mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-2018-4-523-534mimmun-1560Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESОЦЕНКА ЭФФЕКТИВНОСТИ ТЕРАПИИ FCR У БОЛЬНЫХ ХРОНИЧЕСКИМ ЛИМФОЛЕЙКОЗОМ НА ОСНОВАНИИ ИММУНОГЕНЕТИЧЕСКИХ КРИТЕРИЕВEVALUATION OF FCR THERAPY EFFICACY IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA BASED ON IMMUNOGENETIC CRITERIAНазароваЕ. Л.NazarovaE. L.

к.м.н., ведущий научный сотрудник лаборатории иммунологии лейкозов,

610027, г. Киров, ул. Красноармейская, 72

PhD (Medicine), Leading Research Associate, Laboratory of Leukemia Immunology,

610027, Kirov, Krasnoarmeiskaya str., 72

nazarova@niigpk.ruСухоруковаЭ. Е.SukhorukovaE. E.

к.м.н., научный сотрудник лаборатории иммунологии лейкозов,

г. Киров

PhD (Medicine), Research Associate, Laboratory of Leukemia Immunology,

Kirov

МинаеваН. В.MinaevaN. V.

к.м.н., заместитель директора по лечебной работе,

г. Киров

PhD (Medicine), Deputy Director for Clinics,

Kirov

ШардаковВ. И.ShardakovV. I.

д.м.н., профессор, заведующий лабораторией иммунологии лейкозов,

г. Киров

PhD, MD (Medicine), Professor, Head, Laboratory of Leukemia Immunology,

Kirov

ФокинаЕ. С.FokinaE. S.

к.м.н., врач-ординатор клиникодиагностического отделения,

г. Киров

PhD (Medicine), Resident Physician, Department of Clinical Diagnostics,

Kirov

ФГБУН «Кировский научно-исследовательский институт гематологии и переливания крови Федерального медико-биологического агентства»РоссияKirov Research Institute of Hematology and Blood Transfusion, Federal Medical-Biological AgencyRussian Federation201825062018204523534Copyright © Назарова Е.Л., Сухорукова Э.Е., Минаева Н.В., Шардаков В.И., Фокина Е.С., 20182018Назарова Е.Л., Сухорукова Э.Е., Минаева Н.В., Шардаков В.И., Фокина Е.С.Nazarova E.L., Sukhorukova E.E., Minaeva N.V., Shardakov V.I., Fokina E.S.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.mimmun.ru/mimmun/article/view/1560

В многочисленных исследованияx показано, что распространенные варианты генов иммунного/воспалительного ответа могут оказывать влияние на эффективность лечения хронического лимфолейкоза (CLL). В ранее опубликованной работе мы представили данные, что полиморфные варианты ряда генов иммунного ответа у больных CLL ассоциированы с различной скоростью прогрессирования заболевания. Установлены корреляционные связи распределения модификационных профилей генов при доброкачественной и прогрессирующей формах CLL. В данном исследовании отражены результаты фармакогенетических изысканий, направленных на выявление ассоциаций между полиморфизмом генов иммунного ответа и эффективностью лечения FCR больных CLL. Исследовались 19 полиморфных участков 14 генов иммунного ответа у 33 пациентов с CLL, получавших терапию FCR. Генотипы TLR2, TLR3, TLR4, TLR6, TLR9, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-17A, CD14, TNFα, FCGR2A определяли методом полимеразной цепной реакции с аллель-специфичными праймерами. Больные CLL были разделены на несколько групп в зависимости от сроков ответа на лечение FCR: с частичной/полной ремиссией заболевания после двух, четырех, шести курсов лечения и с отсутствием ответа не терапию. Выявленные статистически значимые различия в распределении частот гаплотипов затрагивали гены IL-1β (C-3953T) (р = 0,02-0,009), IL-10 (C-819T) (р = 0,04), IL-10 (G-1082A) (р = 0,04-0,002-0,006), FCGR2A (His166Arg) (р = 0,006), TLR4 (Thr399Ile) (р = 0,02), TLR6 (Ser249Pro) (р = 0,04), TLR9 (A2848G) (р = 0,04-0,007), CD14 (C-159T) (р = 0,03). При проверке гипотезы достоверности результатов множественных сравнений была подтверждена значимость обнаруженных событий только для гена IL-10 (G-1082A) (р < 0,01; χ2 = 20,082). Полученные результаты показывают взаимосвязь между мутационным статусом гена IL-10-1082 и сроками ответа на терапию FCR, а также позволяют выделить группу больных с первично-резистентными к FCR формами CLL до начала лечения. Обсуждается роль взаимоотношений между полиморфизмом гена IL-10 и продукцией IL-10 с вероятностью возникновения и характером течения В-зрелоклеточных опухолей лимфатической системы. Доказанным считается, что IL-10 является фактором роста для неизмененных и трансформированных В-лимфоцитов человека, контролирует баланс между клеточным и гуморальным иммунными ответами, обладает выраженной иммуносупрессивной активностью, наряду со способностью стимулировать пролиферацию опухолевых клеток. Приводятся обоснования проведения фармакогеномных исследований при CLL для прогнозирования эффективности конкретного препарата или комбинации лекарственных средств у каждого пациента, что в перспективе позволит обнаружить фактор, влияющий на успех терапии уже на ранних ее этапах.

A number of studies have shown that distinct common variants of the genes controlling immune/inflammatory response may affect efficiency of chronic lymphocytic leukemia (CLL) treatment. In a recently published paper, we reported polymorphic variants of some immune response genes in CLL patients to be associated with different rates of disease progression. Correlations between the distribution of gene modification profiles in indolent and agressive forms of CLL have been established. The present study describes results of pharmacogenetic studies aimed for identifying associations between the immune response genes polymorphism, and efficacy of FCR treatment regimen in CLL patients. 19 polymorphic loci of 14 immune response genes were studied in 33 patients with CLL who received FCR therapy. The TLR2, TLR3, TLR4, TLR6, TLR9, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-17A, CD14, TNFα, FCGR2A genotypes were determined by polymerase chain reaction with allele-specific primers. CLL patients were divided into several groups depending on the terms of response to FCR treatment, i.e., achieving partial/complete remission after two, four, six courses of treatment, and those who did not respond to the therapy. Statistically significant differences in the distribution of haplotype frequencies were detected for the following genes: IL-1β (C-3953T, p = 0.02-0.009); IL-10 (C-819T, p = 0.04); IL-10 (G-1082A, p = 0.04-0.002-0.006), FCGR2A (His166Arg, p = 0.006); TLR4 (Thr399Ile, p = 0.02); TLR6 (Ser249Pro, p = 0.04); TLR9 (A2848G, p = 0.04-0.007); CD14 (C-159T, p = 0.03). When testing the significance hypothesis by multiple comparisons, the difference for the detected events was confirmed only for IL-10 gene (G-1082A, p < 0.01; χ2 = 20,082). The results show a relationship between the allelic status of the IL-10-1082 gene and the timing of response to FCR therapy, as well as predict a group of patients with primary-resistant CLL before treatment. The role of the relationship between IL-10 gene polymorphism and IL-10 production is discussed in connection with occurrence risk and clinical course of mature B-cell lymphoid malignancies. IL-10 is thought to be a growth factor for normal and transformed human B-lymphocytes, it controls a balance between cellular and humoral immune responses while exerting a pronounced immunosuppressive activity, along with ability to stimulate tumor cell proliferation. A rationale for conducting pharmacogenomic studies in CLL is provided, in order to predict efficiency of a specific drug or their combination in a distinct patient, thus representing chances to detect a factor which may influence success of the therapy since its earlier stage.

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