mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-CVO-2865mimmun-2865Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESКлиническая ценность уровня сывороточного интерлейкина-13 при винкристиновой полиневропатии у детей при остром лимфобластном лейкозеClinical value of serum interleukin-13 levels in vincristineinduced polyneuropathy in children with acute lymphoblastic leukemiaКорякинаО. В.KoryakinaO. V.

Корякина О.В. – к.м.н., доцент кафедры нервных болезней, нейрохирургии и медицинской генетики; врач-невролог 

г. Екатеринбург

Koryakina O.V., PhD (Medicine), Associate Professor, Department of Nervous Diseases, Neurosurgery and Medical Genetic; Neurologist 

Yekaterinburg

koryakina09@mail.ruКовтунО. П.KovtunO. P.

Ковтун О.П. – д.м.н., профессор, академик РАН, ректор 

г. Екатеринбург

Kovtun O.P., PhD, MD (Medicine), Professor, Full Member, Russian Academy of Sciences, Rector 

Yekaterinburg

БазарныйВ. В.BazarnyiV. V.

Базарный В.В. – д.м.н., профессор, главный научный сотрудник Центральной научно-исследовательской лаборатории 

г. Екатеринбург

Bazarnyi V.V., PhD, MD (Medicine), Professor, Chief Research Associate, Central Research Laboratory 

Yekaterinburg

КопенкинМ. А.KopenkinM. A.

Копенкин М.А. – младший научный сотрудник Центральной научно-исследовательской лаборатории 

г. Екатеринбург

Kopenkin M.A., Junior Research Associate, Central Research Laboratory 

Yekaterinburg

ФГБОУ «Уральский государственный медицинский университет» Министерства здравоохранения РФ; ГАУЗ СО «Областная детская клиническая больница»РоссияUral State Medical University; Regional Children Clinical HospitalRussian FederationФГБОУ «Уральский государственный медицинский университет» Министерства здравоохранения РФРоссияUral State Medical UniversityRussian Federation20241110202326612051212Copyright © Корякина О.В., Ковтун О.П., Базарный В.В., Копенкин М.А., 20242024Корякина О.В., Ковтун О.П., Базарный В.В., Копенкин М.А.Koryakina O.V., Kovtun O.P., Bazarnyi V.V., Kopenkin M.A.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/2865

Основным нейротоксическим осложнением при лечении острого лимфобластного лейкоза у детей является винкристиновая полиневропатия. Недавние исследования продемонстрировали участие иммунной системы в патогенетических механизмах поражения периферической нервной системы. В последние годы появляются сообщения по изучению взаимосвязи между интерлейкином-13 (IL-13) и развитием токсических эффектов химиотерапевтических препаратов. Цель работы – оценить клиническую ценность уровня IL-13 у детей при винкристиновой полиневропатии. В исследовании участвовало 27 детей с острым лимфобластным лейкозом в возрасте от 3 до 17 лет, которые получали химиотерапию по протоколу. Проводили определение уровня IL-13 в плазме крови с последующим сравнительным анализом показателей в двух подгруппах в зависимости от развития винкристиновой полиневропатии. Оценка содержания IL-13 проводилась методом мультипараметрического иммунофлуоресцентного анализа с магнитными микросферами (технология xMAP, Luminex 200, США) и использованием тест-системы ProcartaPlex Human Cytokine/Chemokine (Invitrogen, США). В исследуемой группе пациентов винкристиновая полиневропатия регистрировалась у большинства детей (n = 15) с дебютом преимущественно на индукционном этапе химиотерапии и доминированием сенсорных нарушений. При сравнительном анализе уровня IL-13 в плазме крови у пациентов с винкристиновой полиневропатией отмечалось статистически значимое повышение его концентрации в отличие от детей, не имеющих признаков поражения периферической нервной системы (p = 0,042). При оценке клинической цености данного показателя диагностическая чувствительность составила 75%, специфичность – 100%, интегральный показатель, характеризующий точность теста – 0,89. Установлено, что изменение IL-13 имеет достаточно высокий уровень относительного риска, что указывает на его существенную взаимосвязь с развитием винкристиновой полиневропатии.Полученные результаты проведенного исследования о содержании IL-13 в плазме крови у детей с винкристиновой полиневропатией позволили выделить его в качестве предикторного биологического маркера поражения периферической нервной системы.

Vincristine polyneuropathy is the leading neurotoxic effect when treating pediatric acute lymphoblastic leukemia (ALL). Recent studies have demonstrated involvement of immune system in pathogenesis of peripheral nervous system damage. Over recent years, there have been reports examining the relationship between interleukin-13 (IL-13) and development of toxic effects of chemotherapeutic drugs. Our objective was to assess clinical value of IL-13 level in children with vincristine polyneuropathy. The study included 27 children with ALL aged from 3 to 17 years, who received chemotherapy according to the conventional protocol. Plasma IL-13 levels were determined, and the values in two subgroups have been compared taking into account development of vincristine polyneuropathy. IL-13 content was assessed by multiparametric immunofluorescent analysis with magnetic microspheres (xMAP technology, Luminex 200, USA) and using ProcartaPlex Human Cytokine/Chemokine test system (Invitrogen, USA). Vincristine polyneuropathy in the study group was registered in the majority of children (n = 15) manifesting mainly at the induction stage of chemotherapy and presenting as predominance of sensory disorders. In a comparative analysis of IL-13 plasma levels in patients with vincristine polyneuropathy, we observed a statistically significant increase of its concentration, in contrast to patients without signs of peripheral nervous system damage (p = 0.042). The diagnostic sensitivity of this index was 75%, specificity – 100%, the integral index characterizing the accuracy of the test was 0.89. IL-13 changes were found to correlate with higher relative risk level, indicating its significant relationship to the development of vincristine polyneuropathy. The results of the study on the IL-13 content in blood plasma in children with vincristine polyneuropathy allowed us to consider it a predictive biological marker of peripheral nervous system damage.

нейротоксичностьострый лейкоздетиполиневропатияхимиотерапияинтерлейкиныneurotoxicityacute leukemiachildrenpolyneuropathychemotherapyinterleukinsReferencesAl-Mazidi S., Alotaibi M., Nedjadi T., Chaudhary A., Alzoghaibi M., Djouhri L. Blocking of cytokines signalling attenuates evoked and spontaneous neuropathic pain behaviours in the paclitaxel rat model of chemotherapy-induced neuropathy. Eur. J. Pain, 2018, Vol. 22, no. 4, pp. 810-821.Al-Mazidi S., Alotaibi M., Nedjadi T., Chaudhary A., Alzoghaibi M., Djouhri L. Blocking of cytokines signalling attenuates evoked and spontaneous neuropathic pain behaviours in the paclitaxel rat model of chemotherapy-induced neuropathy. Eur. J. Pain, 2018, Vol. 22, no. 4, pp. 810-821.Amo-Aparicio J., Garcia-Garcia J., Francos-Quijorna I., Urpi A., Esteve-Codina A., Gut M., Quintana A., Lopez-Vales R. Interleukin-4 and interleukin-13 induce different metabolic profiles in microglia and macrophages that relate with divergent outcomes after spinal cord injury. Theranostics, 2021, Vol. 11, no. 20, pp. 9805-9820.Amo-Aparicio J., Garcia-Garcia J., Francos-Quijorna I., Urpi A., Esteve-Codina A., Gut M., Quintana A., Lopez-Vales R. Interleukin-4 and interleukin-13 induce different metabolic profiles in microglia and macrophages that relate with divergent outcomes after spinal cord injury. Theranostics, 2021, Vol. 11, no. 20, pp. 9805-9820.Cash E., Minty A., Ferrara P., Caput D., Fradelizi D., Rott O.. Macrophage-inactivating IL-13 suppresses experimental autoimmune encephalomyelitis in rats. J. Immunol., 1994, Vol. 153, no. 9, pp. 4258-4267.Cash E., Minty A., Ferrara P., Caput D., Fradelizi D., Rott O.. Macrophage-inactivating IL-13 suppresses experimental autoimmune encephalomyelitis in rats. J. Immunol., 1994, Vol. 153, no. 9, pp. 4258-4267.Common Terminology Criteria for Adverse Events (СТСAЕ): version 5.0: november 27, 2017 /U.S. Department of Health and Human Services. Available at: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.Common Terminology Criteria for Adverse Events (СТСAЕ): version 5.0: november 27, 2017 /U.S. Department of Health and Human Services. Available at: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.Eyob T., Ng T., Chan R., Chan A. Impact of chemotherapy on cancer-related fatigue and cytokines in 1312 patients: a systematic review of quantitative studies. Curr. Opin. Support. Palliat. Care, 2016, Vol. 10, no. 2, pp. 165-179.Eyob T., Ng T., Chan R., Chan A. Impact of chemotherapy on cancer-related fatigue and cytokines in 1312 patients: a systematic review of quantitative studies. Curr. Opin. Support. Palliat. Care, 2016, Vol. 10, no. 2, pp. 165-179.Gilchrist L.S., Marais L., Tanner L. Comparison of two chemotherapy-induced peripheral neuropathy measurement approaches in children. Support. Care Cancer, 2014, Vol. 22, no. 2, pp. 359-366.Gilchrist L.S., Marais L., Tanner L. Comparison of two chemotherapy-induced peripheral neuropathy measurement approaches in children. Support. Care Cancer, 2014, Vol. 22, no. 2, pp. 359-366.Greiner M., Pfeiffer D., Smith R.D. Principles and practical application of the receiver-operating characteristic analysis for diagnostic tests. Prev. Vet. Med., 2000, Vol. 45, no. 1-2, pp. 23-41.Greiner M., Pfeiffer D., Smith R.D. Principles and practical application of the receiver-operating characteristic analysis for diagnostic tests. Prev. Vet. Med., 2000, Vol. 45, no. 1-2, pp. 23-41.Hong A.R., Jang J.G., Chung Y.C., Won S.Y., Jin B.K. Interleukin 13 on microglia is neurotoxic in lipopolysaccharide-injected striatum in vivo. Exp. Neurobiol., 2022, Vol. 31, no. 1, pp. 42-53.Hong A.R., Jang J.G., Chung Y.C., Won S.Y., Jin B.K. Interleukin 13 on microglia is neurotoxic in lipopolysaccharide-injected striatum in vivo. Exp. Neurobiol., 2022, Vol. 31, no. 1, pp. 42-53.Junttila I.S. Tuning the cytokine responses: an update on interleukin (IL)-4 and IL-13 receptor complexes. Front. Immunol., 2018, Vol. 9, 888. doi: 10.3389/fimmu.2018.00888.Junttila I.S. Tuning the cytokine responses: an update on interleukin (IL)-4 and IL-13 receptor complexes. Front. Immunol., 2018, Vol. 9, 888. doi: 10.3389/fimmu.2018.00888.Kavcic M., Koritnik B., Krzan M., Velikonja O., Prelog T., Stefanovic M., Debeljak M., Jazbec J. Electrophysiological studies to detect peripheral neuropathy in children treated with vincristine. J. Pediatr. Hematol. Oncol., 2017, Vol. 39, no. 4, pp. 266-271.Kavcic M., Koritnik B., Krzan M., Velikonja O., Prelog T., Stefanovic M., Debeljak M., Jazbec J. Electrophysiological studies to detect peripheral neuropathy in children treated with vincristine. J. Pediatr. Hematol. Oncol., 2017, Vol. 39, no. 4, pp. 266-271.Li G.Z., Hu Y.H., Li D.Y., Zhang Y., Guo H. L., Li Y. M., Chen F., Xu J. Vincristine-induced peripheral neuropathy: A mini-review. Neurotoxicology, 2020, Vol. 81, pp. 161-171.Li G.Z., Hu Y.H., Li D.Y., Zhang Y., Guo H. L., Li Y. M., Chen F., Xu J. Vincristine-induced peripheral neuropathy: A mini-review. Neurotoxicology, 2020, Vol. 81, pp. 161-171.Madsen M.L., Due H., Ejskjær N., Jensen P., Madsen J., Dybkær K. Aspects of vincristine-induced neuropathy in hematologic malignancies: a systematic review. Cancer Chemother. Pharmacol., 2019, Vol. 84, no. 3, pp. 471-485.Madsen M.L., Due H., Ejskjær N., Jensen P., Madsen J., Dybkær K. Aspects of vincristine-induced neuropathy in hematologic malignancies: a systematic review. Cancer Chemother. Pharmacol., 2019, Vol. 84, no. 3, pp. 471-485.Mori S., Maher P., Conti B. Neuroimmunology of the interleukins 13 and 4. Brain Sci., 2016, Vol. 6, no. 2, 18. doi: 10.3390/brainsci6020018.Mori S., Maher P., Conti B. Neuroimmunology of the interleukins 13 and 4. Brain Sci., 2016, Vol. 6, no. 2, 18. doi: 10.3390/brainsci6020018.Qin B., Li Y., Liu X., Gong D., Zheng W. Notch activation enhances microglial CX3CR1/P38 MAPK pathway in rats model of vincristine-induced peripheral neuropathy. Neurosci. Lett., 2020, Vol. 715, 134624. doi: 10.1016/j.neulet.2019.134624.Qin B., Li Y., Liu X., Gong D., Zheng W. Notch activation enhances microglial CX3CR1/P38 MAPK pathway in rats model of vincristine-induced peripheral neuropathy. Neurosci. Lett., 2020, Vol. 715, 134624. doi: 10.1016/j.neulet.2019.134624.Scholz J., Woolf C.J. The neuropathic pain triad: neurons, immune cells and glia. Nat. Neurosci., 2007, Vol. 10, no. 11, pp. 1361-1368.Scholz J., Woolf C.J. The neuropathic pain triad: neurons, immune cells and glia. Nat. Neurosci., 2007, Vol. 10, no. 11, pp. 1361-1368.Shankar A., McAlees J.W., Lewkowich I.P. Modulation of IL-4/IL-13 cytokine signaling in the context of allergic disease. J. Allergy Clin. Immunol., 2022, Vol. 150, no. 2, pp. 266-276.Shankar A., McAlees J.W., Lewkowich I.P. Modulation of IL-4/IL-13 cytokine signaling in the context of allergic disease. J. Allergy Clin. Immunol., 2022, Vol. 150, no. 2, pp. 266-276.Singh S.K., Krukowski K., Laumet G.O., Weis D., Alexander J.F., Heijnen C.J., Kavelaars A. CD8+ T cellderived IL-13 increases macrophage IL-10 to resolve neuropathic pain. JCI Insight, 2022, Vol. 7, no. 5, 154194. doi: 10.1172/jci.insight.154194.Singh S.K., Krukowski K., Laumet G.O., Weis D., Alexander J.F., Heijnen C.J., Kavelaars A. CD8+ T cellderived IL-13 increases macrophage IL-10 to resolve neuropathic pain. JCI Insight, 2022, Vol. 7, no. 5, 154194. doi: 10.1172/jci.insight.154194.Starobova H., Monteleone M., Adolphe C., Batoon L., Sandrock C.J., Tay B., Deuis J.R., Smith A.V., Mueller A., Nadar E.I., Lawrence G.P., Mayor A., Tolson E., Levesque J.P., Pettit A.R., Wainwright B.J., Schroder K., Vetter I. Vincristine-induced peripheral neuropathy is driven by canonical NLRP3 activation and IL-1β release. J. Exp. Med., 2021, Vol. 218, no. 5, e20201452. doi: 10.1084/jem.20201452.Starobova H., Monteleone M., Adolphe C., Batoon L., Sandrock C.J., Tay B., Deuis J.R., Smith A.V., Mueller A., Nadar E.I., Lawrence G.P., Mayor A., Tolson E., Levesque J.P., Pettit A.R., Wainwright B.J., Schroder K., Vetter I. Vincristine-induced peripheral neuropathy is driven by canonical NLRP3 activation and IL-1β release. J. Exp. Med., 2021, Vol. 218, no. 5, e20201452. doi: 10.1084/jem.20201452.Wang X.M., Lehky T.J., Brell J.M., Dorsey S.G. Discovering cytokines as targets for chemotherapy-induced painful peripheral neuropathy. Cytokine, 2012, Vol. 59, no. 1, pp. 3-9.Wang X.M., Lehky T.J., Brell J.M., Dorsey S.G. Discovering cytokines as targets for chemotherapy-induced painful peripheral neuropathy. Cytokine, 2012, Vol. 59, no. 1, pp. 3-9.Weiser M.A., Cabanillas M.E., Konopleva M., Thomas D.A., Pierce S.A., Escalante C.P., Kantarjian H.M., O’Brien S.M. Relation between the duration of remission and hyperglycemia during induction chemotherapy for acute lymphocytic leukemia with a hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone/methotrexate-cytarabine regimen. Cancer, 2004, Vol. 100, no. 6, pp. 1179-1185.Weiser M.A., Cabanillas M.E., Konopleva M., Thomas D.A., Pierce S.A., Escalante C.P., Kantarjian H.M., O’Brien S.M. Relation between the duration of remission and hyperglycemia during induction chemotherapy for acute lymphocytic leukemia with a hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone/methotrexate-cytarabine regimen. Cancer, 2004, Vol. 100, no. 6, pp. 1179-1185.Zhou L., Ao L., Yan Y., Li W., Ye A., Hu Y., Fang W., Li Y. The therapeutic potential of chemokines in the treatment of chemotherapy-induced peripheral neuropathy. Curr. Drug. Targets, 2020, Vol. 21, no. 3, pp. 288-301.Zhou L., Ao L., Yan Y., Li W., Ye A., Hu Y., Fang W., Li Y. The therapeutic potential of chemokines in the treatment of chemotherapy-induced peripheral neuropathy. Curr. Drug. Targets, 2020, Vol. 21, no. 3, pp. 288-301.

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