорин, при этом данная функциональная активность IFN-ДК может быть дополнительно усилена при использовании в качестве дозревающего стимула нативной ДНК человека [5].…”

Section: результатыunclassified

FUNCTIONAL ACTIVITY OF IFNα- AND IL-4-INDUCED HUMAN DENDRITIC CELLS: A COMPARATIVE STUDY

Леплина¹,

Тихонова²,

Тыринова³

et al. 2014

Med.Imm.Rus

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Адрес для переписки:Леплина Ольга Юрьевна д.м.н., ведущий научный сотрудник ФГБУ «НИИ клинической иммунологии » СО РАМН 630099, Россия, г. Новосибирск, ул. Ядринцевская, 14. Тел.: 8 (383) 236-03-29. E-mail: ct_lab@mail.ru Авторы: Леплина О.Ю. -д.м.н., ведущий научный сотрудник ФГБУ «НИИ клинической иммунологии» СО РАМН, г. Новосибирск, Россия Тихонова М.А.-к.б.н., старший научный сотрудник, ФГБУ «НИИ клинической иммунологии» СО РАМН, г. Новосибирск, Россия Тыринова Т.В. -к.б.н., научный сотрудник, ФГБУ «НИИ клинической иммунологии» СО РАМН, г. Новосибирск, Россия Алямкина Е.А. -к.б.н., научный сотрудник, ФГБУН «Институт цитологии и генетики» СО РАН, г. Новосибирск, Россия Богачев С.С. -д.б.н., заведующий лабораторией ФГБУН «Институт цитологии и генетики» СО РАН, г. Новосибирск, Россия Останин А.А. -д.м.н., профессор, главный научный сотрудник ФГБУ «НИИ клинической иммунологии» СО РАМН, г. Новосибирск, Россия Черных Е.Р. -д.м.н., профессор, член-корреспондент РАМН, заведующая Резюме. В работе проведена сравнительная оценка аллостимуляторной, Тh1-/Th2-стимулирующей и толерогенной активности дендритных клеток здоровых доноров (n = 52), генерированных in vitro в присутствии IFNα (IFN-ДК) и IL-4 (IL-4-ДК). Установлено, что IL-4-ДК и IFN-ДК не различаются между собой по ключевым функциональным характеристикам (способности стимулировать проли-ферацию Т-клеток на аллоантигены, индуцировать генерацию Treg в СКЛ и способности активиро-вать Т-клетки к продукции Th1/провоспалительных (IFNγ, IL-2, IL-1β, TNFα, IL-12, IL-17) и Th2/ противовоспалительных цитокинов (IL-4, IL-6, IL-10, IL-13), ростовых факторов (G-CSF, GM-CSF, IL-7) и хемокинов (IL-8, MIP-1β). Тем не менее, IFN-ДК оказывают более выраженный стимулиру-ющий эффект на Тh1-и Тh2-клетки, что проявляется достоверно более высоким уровнем продукции IFNγ, IL-5 и MIP-1β, а также обладают более выраженной Th1-стимуляторной и умеренной Th2-стимуляторной активностью (которая отсутствует у IL-4-ДК). Полученные данные обосновывают це-лесообразность использования IFN-ДК в качестве клеточной основы при создании лечебных вакцин для индукции/усиления иммунного ответа. Ключевые слова: дендритные клетки, аллостимуляторная активность, Тh1-/Th2-цитокины, регуляторные Т-клетки 44 Оригинальные статьиOriginal articles Медицинская иммунология 2014, Т. 16, № 1, стр. 43-52 © 2014, СПб РО РААКИ Medical Immunology 2014, Vol. 16, 1, pp. 43-52 © 2014 production. IFN-DCs were characterized by more prominent ability to activate Th1-cells, and by moderate Th2-stimulatory activity, which is absent in IL-4-DCs. These data strongly suggest that IFN-DCs may present a quite promising cellular tool for development of therapeutic vaccines aiming to induce/enhance the immune response.

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Effects of human exogenous DNA on production of perforin-containing CD8+ cytotoxic lymphocytes in laboratory setting and clinical practice

Cited by 11 publications

References 32 publications

Results of multicenter double-blind placebo-controlled phase II clinical trial of Panagen preparation to evaluate its leukostimulatory activity and formation of the adaptive immune response in patients with stage II-IV breast cancer

Results of multicenter double-blind placebo-controlled phase II clinical trial of Panagen preparation to evaluate its leukostimulatory activity and formation of the adaptive immune response in patients with stage II-IV breast cancer

Combination of cyclophosphamide and double-stranded DNA demonstrates synergistic toxicity against established xenografts

FUNCTIONAL ACTIVITY OF IFNα- AND IL-4-INDUCED HUMAN DENDRITIC CELLS: A COMPARATIVE STUDY

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