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МАТЕРИАЛЫ&ИССЛЕДОВАНИЯ

Заключение

В. С. Смирнов, Т. А. Кудрявцева

УДК  615.37:616.006:616.085:616.5

ББК    Р 281.794:Р 353:Р 569.60

Монография

2017 Вартоцид

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Заключение

Открытие С. Janeway [152] системы Толлподобных рецепторов (TLR) явилось одним из тех редких событий, которые радикально изменяют существующие представления о системе иммунитета. В этом смысле они в известной степени напоминают о двух величайших открытиях ХХ в. в области иммунологии — создание F. Burnet [59] клонально-селекционной теории иммунитета и открытие P. Medawar (1960) феномена толерантности. Авторы обоих были удостоены Нобелевской премии 1969 г.

Открытие TLR впервые показало, что существовавшее до этого времени представление о неспецифичности врожденного иммунитета ошибочно. На самом деле, первичная реакция на внедрившийся антиген оказалась вполне специфичной. Особый интерес представляют рецепторы TLR7 и TLR8, которые, кроме вирусной РНК, распознают синтетические молекулы, напоминающие молекулу гуанозина, — имихимод и резихимод. Агонист TLR7 (имихимод), а также TLR7 и 8 (резихимод) оказались подходящим инструментом не только при изучении внутриклеточного сигналинга, но и для лечения широкого круга заболеваний вирусной этиологии и злокачественных опухолей.

Папилломы и бородавки широко распространены у людей, а бородавки, локализованные в аногенитальной области, относятся к инфекциям, передаваемым половым путем. Существует много различных методов лечения бородавок, в основном механическое или химическое удаление, но они не воздействуют на ВПЧ. Это обусловливает довольно высокий уровень рецидивирования в ближайшие 12 мес после удаления бородавки. В отличие от перечисленных методов, имихимод, активирующий продукцию провоспалительных цитокинов, не только удаляет опухоль, но, будучи активным индуктором ИФН 1-го типа, подавляет репликацию вируса. Существенным механизмом терапевтического действия является активация апоптоза, также способного усилить очищение очага от поражения, вызванного ВПЧ. На этих же принципах основано многогранное противоопухолевое действие имихимода при лечении злокачественных заболеваний кожи.

Так, в ответ на местное применение наблюдается нормализация hedgehog сигналинга, а также подавление ангиогенеза, выработка проопухолевого цитокина IL-10 и противовирусного ци-токина ИФН 1-го типа. Вместе с тем, этот потенциал реализуется только при небольших опухолях диаметром до 2,5 см.

Существенным недостатком имихимода при его местной аппликации для лечения злокачественных и незлокачественных ВПЧ-зависимых заболеваний является риск рецидивирования.

В этой связи был сформулирован новый подход — комбинированная терапия, при которой имихимод применяется до или после другого метода, например имихимод может применяться до хирургической эксцизии или криотерапии. Цель такой комбинации — снижение размера папилломы или опухоли. Другой под-ход — хирургическое удаление, например опухоли или аногенитальной бородавки, а затем курс аппликации имихимода. Цель терапии — профилактика рецидива [226].

Среди возможных схем первая предполагает первичную аппликацию препарата на бородавку или опухоль с частотой 1–3 раза/нед ½ –1 мес, после окончания курса иммунотерапии проводят физическое удаление опухоли любым путем. Вторая схема — физическое удаление бородавки или опухоли, а после заживления операционной раны — курс имихимода 2– 4 раза/нед такой же продолжительности. Эффективность такого подхода подтверждена в работе K. Peris и M. C. Fargnoli [232], показавших, что применение имихимода при актиническом кератозе 2 раза/нед в течение 2 мес после 3–5 курсов криотерапии сопровождалось полным исчезновением очагов у 58 % больных, в то время как такой же результат после применения только криотерапии наблюдали у 34 % (p = 0,06). Авторы показали также эффективность комбинированного применения 5-фторурацила и имихимода. Вместе с тем, эта методика нуждается в дальнейшем исследовании и подтверждения в контролируемых рандомизированных исследованиях. К сожалению, как уже было отмечено, в Российской Федерации имихимод в препарате Вартоцид разрешен только при местной терапии аногенитальных бородавок у взрослых. Представляется, что это решение явно недостаточно, однако Вартоцид нуждается в дальнейшем изучении и расширении показаний для применения в клинике, например при злокачественных и условно-злокачественных поражениях кожи.

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