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<article article-type="research-article" dtd-version="1.3" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xml:lang="ru"><front><journal-meta><journal-id journal-id-type="publisher-id">mimmun</journal-id><journal-title-group><journal-title xml:lang="ru">Медицинская иммунология</journal-title><trans-title-group xml:lang="en"><trans-title>Medical Immunology (Russia)</trans-title></trans-title-group></journal-title-group><issn pub-type="ppub">1563-0625</issn><issn pub-type="epub">2313-741X</issn><publisher><publisher-name>SPb RAACI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.15789/1563-0625-2014-3-227-236</article-id><article-id custom-type="elpub" pub-id-type="custom">mimmun-688</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="section-heading" xml:lang="ru"><subject>ОРИГИНАЛЬНЫЕ СТАТЬИ</subject></subj-group><subj-group subj-group-type="section-heading" xml:lang="en"><subject>ORIGINAL ARTICLES</subject></subj-group></article-categories><title-group><article-title>ИЗУЧЕНИЕ ИММУНОГЕННЫХ И ПРОТЕКТИВНЫХ СВОЙСТВ ТЕРМОСТАБИЛЬНОГО ЛЕТАЛЬНОГО ТОКСИНА YERSINIA PSEUDOTUBERCULOSIS И ЕГО ВЛИЯНИЯ НА ГЕМАТОЛОГИЧЕСКИЕ И ЦИТОКИНОВЫЕ ПАРАМЕТРЫ КРОВИ ЛАБОРАТОРНЫХ МЫШЕЙ</article-title><trans-title-group xml:lang="en"><trans-title>A STUDY OF IMMUNOGENIC AND PROTECTIVE PROPERTIES OF THE HEAT-STABLE LETHAL TOXIN OF YERSINIA PSEUDOTUBERCULOSIS AND ITS EFFECTS UPON HEMATOLOGICAL AND BLOOD CYTOKINE PARAMETERS OF LABORATORY MICE</trans-title></trans-title-group></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Цыбульский</surname><given-names>А. В.</given-names></name><name name-style="western" xml:lang="en"><surname>Tsybulsky</surname><given-names>A. V.</given-names></name></name-alternatives><bio xml:lang="ru"><p>к.м.н., доцент кафедры биохимии, микробиологии и биотехнологии Школы естественных наук Дальневосточного федерального университета</p></bio><bio xml:lang="en"><p>PhD (Medicine), Associate Professor, Department of Biochemistry, Microbiology and Biotechnology, Far Eastern Federal University</p></bio><email xlink:type="simple">avt_biotech@mail.ru</email><xref ref-type="aff" rid="aff-1"/></contrib><contrib contrib-type="author" corresp="yes"><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Тимченко</surname><given-names>Н. Ф.</given-names></name><name name-style="western" xml:lang="en"><surname>Timchenko</surname><given-names>N. F.</given-names></name></name-alternatives><bio xml:lang="ru"><p>д.м.н., профессор, заведующая лабораторией молекулярных основ патогенности бактерий ФГБУ «Научно-исследовательский институт эпидемиологии и микробиологии имени Г.П. Сомова»Сибирского отделения Российской академии медицинских наук</p></bio><bio xml:lang="en"><p>PhD, MD (Medicine), Professor,Head, Laboratory of Molecular Basis of Pathogenicity of Bacteria, G.P. Somov Research Institute of Epidemiology and Microbiology, Siberian Branch of Russian Academy of Medical Sciences</p></bio><xref ref-type="aff" rid="aff-2"/></contrib><contrib contrib-type="author" corresp="yes"><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Костецкий</surname><given-names>Э. Я.</given-names></name><name name-style="western" xml:lang="en"><surname>Kostetsky</surname><given-names>E. Ya.</given-names></name></name-alternatives><bio xml:lang="ru"><p>д.б.н., профессор, заведующий кафедрой биохимии, микробиологии и биотехнологии Школыестественных наук Дальневосточного федерального университета</p></bio><bio xml:lang="en"><p>PhD, MD (Biology), Professor, Head, Department of Biochemistry, Microbiology and Biotechnology, Far Eastern Federal University</p></bio><xref ref-type="aff" rid="aff-3"/></contrib><contrib contrib-type="author" corresp="yes"><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Воробьева</surname><given-names>Н. С.</given-names></name><name name-style="western" xml:lang="en"><surname>Vorobieva</surname><given-names>N. S.</given-names></name></name-alternatives><bio xml:lang="ru"><p>аспирант кафедры биохимии, микробиологии и биотехнологии Школы естественных наук Дальневосточного федерального университета</p></bio><bio xml:lang="en"><p>Postgraduate Student, Department of Biochemistry, Microbiology and Biotechnology, Far Eastern Federal University</p></bio><xref ref-type="aff" rid="aff-1"/></contrib></contrib-group><aff-alternatives id="aff-1"><aff xml:lang="ru">Дальневосточный федеральный университет, г. Владивосток<country>Россия</country></aff><aff xml:lang="en">Far Eastern Federal University, Vladivostok, Russian Federation<country>Russian Federation</country></aff></aff-alternatives><aff-alternatives id="aff-2"><aff xml:lang="ru">ФГБУ «Научно-исследовательский институт эпидемиологии и микробиологии имени Г.П. Сомова»&#13;
Сибирского отделения Российской академии медицинских наук, г. Владивосток<country>Россия</country></aff><aff xml:lang="en">Far Eastern Federal University, Vladivostok, Russian Federation<country>Russian Federation</country></aff></aff-alternatives><aff-alternatives id="aff-3"><aff xml:lang="ru">Дальневосточный федеральный университет, г. Владивосток<country>Россия</country></aff><aff xml:lang="en">G.P. Somov Research Institute of Epidemiology and Microbiology, Siberian Branch of Russian Academy of Medical Sciences, Vladivostok<country>Russian Federation</country></aff></aff-alternatives><pub-date pub-type="collection"><year>2014</year></pub-date><pub-date pub-type="epub"><day>01</day><month>08</month><year>2014</year></pub-date><volume>16</volume><issue>3</issue><fpage>227</fpage><lpage>236</lpage><permissions><copyright-statement>Copyright &amp;#x00A9; Цыбульский А.В., Тимченко Н.Ф., Костецкий Э.Я., Воробьева Н.С., 2014</copyright-statement><copyright-year>2014</copyright-year><copyright-holder xml:lang="ru">Цыбульский А.В., Тимченко Н.Ф., Костецкий Э.Я., Воробьева Н.С.</copyright-holder><copyright-holder xml:lang="en">Tsybulsky A.V., Timchenko N.F., Kostetsky E.Y., Vorobieva N.S.</copyright-holder><license license-type="creative-commons-attribution" xlink:href="https://creativecommons.org/licenses/by/4.0/" xlink:type="simple"><license-p>This work is licensed under a Creative Commons Attribution 4.0 License.</license-p></license></permissions><self-uri xlink:href="https://www.mimmun.ru/mimmun/article/view/688">https://www.mimmun.ru/mimmun/article/view/688</self-uri><abstract><p>Представлены данные, характеризующие антигенные и иммуногенные свойства термостабильного летального токсина Yersinia pseudotuberculosis – белка с молекулярной массой 45 кДа. Показана более высокая антителопродукция у мышей, иммунизированных токсином дважды в дозе 0,1 мкг/мышь в сравнении с дозой 0,01 мкг. Выявлены различия в лейкоцитарной реакции: развитие лейкопении, нейтро- и лимфопении при иммунизации дозой токсина 0,01 мкг и лейкоцитоза (а также прироста содержания лимфоцитов и моноцитов) при дозе 0,1 мкг белка. Установлены различия в цитокин-модулирующей активности разных доз токсина: при дозе в 0,01 мкг/мышь развивались преимущественно реакции, имеющие провоспалительную острофазовую направленность, тогда как доза 0,1 мкг/мышь вызывала к 17-м суткам эксперимента индукцию IFNγ и цитокинов, способствующих пролиферации лимфоцитов и активации антителопродуцентов. Токсин проявлял протективные свойства при двукратной иммунизации мышей и последующем их заражении летальной дозой Y. pseudotuberculosis. Замедленная активация антителопродуцентов при реакции организма мышей на ТСТ свидетельствует об актуальности поиска эффективных адъювантных средств усиления и ускорения развития специфической гуморальной иммунной реакции на этот антиген.</p></abstract><trans-abstract xml:lang="en"><p>The article presents some data concerning antigenic and immunogenic properties of the lethal heat-stable toxin (HST) from Yersinia pseudotuberculosis, a protein with molecular weight of 45 kDa. The mice,following double immunization with HST at a dose of 0.1 mg per mouse, displayed higher antibody production, in comparison with a dose of 0.01 mg/mouse. The appropriate differences were revealed with regard ofleukocyte responses, i.e., development of leukopenia, neutropenia, lymphopenia upon immunization with the 0.01 mg of HST per mouse, whereas leukocytosis, and increase in lymphocytes and monocytes was detected after a dose of 0.1 mg/mouse. We detected some doseependent differences in cytokine-modulating activity. I.e., at HST dose of 0.01 mg per mouse, we detected mostly proinflammatory, acutehase responses, whereas a dose of 0.1 mg/mice caused induction of . IFNγ and cytokines promoting lymphocyte proliferation and antibody production by day +17. Upon double immunization of mice, the toxin showed protective properties when injecting them with lethal dose of Y. pseudotuberculosis. A lagging activation of antibody producers duringHST response suggests a need for searching effective adjuvant tools of enhancement and acceleration of specific humoral immune reactions against this antigen.</p></trans-abstract><kwd-group xml:lang="ru"><kwd>Yersinia pseudotuberculosis</kwd><kwd>термостабильный токсин</kwd><kwd>иммуногенность</kwd><kwd>протективность</kwd><kwd>цитокины</kwd></kwd-group><kwd-group xml:lang="en"><kwd>Yersinia pseudotuberculosis</kwd><kwd>heat-stable toxin</kwd><kwd>immunogenicity</kwd><kwd>protective effect</kwd><kwd>cytokines</kwd></kwd-group></article-meta></front><back><ref-list><title>References</title><ref id="cit1"><label>1</label><citation-alternatives><mixed-citation xml:lang="ru">Voskresenskaya E.A., Tseneva G.Ya., Alenushkina T.V., Skvortsov A.E. Immunologicheskie pokazateli pri patologii, obuslovlennoy iersiniozami [The immunological indices in pathology due to yersiniosis]. Zhurnal mikrobiologii, epidemiologii i immunobiologii – Journal of Microbiology Epidemiology and Immunobiology, 1996, no. 5, pp. 68-73.</mixed-citation><mixed-citation xml:lang="en">Voskresenskaya E.A., Tseneva G.Ya., Alenushkina T.V., Skvortsov A.E. Immunologicheskie pokazateli pri patologii, obuslovlennoy iersiniozami [The immunological indices in pathology due to yersiniosis]. Zhurnal mikrobiologii, epidemiologii i immunobiologii – Journal of Microbiology Epidemiology and Immunobiology, 1996, no. 5, pp. 68-73.</mixed-citation></citation-alternatives></ref><ref id="cit2"><label>2</label><citation-alternatives><mixed-citation xml:lang="ru">Dolmatova L.S., Zaika O.A., Nedashkovskaya E.P., Timchenko N.F. Issledovanie mekhanizmov apoptozmoduliruyushchego vliyaniya termostabil`nogo toksina Yersinia pseudotuberculosis i korrigiruyushchego deystviya ekstrakta iz dal`nevostochnykh vidov goloturiy na neytrofily krys in vitro [Investigation of mechanisms of apoptoz-modulating influence of thermostable toxin of Yersinia pseudotuberculosis and corrective effect of the extract of the Far Eastern species of sea cucumbers to the rat neutrophils in vitro]. Tikhookeanskiy meditsinskiy zhurnal – Pacific Medicine Journal, 2010, no. 3, pp. 76-80.</mixed-citation><mixed-citation xml:lang="en">Dolmatova L.S., Zaika O.A., Nedashkovskaya E.P., Timchenko N.F. Issledovanie mekhanizmov apoptozmoduliruyushchego vliyaniya termostabil`nogo toksina Yersinia pseudotuberculosis i korrigiruyushchego deystviya ekstrakta iz dal`nevostochnykh vidov goloturiy na neytrofily krys in vitro [Investigation of mechanisms of apoptoz-modulating influence of thermostable toxin of Yersinia pseudotuberculosis and corrective effect of the extract of the Far Eastern species of sea cucumbers to the rat neutrophils in vitro]. Tikhookeanskiy meditsinskiy zhurnal – Pacific Medicine Journal, 2010, no. 3, pp. 76-80.</mixed-citation></citation-alternatives></ref><ref id="cit3"><label>3</label><citation-alternatives><mixed-citation xml:lang="ru">Isachkova L.M., Raznik S.D., Nedashkovskaya E.P., Timchenko N.F. Patomorfologicheskaya kharakteristika eksperimental`noy toksinemii, vyzvannoy termostabil`nym toksinom Yersinia pseudotuberculosis [Pathomorphological characteristics of experimental toxemia induced by thermostable Yersinia pseudotuberculosis toxin]. Byulleten` eksperimental`noy biologii i meditsiny – Bulletin of Experimental Biology and Medicine, 2000, vol. 130, no. 11, pp. 1123-1126.</mixed-citation><mixed-citation xml:lang="en">Isachkova L.M., Raznik S.D., Nedashkovskaya E.P., Timchenko N.F. Patomorfologicheskaya kharakteristika eksperimental`noy toksinemii, vyzvannoy termostabil`nym toksinom Yersinia pseudotuberculosis [Pathomorphological characteristics of experimental toxemia induced by thermostable Yersinia pseudotuberculosis toxin]. Byulleten` eksperimental`noy biologii i meditsiny – Bulletin of Experimental Biology and Medicine, 2000, vol. 130, no. 11, pp. 1123-1126.</mixed-citation></citation-alternatives></ref><ref id="cit4"><label>4</label><citation-alternatives><mixed-citation xml:lang="ru">Kuznetsova T.A., Krylova N.V., Timchenko N.F., Logvinenko A.A. Vliyanie termostabil`nogo tocsin Yersinia pseudotuberculosis na immunnuyu sistemu [Effect of heat-stable toxin of Yersinia pseudotuberculosis to the immune system]. Epidemiologiya i infektsionnye bolezni – Epidemiology and Infectious Diseases, 2002, no. 1, pp. 25-28.</mixed-citation><mixed-citation xml:lang="en">Kuznetsova T.A., Krylova N.V., Timchenko N.F., Logvinenko A.A. Vliyanie termostabil`nogo tocsin Yersinia pseudotuberculosis na immunnuyu sistemu [Effect of heat-stable toxin of Yersinia pseudotuberculosis to the immune system]. Epidemiologiya i infektsionnye bolezni – Epidemiology and Infectious Diseases, 2002, no. 1, pp. 25-28.</mixed-citation></citation-alternatives></ref><ref id="cit5"><label>5</label><citation-alternatives><mixed-citation xml:lang="ru">Pashin A.C. Sovershenstvovanie metodov vydeleniya i identifikatsii ekzotoksina psevdotuberkuleznogo mikroba. Avtoref. diss. kand. med. nauk [Improvement of methods for isolation and identification of exotoxin pseudotuberculosis bacteria. Autoref. Cand. med. sci. diss.]. Saratov, 1986. 133 p.</mixed-citation><mixed-citation xml:lang="en">Pashin A.C. Sovershenstvovanie metodov vydeleniya i identifikatsii ekzotoksina psevdotuberkuleznogo mikroba. Avtoref. diss. kand. med. nauk [Improvement of methods for isolation and identification of exotoxin pseudotuberculosis bacteria. Autoref. Cand. med. sci. diss.]. Saratov, 1986. 133 p.</mixed-citation></citation-alternatives></ref><ref id="cit6"><label>6</label><citation-alternatives><mixed-citation xml:lang="ru">Persiyanova E.V., Surin A.K., Psareva E.K., Timchenko N.F. Tsitotoksicheskiy nekrotiziruyushchiy faktor Yersinia pseudotuberculosis, vozbuditelya dal`nevostochnoy skarlatinopodobnoy likhoradki [Cytotoxic necrotizing factor of Yersinia pseudotuberculosis as the causative agent of Far Eastern scarlatine-like form fever]. Byulleten` Sibirskogo otdeleniya RAMN – Bulletin of the Siberian Branch of the Russian Academy of Medical Sciences, 2013, vol. 33, no. 2, pp. 16-20.</mixed-citation><mixed-citation xml:lang="en">Persiyanova E.V., Surin A.K., Psareva E.K., Timchenko N.F. Tsitotoksicheskiy nekrotiziruyushchiy faktor Yersinia pseudotuberculosis, vozbuditelya dal`nevostochnoy skarlatinopodobnoy likhoradki [Cytotoxic necrotizing factor of Yersinia pseudotuberculosis as the causative agent of Far Eastern scarlatine-like form fever]. Byulleten` Sibirskogo otdeleniya RAMN – Bulletin of the Siberian Branch of the Russian Academy of Medical Sciences, 2013, vol. 33, no. 2, pp. 16-20.</mixed-citation></citation-alternatives></ref><ref id="cit7"><label>7</label><citation-alternatives><mixed-citation xml:lang="ru">Pokrovskiy V.K., Timchenko N.F., Nedashkovskaya E.P., Grigor`eva E.A. Biologicheskie svoystva termolabil`nogo letal`nogo toksina Yersinia pseudotuberculosis [Biological properties of heat-labile lethal toxin of Yersinia pseudotuberculosis]. Zhurnal mikrobiologii, epidemiologii i immunobiologii – Journal of Microbiology Epidemiology and Immunobiology, 2008, no. 6, pp. 63-66.</mixed-citation><mixed-citation xml:lang="en">Pokrovskiy V.K., Timchenko N.F., Nedashkovskaya E.P., Grigor`eva E.A. Biologicheskie svoystva termolabil`nogo letal`nogo toksina Yersinia pseudotuberculosis [Biological properties of heat-labile lethal toxin of Yersinia pseudotuberculosis]. Zhurnal mikrobiologii, epidemiologii i immunobiologii – Journal of Microbiology Epidemiology and Immunobiology, 2008, no. 6, pp. 63-66.</mixed-citation></citation-alternatives></ref><ref id="cit8"><label>8</label><citation-alternatives><mixed-citation xml:lang="ru">Somov G.P., Pokrovskiy V.I., Besednova N.N., Antonenko F.F. Psevdotuberkulez [Pseudotuberculosis]. Moscow, Medicine, 2001. 238 p.</mixed-citation><mixed-citation xml:lang="en">Somov G.P., Pokrovskiy V.I., Besednova N.N., Antonenko F.F. Psevdotuberkulez [Pseudotuberculosis]. Moscow, Medicine, 2001. 238 p.</mixed-citation></citation-alternatives></ref><ref id="cit9"><label>9</label><citation-alternatives><mixed-citation xml:lang="ru">Timchenko N.F., Nedashkovskaya E.P., Dolmatova L.S., Somova-Isachkova L.M. Toksiny Yersinia pseudotuberculosis [Toxins of Yersinia pseudotuberculosis]. Vladivostok, 2004. 220 p.</mixed-citation><mixed-citation xml:lang="en">Timchenko N.F., Nedashkovskaya E.P., Dolmatova L.S., Somova-Isachkova L.M. Toksiny Yersinia pseudotuberculosis [Toxins of Yersinia pseudotuberculosis]. Vladivostok, 2004. 220 p.</mixed-citation></citation-alternatives></ref><ref id="cit10"><label>10</label><citation-alternatives><mixed-citation xml:lang="ru">Timchenko N.F. Toksiny Yersinia pseudotuberculosis [ Yersinia pseudotuberculosis toxins]. Zhurnal mikrobiologii, epidemiologii i immunobiologii – Journal of Microbiology Epidemiology and Immunobiology, 2006,no. 6, pp. 83-89.</mixed-citation><mixed-citation xml:lang="en">Timchenko N.F. Toksiny Yersinia pseudotuberculosis [ Yersinia pseudotuberculosis toxins]. Zhurnal mikrobiologii, epidemiologii i immunobiologii – Journal of Microbiology Epidemiology and Immunobiology, 2006,no. 6, pp. 83-89.</mixed-citation></citation-alternatives></ref><ref id="cit11"><label>11</label><citation-alternatives><mixed-citation xml:lang="ru">Tsybulsky A.V., Popov A.M, Sanina N.M., Mazeyka A.N., Portnyagina O.Yu., Novikova O.D., Timchenko N.F., Kostetsky E.Ya. Immunogennye i protektivnye svoystva nanorazmernykh konstruktsiy na osnove tubulyarnykh immunostimuliruyushchikh kompleksov i poroobrazuyushchego belka iz Yersinia pseudotuberculosis [Immunogenic and protective properties of nanosized constructs based on tubular immunostimulating complexes and pore forming protein of Yersinia pseudotuberculosis]. Zhurnal mikrobiologii, epidemiologii i immunobiologii – Journal of Microbiology Epidemiology and Immunobiology, 2011, no. 2, pp. 43-47.</mixed-citation><mixed-citation xml:lang="en">Tsybulsky A.V., Popov A.M, Sanina N.M., Mazeyka A.N., Portnyagina O.Yu., Novikova O.D., Timchenko N.F., Kostetsky E.Ya. Immunogennye i protektivnye svoystva nanorazmernykh konstruktsiy na osnove tubulyarnykh immunostimuliruyushchikh kompleksov i poroobrazuyushchego belka iz Yersinia pseudotuberculosis [Immunogenic and protective properties of nanosized constructs based on tubular immunostimulating complexes and pore forming protein of Yersinia pseudotuberculosis]. Zhurnal mikrobiologii, epidemiologii i immunobiologii – Journal of Microbiology Epidemiology and Immunobiology, 2011, no. 2, pp. 43-47.</mixed-citation></citation-alternatives></ref><ref id="cit12"><label>12</label><citation-alternatives><mixed-citation xml:lang="ru">Carnoy C., Loiez C., Faveeuw C., Grangette C., Desreumaux P., Simonet M. Impact of the Yersinia pseudotuberculosis-derived mitogen (YPM) on the murine immune system. Adv. Exp. Med. Biol., 2003, vol. 529,pp. 133-135.</mixed-citation><mixed-citation xml:lang="en">Carnoy C., Loiez C., Faveeuw C., Grangette C., Desreumaux P., Simonet M. Impact of the Yersinia pseudotuberculosis-derived mitogen (YPM) on the murine immune system. Adv. Exp. Med. Biol., 2003, vol. 529,pp. 133-135.</mixed-citation></citation-alternatives></ref><ref id="cit13"><label>13</label><citation-alternatives><mixed-citation xml:lang="ru">Lockman H.A., Gillespie R.A., Baker B.D., Shakhnovich E. Yersinia pseudotuberculosis produces a cytotoxic necrotizing factor. Infect. Immun., 2002, vol. 70, pp. 2708-2714.</mixed-citation><mixed-citation xml:lang="en">Lockman H.A., Gillespie R.A., Baker B.D., Shakhnovich E. Yersinia pseudotuberculosis produces a cytotoxic necrotizing factor. Infect. Immun., 2002, vol. 70, pp. 2708-2714.</mixed-citation></citation-alternatives></ref><ref id="cit14"><label>14</label><citation-alternatives><mixed-citation xml:lang="ru">Rosqvist R., Forsberg A., Wolf-Watz H. Intracellular targeting of the Yersinia YopE cytotoxin in mammalia induces actin microfilament disruption. Infect. Immun., 1991, vol. 59, no. 12, pp. 4562-4569.</mixed-citation><mixed-citation xml:lang="en">Rosqvist R., Forsberg A., Wolf-Watz H. Intracellular targeting of the Yersinia YopE cytotoxin in mammalia induces actin microfilament disruption. Infect. Immun., 1991, vol. 59, no. 12, pp. 4562-4569.</mixed-citation></citation-alternatives></ref></ref-list><fn-group><fn fn-type="conflict"><p>The authors declare that there are no conflicts of interest present.</p></fn></fn-group></back></article>
