Perm Medical JournalPerm Medical JournalПермский медицинский журнал (сетевое издание "Perm medical journal")0136-14492687-1408Eco-Vector57032410.17816/pmj40549-60Original studiesОригинальные исследованияResearch ArticleSignificance of interleukins and chemokines in development of vincristine polyneuropathy in children with acute lymphoblastic leukemiaЗначение интерлейкинов и хемокинов в развитии винкристиновой полиневропатии у детей с острым лимфобластным лейкозомhttps://orcid.org/0000-0002-5250-73519919-9048KovtunO. P.КовтунО. П.
Russian Federation

MD, PhD, Professor, Academician of the Russian Academy of Sciences, Rector

доктор медицинских наук, профессор, академик РАН, ректор

usma@usma.ruhttps://orcid.org/0000-0002-4595-10244880-6913KoryakinaO. V.КорякинаО. В.
Russian Federation

Candidate of Medical Sciences, Associate Professor, Department of Nervous Diseases, Neurosurgery and Medical Genetics

кандидат медицинских наук, доцент кафедры нервных болезней, нейрохирургии и медицинской генетики

koryakina09@mail.ruhttps://orcid.org/0000-0003-0966-95714813-8710BazarnyiV. V.БазарныйВ. В.
Russian Federation

MD, PhD, Professor, Chief Researcher of the Central Research Laboratory

доктор медицинских наук, профессор, главный научный сотрудник Центральной научно-исследовательской лаборатории

vlad-bazarny@yandex.ruhttps://orcid.org/0000-0002-8665-52999225-0209RezaykinA. V.РезайкинА. В.
Russian Federation

Candidate of Medical Sciences, Associate Professor, Department of Medical Physics and Digital Technologies

кандидат медицинских наук, доцент кафедры медицинской физики и цифровых технологий

alexrez@yandex.ruUral State Medical UniversityУральский государственный медицинский университетRegional Children’s Clinical HospitalОбластная детская клиническая больница18102023405496015092023Copyright ©; 2023, Eco-VectorCopyright ©; 2023, Эко-Вектор2023Eco-VectorЭко-Векторhttps://permmedjournal.ru/PMJ/article/view/570324

Objective. To analyze the content of interleukins, chemokines in plasma and liquor of children with acute lymphoblastic leukemia depending on the development of vincristine polyneuropathy.

Materials and methods. A single-center prospective cohort non-randomized study was conducted involving 131 children aged 3 to 17 years with acute lymphoblastic leukemia who received chemotherapy according to the protocol. The content of interleukins and chemokines in blood plasma and liquor was assessed with the subsequent comparative analysis of the indicators in two groups depending on the development of vincristine polyneuropathy. The level of the studied parameters was determined before the administration of chemotherapy and on the 36th day of treatment using multiparametric immunofluorescence analysis.

Results. In the studied cohort of patients vincristine polyneuropathy was registered in 80.9 % (n = 106) of patients. In the majority of cases – 84.9 % (n = 90) neurotoxic complication developed during the induction stage of chemotherapy. In the clinical picture there dominated sensory and motor disorders in 70.7 % (n = 75) of patients. The data of electrophysiologic study testified to motor axonal polyneuropathy with peroneal nerves lesion. When comparing the primary level of interleukins with their concentration after completion of the induction stage of chemotherapy, it was found that in children without vincristine polyneuropathy there was a statistically significant increase in almost all proinflammatory and anti-inflammatory interleukins. Besides, in this group high and medium direct statistically significant correlations between these cytokines were established. Especially close correlations were noted between pro-inflammatory IL-1, IL-17 and anti-inflammatory interleukins (IL-10, IL-13, IL-22 and IL-27). Additionally, in patients with vincristine polyneuropathy, a 3.7-fold increase in CXCL10 (IP-10) and a 1.4-fold increase in CXCL12 (SDF-1α) chemokines (p = 0.005 and p = 0.054, respectively) was detected in the liquor during the completion of the induction phase of chemotherapy.

Conclusions. The balanced interleukin response in children with acute lymphoblastic leukemia receiving vincristine probably reflects a link between the immune and nervous systems aimed at preventing peripheral nerve damage. An imbalance of proinflammatory and anti-inflammatory interleukins may contribute to the development of vincristine polyneuropathy. Significant increase in the content of chemokines CXCL10 (IP-10) and CXCL12 (SDF-1α) in the liquor of children with vincristine polyneuropathy gives grounds to consider them as biological markers of vincristine neurotoxicity.

Цель. Проанализировать содержание интерлейкинов, хемокинов в плазме крови и ликворе у детей с острым лимфобластным лейкозом в зависимости от развития винкристиновой полиневропатии.

Материалы и методы. Проведено одноцентровое проспективное когортное нерандомизированное исследование с участием 131 ребёнка с острым лимфобластным лейкозом в возрасте от 3 до 17 лет, которые получали химиотерапию по протоколу. Оценивали в плазме крови и ликворе интерлейкины и хемокины с последующим сравнительным анализом показателей в двух группах в зависимости от развития винкристиновой полиневропатии. Содержание изучаемых показателей определяли до назначения химиотерапии и на 36-й день лечения с помощью мультипараметрического иммунофлюоресцентного анализа.

Результаты. В исследуемой когорте пациентов винкристиновая полиневропатия регистрировалась у 80,9 % (n = 106) больных. В большинстве случаев 84,9 % (n = 90) нейротоксическое осложнение развивалось на индукционном этапе химиотерапии. В клинической картине преобладали чувствительные и двигательные нарушения у 70,7 % (n = 75) пациентов. Данные электрофизиологического исследования свидетельствовали о моторной аксональной полиневропатии с поражением малоберцовых нервов. При сравнительном анализе первичного уровня интерлейкинов с их концентрацией после завершения индукционного этапа химиотерапии обнаружено, что у детей без винкристиновой полиневропатии наблюдалось статистически значимое повышение практически всех провоспалительных и противовоспалительных интерлейкинов. Также в этой группе между этими цитокинами установлены высокие и средние прямые статистически значимые корреляционные связи. Наиболее значимые корреляции отмечены между провоспалительными IL-1, IL-17 и противовоспалительными интерлейкинами (IL-10, IL-13, IL-22 и IL-27). Дополнительно у пациентов с винкристиновой полиневропатией в период завершения индукционного этапа химиотерапии выявлено увеличение в ликворе хемокинов CXCL10 (IP-10) в 3,7 раза и CXCL12 (SDF-1α) в 1,4 раза (p = 0,005 и p = 0,054 соответственно).

Выводы. Сбалансированная реакция интерлейкинов у детей с острым лимфобластным лейкозом, получающих винкристин, вероятно, отражает связь между иммунной и нервной системами, направленную на предупреждение поражения периферических нервов. Дисбаланс провоспалительных и противовоспалительных интерлейкинов может вносить вклад в развитие винкристиновой полиневропатии. Значимое повышение содержания хемокинов CXCL10 (IP-10) и CXCL12 (SDF-1α) в ликворе у детей с винкристиновой полиневропатией дает основание рассматривать их в качестве биологических маркеров нейротоксичности винкристина.

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