Адрес для переписки:Боголюбова Аполлинария Васильевна ФГБУН «Институт молекулярной биологии им. В.А. Энгельгардта» РАН 119991, Россия, Москва, ул. Вавилова, 32. Тел.: 8 (499) 135-99-64. Факс: 8 (499) 135-14-05. E-mail: apollinariya.bogolyubova@gmail.com Sciences 119991, Russian Federation, Moscow, Vavilov str., 32. Phone: 7 (499) 135-99-64. Fax: 7 (499) 135-14-05. E-mail: apollinariya.bogolyubova@gmail.com Образец цитирования: А.В. Боголюбова, Г.А. Ефимов, М.С. Друцкая, С.А. Недоспасов, «Иммунотерапия опухолей, основанная на блокировке иммунологических контрольных «точек» («чекпойнтов»)» // Медицинская иммунология, 2015. Т. 17, № 5. С. 395-406. doi: 10.15789/1563-0625-2015-5-395-406 © Боголюбова А.В. и соавт., 2015 For citation: A.V. Bogolyubova, G.A. Efimov, M.S. Drutskaya, S.A. Nedospasov, "Cancer immunotherapy based on the blockade of immune checkpoints", Medical Immunology (Russia) /Meditsinskaya Immunologiya, 2015, Vol. 17, no. 5, pp. 395-406. doi: 10.15789/1563-0625-2015 Резюме. Иммунологические контрольные «точки» (ИКТ, англ. Immunological checkpoints) -это система ингибиторных механизмов, которые регулируют активацию иммунного ответа, препятствуя запуску аутоиммунных процессов, а также модулируют его, уменьшая вызванные иммунными клет-ками повреждения в органах и тканях. Опухолевые клетки могут использовать такие контрольные точки для предотвращения активации опухоль-специфических лимфоцитов, таким образом, приоб-ретая устойчивость к действию иммунной системы. Одним из перспективных методов иммунотера-пии опухолей является блокировка ингибирующего сигнала, передающегося через иммунологические контрольные точки, приводящая к реактивации противоопухолевого иммунного ответа. Поскольку большая часть контрольных точек функционирует за счет взаимодействий лиганд-рецептор, одна из стратегий современной противоопухолевой терапии основана на создании терапевтических моно-клональных антител, блокирующих лиганд или рецептор, а также растворимых рекомбинантных ре-цепторов, которые могли бы конкурировать за лиганд и таким образом модулировать передачу сигна-ла. В последние годы в этом направлении иммунотерапии опухолей получены впечатляющие успехи, однако потенциальной платой за вмешательство в естественные супрессорные механизмы является развитие аутоиммунных реакций. .V. et al. Боголюбова А.В. и др. Medical Immunology (Russia) Address for correspondence: Bogolyubova Apollinariya V. Engelhardt Institute of Molecular Biology of Russian Academy of /Meditsinskaya ImmunologiyaМедицинская Иммунология the immune cell-mediated damage of tissues and organs. Tumor cells may utilize these checkpoints to prevent the activation of tumor-specific lymphocytes, thereby acquiring resistance against the immune response. The blockade of inhibitory signal that is transduced in immune checkpoints leading to the reactivation of antitumor immune response is a promising method of tumor immunotherapy. Since the majority of immune checkpoints are based on the ligand-receptor interactions, one of contempor...
More than 40 years ago ethyl nitrosoеurea was identified as a powerful mutagen for mammalian germ cells resulting in random point mutations in gamete DNA. This feature allowed the use of this mutagen for genetic studies on the mechanisms of various pathological and physiological processes in model organisms. In our study genome-wide mutagenesis in C3H mice by ethyl nitrosourea followed in generation F3 by selection of animals resistant to acute lethal hepatotoxicity caused by a combination of E. coli lipopolysaccharide (LPS) and D-galactosamine (D-gal). Tumor necrosis factor (TNF) is known to be a critical mediator of this pathology. Exposure to D-galactosamine increases sensitivity of hepatocytes to TNF leading to their necrosis and/or apoptosis. After double LPS/D-gal screening in F3 several mice resistant to LPS/D-gal-induced hepatotoxicity were identified, and became the founders of the corresponding “mutant” families. Using outcrossing to C57BL6 background followed by intercrossing, generations F5 and F7 were obtained. Among families of mutant animals only one family showed the resistance to the combination of LPS and D-gal, but sensitivity to TNF-D-galactosamine. This phenotype showed approximately Mendelian inheritance consistent with the recessive mutation hypothesis. This latter fact was confirmed by the sensitivity of mice from “heterozygous generations” (F4 and F6) to lethal LPS/Dgal hepatotoxicity. Primary bone marrow macrophages obtained from half of the mutant mice showed significantly reduced levels of TNF after LPS stimulation in vitro. At the same time, the serum TNF levels 1 hour after the administration of a non-lethal LPS dose did not differ in the mutant family mice and wild-type mice. These results implicate a recessive mutation either in innate TLR4-mediated signaling pathway, including proteins associated with LPS transfer, adapter molecules, components of kinase signaling cascades, transcription factors, or in enzymes involved in regulation of TLR4 cascades, such as components of the ubiquitin cycle, or in genomic regulatory sequences that control the expression of one of these genes, including the tnf gene.
Cytokines comprise the molecular language of communication between the cells, which is needed to maintain the homeostatic functions of the body (including the immune system) and mediate various diseases. Many aspects of inflammation, autoimmune diseases and neoplasia are associated with cytokine signaling through specific receptors. The establishment of new physiological functions of “old” cytokines and understanding the molecular and cellular mechanisms of their involvement in disease pathogenesis, as well as the search for new therapeutic targets and development of innovative approaches to anti-cytokine therapy, present a fundamental problem. When assessing the tremendous success of anti-cytokine therapy in treatment of certain autoimmune diseases, we should not forget that (a) this treatment does not eliminate the causes of the disease:autoreactive T-cell clones; and that (b) less than half of the patients respond to this therapy; and that (c) anti-cytokine therapy has serious side effects.
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