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 ( подробнее о клинических исследованиях лекарств в России). 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.

Литература:

Аксенов О. А. Особенности интерфероногенеза при вирусных и бактери-альных инфекциях (экспериментальные и клинические данные). Автореф. дис. докт. мед. наук. Л., 1987.

Бозрова С. В., Левицкий В. А., Недоспасов С. А., Друцкая М. С. Имиквимод: биохимические механизмы иммуномодулирующей и противовоспалитель-ной активности. Биомед. химия. 2013. 59 (3): 249–266.
Бохян Б. Ю., Медведев С. В., Феденко А. А., Харатишвили Т. К. Клиниче-ские рекомендации по лечению базально-клеточного и плоскоклеточного рака кожи. М., 2014.
Ганковская О. А. Исследование ассоциации полиморфных маркеров генов TLR2 и TLR9 с преждевременными родами и внутриутробным инфициро-ванием. Мед. иммунол. 2010; 12 (1–2): 87–94.
Колев Н., Бакарджиев И., Ковачев Е., Иванов С. Глицирретинова кисели-на — алтернативен метод за лечение на Condylomata acuminate. Акуш. ги-некол. (София). 2015; 54 (9): 16–18.
Лебедев К. А., Понякина И. Д. Иммунология образ-распознающих рецепто-ров. М.: Либроком, 2009.
Смирнов В. С. Комплексная иммуномодулирующая терапия папилломато-зов. Тез. докл. ХI Национального конгресса «Человек и лекарство». М., 2004.
Смирнов В. С. Сравнительная оценка интерфероногенных свойств неко-торых индукторов интерферона. Тез. докл. ХVI Национального конгресса «Человек и лекарство». М., 2009.
Смирнов В. С., Петленко С. В. Сравнительное влияние топических препа-ратов имихимода на неповрежденную кожу морских свинок. Рос. имму-нол. журн. 2016; 10 (19); 3: 346–349.
Смирнов В. С., Саватеева-Любимова Т. Н., Саватеев А. В. Влияние комби-нированного препарата глицирризиновой кислоты и глутамил-триптофана на течение контактного дерматита у крыс и их комбинации на экспрес-сию маркеров апоптоза при аллергическом контактном дерматите у крыс. Вестн. дерматол. и венерол. 2013; 5: 124–131.

Уэллс Х. Г. Химия иммунитета (пер. с англ.). М.: ГосМедИздат, 1929.

Цветков Э. А., Савенко И. В., Смирнов В. С. Способ лечения папилломатоза гортани у детей: Патент № 2111755, 1998.

Aaronson C. M., Lutzner M. A. Epidermodysplasia verruciformis and epider-moid carcinoma: electron microscopic observations. A.M.A.1967; 201 (10): 149–151.
Accardi R., Gheit T. Cutaneous HPV and skin cancer. Presse méd. 2014; 43 (12 Pt 2): e435–443.
Agrawal S., Gupta S. TLR1/2, TLR7, and TLR9 signals directly activate human peripheral blood naive and memory B cell subsets to produce cytokines, chemo-kines, and hematopoietic growth factors. clin. Immunol. 2011; 31 (1): 89–98.
Ahn C. S., Huang W. W. Imiquimod in the treatment of cutaneous warts: an evidence-based review. Amer. J. clin. Dermatol. 2014; 15 (5): 387–399.

Ajibade A. A., Wang H. Y., Wang R. F. Celltype-specificfunction of TAK1in in-nate immune signaling. Trends Immunol. 2013; 34: 307–316.
Akcali S., Goker A., Ecemis T. et al. Human papilloma virus frequency and genotype distribution in a Turkish population. Asian Pac. J. Cancer Prev. 2013; 14 (1): 503–506.
Akhavizadegan H. Electrocautery resection, shaving with a scalpel, and podo-phyllin: a combination therapy for giant condyloma acuminatum. Wld J. Mens Hlth. 2015; 33 (1): 39–41.
Akira S., Uematsu S., Takeuchi O. Pathogen recognition and innate immunity. 2006; 124: 783–801.
Alessi S. S., Sanches J. A., Oliveira W. R. et al. Treatment of cutaneous tumors with topical 5% imiquimod cream. Clinics (Sao Paulo). 2009; 64 (10): 961–966.
Almomen A., Jarboe E. A., Dodson M. K. et al. Imiquimod Induces Apoptosis in Human Endometrial Cancer Cells In vitro and Prevents Tumor Progression In vivo. Res. 2016; 33 (9): 2209–2217.
Alomar A., Bichel J., McRae S. Vehicle-controlled, randomized, double-blind study to assess safety and efficacy of imiquimod 5% cream applied once daily 3 days per week in one or two courses of treatment of actinic keratoses on the head. J. Dermatol. 2007; 157: 133–141.

Ambach A., Bonnekoh B., Nguyen M. et al. Imiquimod, a tolllike receptor-7 agonist, induces perforin in cytotoxic T lymphocytes in vitro. Immunol. 2004; 40: 1307–1314.
Anne M., Kuwabara B. A., Barbara M. et al. Children with warts: a retrospective study in an outpatient setting. Pediatric Dermatology. 2015; 32 (5): 679–683, anogenital warts. J. Europ. Acad. Dermatol. Venereol. 2013; 27:e263–e270.

Aranda-Flores C. E. Infecciуn por el virus del papiloma humano en varones. Obstet. Mex. 2015; 83 (11): 697–706.
Arany I., Tyring S. K., Stanley M. A. et al. Enhancement of the innate and cellular immune response in patients with genital warts treated with topical imiquimod cream 5%. Antiviral Res. 1999; 43 (1): 55–63.

Arends T. J., Lammers R. J., Falke J. et al. Pharmacokinetic, pharmacodynamic, and activity evaluation of TMX-101 in a multicenter phase 1 study in patients with papillary non-muscle-invasive bladder cancer. Genitourin. Cancer. 2015; 13 (3): 204–209.e2.

Asiaf A., Ahmad S. T., Mohammad S. O., Zargar M. A. Review of the current knowledge on the epidemiology, pathogenesis, and prevention of human papil-lomavirus infection. J. Cancer Prev. 2014; 23 (3): 206–224.
Assi R., Reddy V., Einarsdottir H., Longo W. E. Anorectal human papillomavi-rus: current concepts Yale. J. biol. 2014; 87 (4): 537–547.
Athar M., Li C., Kim A. L. et al. Sonic hedgehog signaling in basal cell nevus Cancer Res. 2014; 74 (18): 4967–4975.
Aubouy A., Olagnier D., Bertin G. et al. Nrf2-driven CD36 and HO-1 gene ex-pression in circulating monocytes correlates with favourable clinical outcome in pregnancy-associated malaria. Malar J. 2015; 14:358.
Averett D. R., Fletcher S. P., Li W. et al. The pharmacology of endosomal TLR agonists in viral disease. Soc. Transactions. 2007; 35 (6): 1468–1472.
Azuma M., Takeda Y., Nakajima H. et al. Biphasic function of TLR3 adjuvant on tumor and spleen dendritic cells promotes tumor T cell infiltration and regres-sion in a vaccine therapy. 2016; 5 (8): e1188244.
Bachman G. B., Bennet G. E., Barker R. S. Synthesis of substituted quinolynamines. Derivatives of 4-amino-7-cloroquinoline. J. Org. Chem. 1950; 15 (6): 1278–1284.

Backeberg O. G., Friendmann C. A. The reaction between hydrazine and 4-chlo-roquinoline derivatives. Chem. Soc. 1938; 972–977.
Backeberg O. G. The reaction between hydrazine and 4-chloroquinoline deriva-tives, and the preparation of the corresponding 4-benzeneazo- and 4-amino-compouns. Chem. Soc. 1938; 1083–1089.
Baker G. E., Tyring S. K. Therapeutic approaches to papillomavirus infections. Dis. Dermatol. 1997; 15: 331–340.
Bartoš V., Kullová M. Basal cell carcinoma of the skin with mixed histomor-phology: a comparative study. Čsl. Patol. 2016; 52 (4): 222–226.
Barzon L., Militello V., Pagni S. et al. Distribution of human papillomavirus types in the anogenital tract of females and males. med. Virol. 2010; 82 (8): 1424–1230.
Bath-Hextall F. J., Bong J., Perkins W., Williams H. C. Interventions for basal cell carcinoma of the skin. Cochrane Database Syst Rev. 2003; (2): CD003412.
Bath-Hextall F. J., Perkins W., Bong J., Williams H. C. Interventions for basal cell carcinoma of the skin. Cochrane Database Syst. Rev. 2007; (1): CD003412.
Bath-Hextall F., Bong J., Perkins W., Williams H. Interventions for basal cell carcinoma of the skin: systematic review. med. J. 2004; 329: 705.
Baumann J. L., Cohen S., Evjen A. N. et al. Human papillomavirus in early laryn-geal carcinoma. 2009; 119 (8): 1531–1537.
Bechtel M. A., Trout W. Sexually Transmitted Diseases. Obstet. Gynec. 2015; 58 (1): 172–184.

Behan J. W., Sutton A., Wysong A. Management of Skin Cancer in the High-Risk Curr. Treat. Options Oncol. 2016; 17 (12): 60.
Benevolo M., Doná M. G., Ravenda P. S., Chiocca S. Anal human papilloma-virus infection: prevalence, diagnosis and treatment of related lesions. Rev. Anti. Infect. Ther. 2016; 14 (5): 465–477.
Berg D., Otley C. C. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J. Amer. Acad. Dermatol. 2002; 47: 1–17.

Bernard H.-U., Burk R. D., Chen Z. et al. Classification of papillomaviruses (pvs) based on 189 pv types and proposal of taxonomic amendments. 2010; 401 (1): 70–79.
Beutner K. R., Tyring S. K., Trofatter K. F. Jr. et al. Imiquimod, a patient-applied immune-response modifier for treatment of external genital warts. Agents Chemother. 1998; 42: 789–794.
Bhatia S. K., Singh R., Bhatia R., Moudgil A. Perianal giant condylomata acu-minata: Buschke-Lowenstein tumour. West Indian Med. J. 2015. pii: wimj. 2015.147. doi: 10.7727/ wimj.2015.147.
Boatright K. M., Salvesen G. S. Mechanisms of caspase activation. Opin. Cell Biol. 2003; 15 (6): 725–731.
Bouchama F., van Aken G. A., Autin A. J. On the mechanism of catastrophic phase inversion in emulsions Colloids and Surfaces. Eng. Aspects. 2003; 231:11–17.
Brendle S. A., Bywaters S. M., Christensen N. D. Pathogenesis of infection by human papillomavirus. Probl. Dermatol. 2014; 45: 47–57.
Brestovac B., Harnett G. B., Smith D. W. et al. Human papillomavirus genotypes and their association with cervical neoplasia in a cohort of Western Australian women. med. Virol. 2005; 76 (1): 106–110.
Brodsky I., Medzhitov R. Two modes of ligand recognition by TLR. 2007; 130 (6): 979–981.
Broganelli P., Chiaretta A., Fragnelli B., Bernengo M. G. Intralesional cidofovir for the treatment of multiple and recalcitrant cutaneous viral warts. Ther. 2012; 25: 468–471.
Brown B., Davtyan M., Galea J. et al. The role of human papillomavirus in human immunodeficiency virus acquisition in men who have sex with men: a review of the literature. 2012; 4 (12): 3851–3858.
Burnet M. The clonal selection theory of acquired Immunity. Cambridge, 1959.

Cain K. Chemical-induced apoptosis: formation of the Apaf-1 apoptosome. Drug Metab. Rev. 2003; 35 (4): 337–363.

Carrasco D., Van der Straten M., Tyring S. K. Treatment of anogenital warts with imiquimod 5% cream followed by surgical excision of residual lesions. Amer. Acad. Dermatol. 2002; 47(4 Suppl): S212–216.
Catarino R., Vassilakos P., Jinoro J. et al. Human papillomavirus prevalence and type-specific distribution of high- and low-risk genotypes among Malagasy women living in urban and rural areas. Cancer Epidem. 2016; 42: 159–166.

Cenni V., Sirri A., De Pol A. et al. Interleukin-1-receptor-associated kinase 2 (IRAK2)-mediated interleukin-1-dependent nuclear factor kappaB transactiva-tion in Saos2 cells. J. 2003; 376 (Pt 1): 303–311.

Cha S., Johnston L., Natkunam Y., Brown J. Treatment of verruca vulgaris with topical cidofovir in an immunocompromised patient: A case report and review of the literature. Infect. Dis. 2005; 7: 158–161.
Chan S. Y., Bernard H. U., Ong C. K. et al. Phylogenetic analysis of 48 papil-lomavirus types and 28 subtypes and variants: a showcase for the molecular evolution of DNA viruses. Virol. 1992; 66 (10): 5714–5725.
Chang Y. C., Madkan V., Cook-Norris R. et al. Current and potential uses of South Med. J. 2005; 98 (9): 914–920.
Chao M. W., Gibbs P. Squamous cell carcinoma arising in a giant condyloma acu-minatum (Buschke-Lowenstein tumour). Asian J. Surg. 2005; 8 (3): 238–240.
Chen M., Griffi th B. P., Lucia H. L., Hsiung G. D. Efficacy of S26308 against guinea pig cytomegalovirus infection. Agents Chemother. 1988; 32 (5): 678–683.
Choi S. H., Kim K. H., Song K. H. Clinical features of cutaneous premalignant lesions in busan city and the eastern gyeongnam province, korea: a retrospective review of 1,292 cases over 19 years (1995~2013). Dermatol. 2016; 28 (2): 172–178.

Chosidow O., Dummer R. Imiquimod: Mode of action and therapeutic potential. Acta Derm. Venereol. 2003; 214 (Suppl.): 8–11.

Chrysagi A., Kaparos G., Vrekoussis T. et al. Prevalence of HPV genotypes in cervical adenocarcinoma: a study in Greek women. BUON. 2016; 21 (3): 666–672.
Claesson U., Lassus A., Happonen H. et al. Topical treatment of venereal warts: a comparative open study of podophyllotoxin cream versus solution. J. STD AIDS. 1996; 7: 429–434.
Clark R. A., Huang S. J., Murphy G. F. et al. Human squamous cell carcinomas evade the immune response by down-regulation of vascular E-selectin and re-cruitment of regulatory T cells. exp. Med. 2008; 205: 2221–2234.
Correa R. M., Vladimirsky S., Heideman D. A. Cutaneous human papillomavirus genotypes in different kinds of skin lesions in Argentina. med. Virol. 2017; 89 (2): 352–357.
Cotsarelis G., Sun T. T., Lavker R. M. Label-retaining cells reside in the bulge area of pilosebaceousunit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. 1990; 61 (7): 1329–1337.
Cranston R. D. Anal human papillomavirus infection in a street-based sample of drug using HIV-positive men. J. STD AIDS. 2012; 23: 195–200.
Cubie H. A. Diseases associated with human papillomavirus infection. 2013; 445: 21–34.
Czelusta A., Evans T., Arany I., Tyring S. A guide to immunotherapy of genital Biodrugs. 1999; 11: 319–332.

Dahl M. V. Imiquimod: an immune response modifier. Amer. Acad. Dermatol. 2000; 43: S1–S5.

Das G., Tan B., Nicholls K. Safety and efficacy of a novel short occlusive regi-men of imiquimod for selected non-melanotic skin lesions in renal transplant patients. med. J. 2016; 46 (3): 352–355.
David C. V., Nguyen H., Goldenberg G. Imiquimod: a review of off-label clinical applications. J. Drugs Dermatol. 2011; 10 (11): 1300–1306.

De Villiers E. M. Cross-roads in the classification of papillomaviruses. 2013; 445 (1–2): 2–10.
De Villiers E.-M., Fauquet C., Broker T. R. et al. Classification of papillomavi-ruses. Virology. 2004; 324: 17–27.
Deleuze-Masquefa C., Moarbess G., Khier S. et. al. New imidazo[1,2-a]qui-noxaline derivatives: synthesis and in vitro activity against human melanoma. J. med. Chem. 2009; 44 (9): 3406–3411.
Delius H., Saegling B., Bergmann K. et al. The genomes of three of four novel HPV types, defined by differences of their L1 genes, show high conservation of the E7 gene and the URR. 1998; 240 (2): 359–365.
Diamantis M. L., Bartlett B. L., Tyring S. K. Safety, efficacy & recurrence rates of imiquimod cream 5% for treatment of anogenital warts. Skin Ther. Lett. 2009; 14 (5): 1–3, 5.
Diebold S. S., Massacrier C., Akira S. et al. Nucleic acid agonists for Toll-like receptor 7 are defined by the presence of uridine ribonucleotides. J. Im-munol. 2006; 36 (12): 3256–3267.
Diepgen T. L., Mahler V. The epidemiology of skin cancer. J. Dermatol. 2002; 146 (Suppl. 61): 1–6.
Diez L. E., Iñarrea A., De la Orden A. et al. Prevalence and concordance of high-risk papillomavirus infection in male sexual partners of women diagnosed with high grade cervical lesions. Infec. Microbiol. Clin. 2016; pii: S0213-005X(16)00084-7.

Domínguez Gómez J., Simón R. D., Abreu D. A., Zelenkova H. Effectiveness of glycyrrhizinic Acid (glizigen) and an immunostimulant (viusid) to treat ano-genital warts. ISRN Dermatol. 2012; 2012: 863692.
Dona M. G., Latini A., Benevolo M. et al. Anal human papillomavirus infection prevalence in men who have sex with men is age-independent: a role for recent sexual behavior? Future Microbiol. 2014; 9 (7): 837–844.
Donalisio M., Poli A., Civra A. et al. Effects of cytokines on long control re-gion transcriptional activity in high-risk cutaneous human papillomavirus types 5 and 8. Virol. 2010; 155 (4): 583–587.
Douagi I., Gujer C., Sundling C. Human B cell responses to TLR ligands are dif-ferentially modulated by myeloid and plasmacytoid dendritic cells. Immunol. 2009 Feb 15; 182 (4): 1991–2001.
Dowling J. K., Dellacasagrande J. Toll-like receptors: ligands, cell-based models and readouts for receptor action. Methods Molec. Biol. 2016; 1390: 3–27.

Dowling J. K., Mansell A. Toll-like receptors: the swiss army knife of endeav-or immunity and vaccine development Clinical & Translational Immunology (2016) 5, e85; doi: 10.1038/cti.2016.22. eCollection 2016.

Drobits B., Holcmann M., Amberg N. et al. Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing ef-fector cells. clin. Invest. 2012; 122 (2): 575–585.
Erb P., Ji J., Wernli M. et al. Role of apoptosis in basal cell and squamous cell carcinoma formation. Lett. 2015; 100 (1): 68–72.
Erb P., Ji J., Kump E. et al. Apoptosis and pathogenesis of melanoma and non-melanoma skin cancer. exp. med. Biol. 2008; 624: 283–295.
Erkek E., Basar H., Bozdogan O., Emeksiz M. C. Giant condyloma acuminata of Buschke-Löwenstein: successful treatment with a combination of surgical excision, oral acitretin and topical imiquimod. exp. Dermatol. 2009; 34 (3): 366–368.

Fan Q., Cohen S., John B., Riker A. I. Melanoma in situ treated with topical imiquimod for management of persistently positive margins: a review of treat-ment Methods. Ochsner J. 2015; 15 (4): 443–447.
Faust H., Andersson K., Luostarinen T. et al. Cutaneous human papilloma-viruses and squamous cell carcinoma of the skin: nested case-control study. Cancer Epidem. Biomarkers Prev. 2016; 25 (4): 721–724.
Ferrándiz C., Malvehy J., Guillénc C. et al. Precáncer cutáneo. Actas Dermosi-filiogr. 2016; pii: S0001-7310(16)30284-8. doi: 10.1016/j.ad.2016.07.016.
Forsbach A., Samulowitz U., Völp K. et al. Dual or triple activation of TLR7, TLR8, and/or TLR9 by single-stranded oligoribonucleotides. Nucleic Acid Ther. 2011; 21: 423–436.
Forslund O., Hansson B. G. Human papillomavirus type 70 genome cloned from overlapping PCR products:complete nucleotide sequence and genomic organization. clin. Microbiol. 1996; 34 (4): 802–809.
Frost C., Williams G., Green A. High incidence and regression rates of solar keratoses in a queensland community. Invest. Dermatol. 2000; 115: 273–277.
Fuchs P. G., Girardi F., Pfi ster H. Human papillomavirus DNA in normal, metaplastic, preneoplastic and neoplastic epithelia of the cervix uteri. J. Cancer. 2006; 41: 41–45.
Ganjian S., Ourian A. J., Shamtoub G. et al. Off-label indications for imiqui-mod. Online J. 2009. May 15; 15 (5): 4.
Garland S. M. Curr. Opin. Infect. Dis. 2003; 16 (2): 85–89.

Gaspari A. A. Mechanism of action and other potential roles of an immune response modifier. 2007; 79 (4 Suppl.): 36–45.

Geisse J., Caro I., Lindholm J. et al. Imiquimod 5 % cream for the treatment of superficial basal cell carcinoma: results from two Phase III, randomized, vehicle-controlled studies. Amer. Acad. Dermatol. 2004; 50 (5): 722–733.
Gentile F., Deriu M. A., Licandro G. el al. Structure based modeling of small molecules binding to the TLR7 by atomistic level simulations. 2015; 20: 8316–8340.

Ghittoni R., Accardi R., Chiocca S., Tommasino M. Role of human papilloma-viruses in carcinogenesis. Cancer Med. Sci. 2015; 9: 526.
Giardino G., Cirillo E., Gallo V. et al. B cells from nuclear factor kB essential modulator deficient patients fail to differentiate to antibody secreting cells in response to TLR9 ligand. Immunol. 2015; 161 (2): 131–135.
Gibson S. J., Imbertson L. M., Wagner T. L. et al. Cellular requirements for cytokine production in response to the immunomodulators imiquimod and S-27609. Interferon Cytokine Res. 1995; 15 (6): 537–545.
Glick A. B. The role of TGFβ signaling in squamous cell cancer: Lessons from mouse models. J. Skin Cancer. 2012; 2012: 249063.

Gormley R. H., Kovarik C. L. Dermatologic manifestations of HPV in HIV-infected individuals. Curr HIV/AIDS Rep. 2009; 6 (3): 130–138.
Götz A. W., Williamson M. J., Xu D. et al. Microsecond molecular dynamics simulations with AMBER on GPUs. 1. Generalized born. J. Chem. Theory Comput. 2012; 8: 1542–1555.
Grachtchouk M., Pero J., Yang S. H. et al. Basal cell carcinomasin mice arise from hair follicle stem cells and multiple epithelial progenitor populations. clin. Invest. 2011; 121 (5): 1768–1781.
Greensill A., Yong M., O’Mahony C. Imiquimod use in adolescents: off-label but effective. Int. J. STD AIDS. 2012; 23 (4): 297–299.

Griffi n L. L., Rehman A. F., Ali B., Lear J. T. Nonmelanoma skin cancer. Med. 2016; 16 (1): 62–65.
Grillo-Ardila C. F., Angel-Müller E., Salazar-Díaz L. C. et al. Imiquimod for anogenital warts in non-immunocompromised adults (Review). Cochrane Da-tabase Syst Rev. 2014; 11: CD010389.
Gross G. Klinik und Therapie anogenitaler Warzen und papillomvirusassozi-ierter Krankheitsbilder. 2001; 52: 6–17.
Gross G. Therapy of human papillomavirus infection and associated epithelial Intervirology. 1997; 40 (5–6): 368–377.
Guerrero A. T., Pinto L. G., Cunha F. Q. et al. Mechanisms underlying the hy-peralgesic responses triggered by joint activation of TLR4. Rep. 2016; 68 (6): 1293–1300.
Gupta A. K., Browne M., Bluhm R. Imiquimod: A Review. Cutan. Med. Surg. 2002; 6 (6): 554–560.

Hagiwara K., Uezato H., Arakaki H. et al. A genotype distribution of human papil-lomaviruses detected by polymerase chain reaction and direct sequencing analysis in a large sample of common warts in Japan. med. Virol. 2005; 77 (1): 107–112.

Hanke C. W., Beer K. R., Stockfl eth E. et al. Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of two placebo-controlled studies of daily application to the face and balding scalp for two 3-week cycles. Amer. Acad. Dermatol. 2010; 62: 573–581.

Hanna E., Abadi R., Abbas O. Imiquimod in dermatology: an overview. J. Dermatol. 2016; 55 (8): 831–844.

Harrison C. J., Stanberry L. R., Bernstein D. I. Effects of cytokines and R-837, a cytokine inducer, on UV-irradiation augmented recurrent genital herpes in guinea pigs. Antiviral Res. 1991; 15 (4): 315–322.

Harrison L. I., Skinner S. L., Marbury T. C. et al. Pharmacokinetics and safety of imiquimod 5 % cream in the treatment of actinic keratoses of the face, scalp, or hands and arms. Dermatol. Res. 2004; 296: 6–11.
Harrison L. I., Stoesz J. D., Battiste J. L. et al. A pharmaceutical comparison of different commercially available imiquimod 5 % cream products. Dermato-log. Treat. 2009; 20 (3): 1–5.
Heil F., Hemmi H., Hochrein H. et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 2004; 303: 1526–1529.
Hemmi H., Kaisho T., Takeuchi O. et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Immu-nol. 2002; 3: 196–200.
Hemper E., Wittau M., Lemke J. et al. Management of a giant perineal condylomata GMS Interdiscip. Plast. Reconstr. Surg. DGPW. 2016; 5: Doc07.

Heppt M., Von Braunmühl T., Berking C. Was gibt es Neues zum Basalzellkar-zinom? 2016; 67 (11): 876–883.
Herrel N. R., Johnson N. L., Cameron J. E. et al. Development and validation of a HPV-32 specific PCR assay. J. 2009; 6: 90.
Herrero R., Castle P. E., Schiffman M. Epidemiologic profile of type-specific human papillomavirus infection and cervical neoplasia in Guanacaste, Costa Rica. J. Infect. 2005; 191 (11): 1796–1807.
Higgs R., Lazzari E., Wynne C. Self protection from anti-viral responses–Ro52 promotes degradation of the transcription factor IRF7 downstream of the viral Toll-Like receptors. PLoS One. 2010; 5 (7): e11776.
Hipp M. M., Shepherd D., Gileadi U. et al. Processing of Human Toll-likeRe-ceptor 7 by Furin-like Proprotein Convertases Is Required for Its Accumulation and Activity in Endosomes. 2013; 39: 711–721.
Hoyme U. B., Hagedorn M., Schindler A.-E. et al. Effect of adjuvant imiqui-mod 5 % cream on sustained clearance of anogenital warts following laser treatment. Dis. Obstet. Gynec. 2002; 10: 79–88.
Huang H. F., Zeng Z., Wang K. H. et al. Heme oxygenase-1 protects rat liver against warm ischemia/reperfusion injury via TLR2/TLR4-triggered signaling pathways. Wld J. Gastroenterol. 2015; 21 (10): 2937–2948.
Huang S. J., Hijnen D., Murphy G. F. et al. Imiquimod enhances ИФНγ pro-duction and effector function of Tcells infiltrating human squamous cell carci-nomas of the skin. Invest. Dermatol. 2009; 129 (11): 2676–2685.
Hussein N. R., Balatay A. A., Assafi M. S. et al. High Risk Human Papilloma Vi-rus Genotypes in Kurdistan Region in Patients with Vaginal Discharge. Asian Pac. J. Cancer Prev. 2016; 17 (7): 3191–3193.
Hussein W. M., Choi P., Zhang C. et al. Evaluation of lipopeptides as toll-like receptor 2 ligands. Drug Deliv. 2016; 13 (8).

Iavarone C., Ramsauer K., Kubarenko A. V., Debasitis J. C. et al. A point mu-tation in the amino terminus of TLR7 abolishes signaling without affecting ligand binding. Immunol. 2011; 186: 4213–4222.

Ichinohe T., Tamura S., Kawaguchi A. et al. Cross-protection against H5N1 influenza virus infection is afforded by intranasal inoculation with seasonal trivalent inactivated influenza vaccine. Infect. Dis. 2007; 196: 1313–1320.
Imbertson L. M., Beaurline J. M., Couture A. M. et al. Cytokine induction in hairless mouse and rat skin аfter topical application of the immune re-sponse modifiers imiquimod and S-28463. Invest. Dermatol. 1998; 110: 734–739.

Inglefield J. R., Dumitru C. D., Alkan S. S. et al. TLR7 agonist 852A inhibition of tumor cell proliferation is dependent on plasmacytoid dendritic cells and type I ИФН. J. Interferon Cytokine Res. 2008; 28 (4): 253–263.
Ishii N., Funami K., Tatematsu M. et al. Endosomal localization of TLR8 con-fers distinctive proteolytic processing on human myeloid cells. Immunol. 2014; 193 (10): 5118–5128.
Işik S., Koca R., Sarici G., Altinyazar H. C. A comparison of a 5% potassium hydroxide solution with a 5-fluorouracil and salicylic acid combination in the treatment of patients with anogenital warts: a randomized, open-label clinical trial. J. Dermatol. 2014; 53 (9): 1145–1150.

Jähnisch H., Wehner R., Tunger A. et al. TLR7/8 agonists trigger immunos-timulatory properties of human 6-sulfo LacNAc dendritic cells. Cancer Lett. 2013; 335: 119–127.
Janeway C. A. Pillars article: approaching the asymptote? Evolution and revolution in immunology. spring harb. symp. quant. biol. 1989. 54: 1–13.
Janeway C. A. Jr. Medzhitov R. Innate immune recognition. Rev. Immu-nol. 2002; 20: 197–216.
Jenkins A. L., Lang C. M., Budgeon L. R. et al. Mucosally-derived HPV-40 can infect both human genital foreskin and cutaneous hand skin tissues grafted into athymic mice. Virus Res. 2003; 93 (1): 109–114.
Jin S. X., Yin K. S., Bian T., Sun P. L. Imiquimod attenuates airway inflammation and decreases the expression of thymus and activation regulated chemokine in allergic asthmatic mice. Med. J. (Engl). 2006; 119 (5): 412–416.
Jobanputra K. S., Rajpal A. V., Nagpur N. G. Indian J. Dermatol. Veneriol. Leprol. 2006; 72 (6): 466–469.
Joseph R. W., Cappel M., Tzou K. et al. Treatment of in-transit and metastatic melanoma in two patients treated with ipilimumab and topical imiquimod. Melanoma Res. 2016; 26 (4): 409–412.
Juhl M. E., Seferovic V., Antonijevic S., Krunic A. Combined treatment of ano-genital HPV infection with cryodestruction, podophyllin 25 % and post-abla-tion immunomodulation with sinecatechins 15 % ointment — a retrospective analysis. J. STD AIDS. 2016; 27 (12): 1071–1078.

Kadowaki N., Ho S., Antonenko S. et al. Subsets of human dendritic cell pre-cursors express different toll-like receptors and respond to different microbial antigens. exp. Med. 2001; 194 (6): 863–869.

Kan Y., Okabayashi T., Yokota S. et al. Imiquimod suppresses propagation of herpes simplex virus 1 by upregulation of cystatin A via the adenosine receptor A1 pathway. Virol. 2012; 86 (19): 10338–10346.
Kaur P., Mulvaney M., Carlson J. A. Basal cell carcinoma progression corre-lates with host immune response and stromalalterations: a histologic analysis. J. Dermatopathol. 2006; 28 (4): 293–307.
Kawai T., Akira S. The role of pattern-recognition receptors in innate immu-nity: update on Toll-like receptors. Immunol. 2010; 11 (5): 373–384.
Kawasaki T., Kawai T. Toll-like receptor signaling pathways. Front Immunol. 2014; 5: 461.
Kim C., Cheng J., Colegio O. R. Cutaneous squamous cell carcinomas in solid organ transplant recipients: emerging strategies for surveillance, staging, and treatment. Oncol. 2016; 43 (3): 390–394.
King C. M., Johnston J. S., Ofi li K. et al. Human papillomavirus types 2, 27, and 57 Identified in plantar verrucae from HIV-positive and HIV-negative individuals. Amer. Podiat. Med. Ass. 2014; 104 (2): 141–146.
Koeneman M. M., Kruse A. J., Kooreman L. F. et al. Topical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia (TOPIC trial): study protocol for a randomized controlled trial. BMC Cancer. 2016; 16: 132.

Koenigs E., Freund J. Uber die Einwirkung von Hydrazinen auf 4-Chlor-cho-naldin Chemische Berichte.1947; 80: 143–149.
Kollipara R., Ekhlassi E., Downing C. et al. Advancements in Pharmaco-therapy for Noncancerous Manifestations of HPV. J. clin. 2015; 4 (5): 832–846.
Konstantopoulou M., Lord M. G., Macfarlane A. W. Treatment of invasive squamous cell carcinoma with 5-percent imiquimod cream. Online
1. 2006; 12 (3): 10.
Kremsdorf D., Jablonska S., Favre M., Orth G. Human papillomaviruses as-sociated with epidermodysplasia verruciformis. II. Molecular cloning and bio-chemical characterization of human papillomavirus 3a, 8, 10, and 12 genomes.
1. 1983; 48 (2): 340–351.
Kuznetsova S. A., Starikova E. A., Freidlin I. S., Smirnov V. S. In vitro studies of changes in human endothelial cell functions under the effect of imiquimod. exp. Biol. Med. 2012; 154 (2): 237–240.
Kwok C. S., Gibbs S., Bennett C. et al. Topical treatments for cutaneous warts. Cochrane Database of Syst. Rev. 2012; 9. Art. No. CD001781.
Lacey C. J., Woodhall S. C., Wikstrom A., Ross J. 2012 European guideline for the management of anogenital warts. Europ. Acad. Dermatol. Venereol. 2013; 27(3): e263–270.

Lathers D. M., Young M. R. Increased aberrance of cytokine expression in plas-ma of patients with more advanced squamous cell carcinoma of the head and neck. 2004; 25: 220–228.

Lee S. H., Toth Z., Wong L. Y. et al. Novel phosphorylations of IKKγ/NEMO. 2012; 3 (6): e00411–412.
Leigh I. M. Progress in skin cancer: the U. K. experience. J. Dermatol. 2014; 443–445.

Leiter U., Gutzmer R., Alter M. et al. Kutanes Plattenepithelkarzinom. Hautarzt. 2016; 67 (11): 857–866.
Lewandowsky F., Lutz W. Ein Fall einer bisher nicht beschriebenen Hauterkrankung (Epidermodysplasia Verruciformis). Derm. Syph. 1922; 141: 193–203.

Li J., Zhang T. Y., Tan L. T. et al. Expression of human papillomavirus and prognosis of juvenile laryngeal papilloma. J. clin. Exp. Med. 2015; 8(9): 15521–15527.

Li V. W., Li W. W. Antiangiogenesis in the treatment of skin cancer. Drugs Dermatol. 2008; 7 (Suppl. 1): s17–24.
Li X., Liang L., Feng Y. A. et al. Height, height-related SNPs, and risk of non-melanoma skin cancer. J. Cancer. 2016; doi: 10.1038/bjc.2016.366.
Lichon V., Khachemoune A. Plantar warts: a focus on treatment modalities.Dermatol. Nurs. 2007; 19 (4): 372–375.

Liu F., Xia Y., Parker A. S., Verma I. M. IKK biology. Rev. 2012; 246 (1): 239–253.
Liu R., Luo F., Liu X. et al. Biological response modifier in cancer immuno-therapy. exp. Med. Biol. 2016; 909: 69–138.
Longo C., Pellacani G. Dermatol. Clin. 2016; 34 (4): 411–419.

Loo S. K., Tang W. Y. Warts (non-genital). Brit. med. J. Clin. Evid. 2009; pii:

Love W. E., Bernhard J. D., Bordeaux J. S. Topical imiquimod or fluorouracil therapy for basal and squamous cell carcinoma: a systematic review. Dermatol. 2009; 145 (12): 1431–1438.
Lu H., Wagner W. M., Gad E. et al. Treatment failure of a TLR-7 agonist occurs due to self-regulation of acute inflammation and can be overcome by IL-10 blockade. Immunol. 2010; 184 (9): 5360–5367.
Luis B. A. Estudio multićentrico, prospectivo, abierto, controlado, sobre la efi-cacia, la seguridad clı́nica y la tolerabilidad local de la administracion repetitiva (t.i.d.) por 5 dı́as del ácidó glicirricı́nico activado (Epigen) en pulverizaciones locales a pacientes cursando con herpes genital, Hospital General de Mexíco, Servicio de Infectologia, Mexíco City, Mexíco, 1997.

Lund J. M., Alexopoulou L., Sato A. et al. Recognition of single-stranded RNA viruses by Toll-like receptor 7. nat. Acad. Sci. USA 2004; 101: 5598–5603.
Madan V., Lear J. T., Szeimies R. M. Non-melanoma skin cancer . 2010; 673–685 .

Magrane M., Consortium U. UniProt Knowledgebase: A hub of integrated protein data. Database (Oxford). 2011: bar009.

Majewski S., Marczak M., Mlynarczyk B. et al. Imiquimod is a strong inhibitor of tumor cell-induced angiogenesis Int. J. Dermatol. 2005; 44 (1): 14–19.

Maniar K. P., Ronnett B. M., Vang R., Yemelyanova A. Coexisting high-grade vulvar intraepithelial neoplasia (VIN) and condyloma acuminatum: indepen-dent lesions due to different HPV types occurring in immunocompromised pa-tients. J. Surg. Pathol. 2013; 37 (1): 53–60.

Mariotti E., Allegrini P., Castaldi G. Process for the preparation of imiquimod and intermediates thereof. Diapharma S.p.A. Data of filing 28.10.1004.
Marks R., Gebauer K., Shumack S. et al. Australasian Multicentre Trial Group. Imiquimod 5% cream in the treatment of superficial basal cell carcinoma: re-sults of a multicenter 6-week dose-response trial. Amer. Acad. Dermatol. 2001; 44: 807–813.

Marsden J. R., Fox R., Boota N. M. et al. Effect of topical imiquimod as pri-mary treatment for lentigo maligna — the LIMIT-1 study. J. Dermatol. 2016: doi 10.1111/bjd.15112.
Martinelli C., Farese A., Mistro A. D. et al. Resolution of recurrent perianal condylomata acuminate by topical cidofovir in patients with HIV infection. Europ. Acad. Dermatol. Venereol. 2001; 15: 568–569.
Maschalidi S., Hässler S., Blanc F. et al. Asparagine endopeptidase controls anti-influenza virus immune responses through TLR7 activation. PLoS Pathog. 2012; 8: e1002841.
Matsushima N., Tanaka T., Enkhbayar P. et al. Comparative sequence analysis of leucine-rich repeats (LRRs) within vertebrate toll-like receptors. BMC Ge-nomics. 2007; 8: 124.
Maverakis E., Cornelius L. A., Bowen G. M. Metastatic Melanoma — A Review of Current and Future Treatment Options. Acta Derm. Venereol. 2015; 95: 516–524.

McGettrick A. F., O’Neill L. A. Toll-like receptors: key activators of leucocytes and regulator of haematopoiesis. Brit. J. Haematol. 2007; 139 (2): 185–193.

Medzhitov R., Preston-Hurlburt P., Janeway C. A. Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. 1997; 388: 394–397.
Medzhitov R., Janeway C. A. Jr. Innate immune recognition and control of adaptive immune responses. Immunol. 1998; 10 (5): 351–353.
Medzhitov R., Janeway C. A. Jr. Innate immunity: the virtues of a nonclonal system of recognition. Cell. 1997; 91(3): 295–298.

Medzhitov R., Shevach E. M., Trinchieri G. et al. Highlights of 10 years of immunol-ogy in Nature Reviews Immunology. Rev. Immunol. 2011; 11 (10): 693–702.

Memar O. M., Tyring S. K. Antiviral agents in dermatology: current status and future prospects. Int. J. Dermatol. 1995; 34 (9): 597–606.

Meyer T., Nindl I., Schmook T. et al. Induction of apoptosis by Toll-like recep-tor-7 agonist in tissue cultures. J. Dermatol. 2003; 149 (Supl. 66): 9–13.
Micallef M. J., Ohtsuki T., Kohno K. et al. Interferon-gamma inducing factor enhances Th1 cytokine production by stimulated human T cells: synergism with interleukin 12 for interferon gamma production. Europ. J. Immunol. 1996; 26: 1647–1651.

Mihaly S. R., Ninomiya-Tsuji J., Morioka S. TAK1 control of cell death. Cell Death Differ. 2014; 21 (11): 1667–1676.

Miller R. L., Gerster J. F., Owens M. L. et al. Imiquimod applied topically: a novel immune response modifier and new class of drug. Int. J. Immunophar-macol. 1999; 21: 1–14.

Mlakar B., Kocjan B. J., Hošnjak L. et al. Betapapillomaviruses in the anal canal of HIV positive and HIV negative men who have sex with men. clin. Virol. 2014; 61 (2): 237–241.
Mohtasebi P., Rassi H., Maleki F. et al. Detection of Human Papillomavirus Genotypes and Major BRCA Mutations in Familial Breast Cancer. Antib. Immunodiagn. Immunother. 2016; 35 (3): 135–140.
Molteni M., Gemma S., Rossetti C. The Role of Toll-Like Receptor 4 in In-fectious and Noninfectious Inflammation. Mediators Inflamm. 2016; 2016: 6978936.
Moore R. A., Edwards J. E., Hopwood J., Hicks D. Imiquimod for the treatment of genital warts: a quantitative systematic review. BMC Infect. Dis. 2001; 1: 3.
Morales-Sánchez A., Fuentes-Pananá E. M. Human viruses and cancer. Virus-es. 2014; 6 (10): 4047–4079.
Motoi Y., Shibata T., Takahashi K. et al. Lipopeptides are signaled by Toll-like receptor 1, 2 and 6 in endolysosomes. Immunol. 2014; 26 (10): 563–573.
Müller C., Tufa D. M., Chatterjee D. The TLR-2/TLR-6 agonist macrophage-activating lipopeptide-2 augments human NK cell cytotoxicity when PGE2 production by monocytes is inhibited by a COX-2 blocker. Cancer Immunol. Immunother. 2015; 64 (9): 1175–1184.

Natoli G., Saccani S., Bosisio D., Marazzi I. Interactions of NF-kappaB with chromatin: the art of being at the right place at the right time. Immunol. 2005; 6 (5): 439–445.
Navi D., Huntley A. Imiquimod 5 % cream and the treatment of cutaneous ma-lignancy. Online J. 2004; 10.
Nishimura M., Naito S. Tissue-specific mRNA expression profiles of human toll-like receptors and related genes. Pharm. Bull. 2005; 28 (5): 886–892.
Ntoufa S., Vilia M. G., Stamatopoulos K. et al. Toll-like receptors signaling: A complex network for NF-κB activation in B-cell lymphoid malignancies Se-min Cancer Biol. 2016; 39: 15–25.
Nürnberger T., Brunner F. Innate immunity in plants and animals: emerging parallels between the recognition of general elicitors and pathogen-associated molecular patterns. Opin. Plant. Biol. 2002; 5 (4): 318–324.
Nüsslein-Volhard C., Wieschaus E. Mutations affecting segment number and polarity in Drosophila. 1980; 287: 795–801.
Nyitray A. G. Iannacone M. R. The Epidemiology of Human Papillomaviruses Probl. Dermatol. 2014; 45: 75–91.

Ondo A. L., Padilla R. S., Miedler J. D., Cockerell C. J. et al. Treatment-re-fractory actinic keratoses successfully treated using simultaneous combina-tion topical 5-fluorouracil cream and imiquimod cream: a case-control study. Surg. 2012; 38: 1469–1476.

Papakostas D., Stockfleth E. Topical treatment of basal cell carcinoma with the immune response modifier imiquimod. Future Oncol. 2015; 11 (22): 2985–2990.
Park I. U., Introcaso C., Dunne E. F. Human Papillomavirus and Genital Warts: A Review of the Evidence for the 2015 Centers for Disease Control and Pre-vention Sexually Transmitted Diseases Treatment Guidelines. Infect. Dis. 2015. 61 (Suppl. 8): S849–855.

Patel H., Wagne M., Singhal P., Kothari S. Systematic review of the incidence and prevalence of genital warts. BMC Infect. Dis. 2013; (13): 39.
Patel R. V., Yanofsky V. R., Goldenberg G. Genital warts: a comprehensive review. J. clin. Aesthet. Dermatol. 2012; 5: 25–36.

Pérez M. P. B., Ruiz-Villaverde R., Díaz M. J. N. et al. Basal cell carcinoma: treatment with Imiquimod. J. Dermatol. 2007; 46: 539–542.
Peris K., Fargnoli M. C. Conventional Treatment of Actinic Keratosis: An Overview. Curr. Probl. Dermatol. (Basel, Karger). 2015; 46: 108–114.

Peterson C. S., Agner T., Ottevanger A. et al. A single blind study of podophyl-lotoxin cream 0.5 % and podophyllotoxin solution 0,5 % in male patients with genital warts. Med. 1995; 71: 391–392.
Petzke M. M., Brooks A., Krupna M. A. et al. Recognition of Borrelia burgdor-feri, the Lyme disease spirochete, by TLR7 and TLR9 induces a type I ИФН response by human immune cells. Immunol. 2009; 183 (8): 5279–5292.
Płóciennikowska A., Hromada-Judycka A., Dembińska J. et al. Contribution of CD14 and TLR4 to changes of the PI (4,5)P2 level in LPS-stimulated cells. Leukoc. Biol. 2016; pii: jlb.2VMA1215–577R.
Pope S. D., Medzhitov R. Unwinding inducible gene expression. 2016; 352 (6289): 1058–1059.
Qi H., Sun L., Wu X. et al. Toll-like receptor 1 (TLR1) Gene SNP rs5743618 is associated with increased risk for tuberculosis in Han Chinese children. Tuberculosis (Edinb). 2015; 95 (2): 197–203.
Ramnath D., Powell E. E., Scholz G. M., Sweet M. J. The toll-like receptor 3 pathway in homeostasis, responses to injury and wound repair. Seminars Cell Dev. Biol. 2016; pii: S1084-9521(16)30252-X.
Ratushny V., Gober M. D., Hick R. et al. From keratinocyte to cancer: the patho-genesis and modeling of cutaneous squamous cell carcinoma. clin. Invest. 2012; 122: 464–472.
Rechtsteiner G., Warger T., Osterloh P. et al. Cutting edge: priming of CTL by transcutaneous peptide immunization with imiquimod. Immunol. 2005; 174: 2476–2480.
Reiter M. J., Testerman T. L., Miller R. L. et al. Cytokine induction in mice by the immunomodulator Imiquimod. Leukoc. Biol. 1994. 55 (2): 234–240.

Relieving DNA torsional stress may follow chromatin remodeling to facili-tate transcription requires the Akt/protein kinase B kinase. J. 2003; 376 (Pt 1): 303–311.

Rhodes J. Discovery of immunopotentiatory drugs: current and future strategies. Clin. Exp. Immunol. 2002; 130 : 363–369.

Rhyasen G. W., Starczynowski D. T. IRAK signalling in cancer. J. Cancer. 2015; 112 (2): 232–237.
Rialdi A., Campisi L., Zhao N. et al. Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation. 2016; 352(6289): aad7993.
Ripabelli G., Grasso G. M., Del Riccio I. et al. Prevalence and genotype identifi-cation of human papillomavirus in women undergoing voluntary cervical cancer screening in Molise, central Italy. Cancer Epidem. 2010; 34 (2): 162–167.
Rivera A., Tyring S. K. Therapy of cutaneous human Papillomavirus infections. Ther. 2004; 17: 441–448.
Rodier C., Lapointe A., Coutlée F. et al. Juvenile respiratory papillomatosis: risk factors for severity. med. Virol. 2013; 85 (8): 1447–1458.
Roman M., Martin-Orozco E., Goodman J. S. et al. Immunostimulatory DNA se-quences function as T helper-1-promoting adjuvants. Nat Med 1997; 3: 849–54.
Rubin A. I., Chen E. H., Ratner D. Basal cell carcinoma. New Engl. J. Med. 2005; 353 : 2262–2269.
Rudolph S. E., Lorincz A., Wheeler C. M. et al. Population-based prevalence of cervical infection with human papillomavirus genotypes 16 and 18 and other high risk types in Tlaxcala, Mexico. BMC Infect. Dis. 2016; 16: 461.
Russo C., Cornella-Taracido I., Galli-Stampino L. et al. Small molecule Toll-like receptor 7 agonists localize to the MHC class II loading compartment of human plasmacytoid dendritic cells. 2011; 117 (21): 5683–5691.
Safi F., Bekdache O., Al-Salam S. et al. Management of peri-anal giant condyloma acuminatum a case report and literature review. Asian J Surg. 2013; 36 (1): 43–52.

Safrin S., Cherington J., Jaffe H. S. Clinical uses of cidofovir. Med. Virol. 1997; 7: 145–156.
Sakaguchi S., Sakaguchi N., Asano M. et al. Immunologic self-tolerance main-tained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoim-mune diseases. Immunol. 1995; 155: 1151–1164.

Sauder D. N. Imiquimod: modes of action. J. Dermatol. 2003; 149 (Suppl. 66): 5–8.

Scheinfeld N., Lehman D. S. An evidence-based review of medical and surgical treatments of genital warts. Online J. 2006; 12: 5.
Schiller M., Metze D., Luger T. A. et al. Immune response modifiers–mode of Exp. Dermatol. 2006;15 (5): 331–341.
Schön M. P., Schön M. Imiquimod: mode of action. J. Dermatol. 2007; 157 (Suppl. 2): 8–13.

Schön M. P., Schön M., Klotz K. N. The small antitumoral immune response modifier imiquimod interacts with adenosine receptor signaling in a TLR7- and TLR8-independent fashion. Invest. Dermatol. 2006; 126 (6): 1338–1347.

Schön M. P., Wienrich B. G., Drewniok C. et al. Death receptor-independent apoptosis in malignant melanoma induced by the smallmolecule immune re-sponse modifier imiquimod. Invest. Dermatol. 2004; 122: 1266–1276.
Schön M. P. Inflammation and Tumor Biology. New Engl. J. Med. 2005; 352 (18): 1899–1912.
Schön M. P., Bong A. B., Drewniok C. Tumor-selective induction of apoptosis and the small-molecule immune response modifier imiquimod. nat. Cancer Inst. 2003; 95 (15): 1138–1149.
Serra-Guillén C., Nagore E., Hueso L. et al. A randomized pilot comparative study of topical methyl aminolevulinate photodynamic therapy versus imiqui-mod 5% versus sequential application of both therapies in immunocompetent patients with actinic keratosis: clinical and histologic outcomes. Amer. Acad. Dermatol. 2012; 66: 131–137.

Shinohara M. L., Lu L., Bu J. Osteopontin expression is essential for interferon-alpha production by plasmacytoid dendritic cells. Immunol. 2006; 7 (5): 498–506.
Sidky Y. A., Borden E. C., Weeks C. E. et al. Inhibition of murine tumor growth by an interferon-inducing imidazoquinolinamine. Cancer Res. 1992; 52 (13): 3528–3533.
Sidky Y. A., Borden E. G., Weeks G. E. Inhibition of tumorinduced angiogenesis by the interferon inducer Imiquimod. Amer. Ass. Cancer Res. 1992; 33: 458.

Siegel J. A. Korgavkar K., Weinstock M. A. Current perspective on actinic kera-tosis: a review. J. Dermatol. 2016: doi: 10.1111/bjd.14852.
Silverberg J. I., Silverberg N. B. The US prevalence of common warts in child-hood: a population-based study. Invest. Dermatol. 2013; 133: 2788–2790.
Silverberg M. J., Leyden W., Warton E. M. et al. HIV infection status, immuno-deficiency, and the incidence of non-melanoma skin cancer. nat. Cancer Inst. 2013; 105: 350–360.
Sin C. W., Barua A., Cook A. Recurrence rates of periocular basal cell carcinoma following Mohs micrographic surgery: a retrospective study. J. Dermatol. 2016; 55 (9): 1044–1047.
Singal A., Daulatabad D., Pandhi D., Arora V. K. Facial Basal Cell Carcinoma Treated with Topical 5% Imiquimod Cream with Dermoscopic Evaluation. Cutan Aesthet. Surg. 2016; 9 (2): 122–125.
Slade H. B., Owens M.L., Tomai M. A., Miller R. L. Imiquimod 5 % cream (Al-dara™). Opin. Invest. Drugs. 1998; 7 (3): 437–449.
Smith C. W., Chen Z., Dong G. et al. The host environment promotes the devel-opment of primary and metastatic squamous cell carcinomas that constitutively express proinflammatory cytokines IL-1alpha, IL-6, GM-CSF, and KC. exp. Metastasis. 1998; 16: 655–664.

Smits E. L., Ponsaerts P., Berneman Z. N. et al. The Use of TLR7 and TLR8 Ligands for the Enhancement of Cancer Immunotherapy. 2008; 13: 859–875.

Soltani-Arabshahi R., Tristani-Firouzi P. Chemoprevention of nonmelanoma skin cancer. Facial Plast. Surg. 2013; 29 (5): 373–383.
Song F., Qureshi A. A., Giovannucci E. L. et al. Risk of a second primary cancer after non-melanoma skin cancer in white men and women: a prospective cohort study. PLoS Med. 2013; 10 (4): e1001433.
Song S. S., Goldenberg A., Ortiz A. et al. Nonmelanoma Skin Cancer With Aggressive Subclinical Extension in Immunosuppressed Patients. A.M.A. Dermatol. 2016; 152 (6): 683–690.
Spelmink L., Sender V., Hentrich K. et al. Toll-Like Receptor 3/TRIF-Depen-dent IL-12p70 Secretion Mediated by Streptococcus pneumoniae RNA and Its Priming by Influenza A Virus Coinfection in Human Dendritic Cells. 2016; 7 (2): e00168-16.

Stanley M. A. Imiquimod and the imidazoquinolones: mechanism of action and therapeuticpotential. Clin. exp. Dermatol. 2002; 27 (7): 571–577.

Stein P., Weber M., Prüfer S. et al. Regulatory T cells and IL-10 independently counterregulate cytotoxic T lymphocyte responses induced by transcutaneous immunization. PLoS One. 2011; 6 (11): e27911.
Stockfleth E., Meyer T., Benninghoff B., Christophers E. Successful treatment of actinic keratosis with imiquimod cream 5%: a report of six cases. J. Dermatol. 2001; 144: 1050–1053.
Stojanović S., Poljacki M., Vucković N., Tasić S. Kliničko histološki karakteris-tike spinocellular karcinoma kože. Med. Pregl. 1998; 51(1–2): 61–67.
Stokes J. R., Sorkness R. L., Kaplan M. R. et al. Attenuation of virus-induced airway dysfunction in rats treated with imiquimod. Respir. J. 1998; 11: 324–329.

Strunk T., Braathen L. R., Szeimies R.-M. Актинический кератоз — обзор литературы. Вестн. дерматол. венерол. 2014; 5: 42–52.
Suárez-Ibarrola R., Heinze A., Sánchez-Sagástegui F. et al. Giant Condyloma Acuminatum in the Genital, Perineal and Perianal Region in a Pediatric Patient. Literature Review and Case Report. Urol. Case Rep. 2016; 7: 14–16.
Sun Q., Bai J., Ly R. Hedgehog/Gli1 signal pathway facilitates proliferation, invasion, and migration of cutaneous SCC through regulating VEGF. Tumour Biol. 2016: doi: 10.1007/s13277-016-5435-x.
Surrey A. R., Culter R. A. The synthesis of some 3-Nitro- and 4-dialkylaminoal-kylamino-quinoline Deriatives. Amer. Chem. Soc. 1951; 73 (6): 2413–2416.
Swanson N., Abramovits W., Berman B. et al. Imiquimod 2.5 % and 3.75 % for the treatment of actinic keratoses: results of two placebocontrolled studies of daily application to the face and balding scalp for two 2-week cycles. Amer. Acad. Dermatol. 2010; 62: 582–590.

Swanson N., Smith C. C., Kaur M. et al. Imiquimod 2.5 % and 3.75 % for the treatment of actinic keratoses: two phase 3 multicenter, randomized, double-blind, placebo-controlled studies. J. Drugs Dermatol. 2013; 12:1278–1282.

Syed T. A., Cheema K. M., Khayyami M. et al. Human leukocyte interferon-alpha versus podophyllotoxin in cream for the treatment of genital warts in males. A placebo-controlled, double-blind, comparative study. Dermatology. 1995: 191: 129–132.

Szentirmay Z., Szántó I., Bálint I. et al. Oki összefüggés a humán papilloma-vírus-fertôzés és a fej-nyaki régió valamint a nyelôcsô laphámrákjának egyes típusai között. Magyar Onkológia. 2002; 46: 35–41.
Takeda K., Akira S. Toll-like receptors in innate immunity. Immunol. 2005; 17: 1–14.
Taner Z. M., Taskiran C., Onan A. M. et al. Therapeutic value of trichloroacetic acid in the treatment of isolated genital warts on the external female genitalia. Reprod. Med. 2007; 52 (6): 521–525.
Tanji H., Ohto U., Shibata T. et al. Structural reorganization of the Toll-like receptor 8 dimer induced by agonistic ligands. 2013; 339: 1426– 1429.
Tardos Th. F. Emulsion science and Technology, 2009.

Tardos Th. F. Rheology of Dispersions, 2010.

Tchernev G. Sexually transmitted papillomavirus infections: epidemiology, patho-genesis, clinic, morphology, important differential diagnostic aspects, current diag-nostic and treatment options. Bras. Dermatol. 2009; 84 (4): 377–389.

Telo I., Pescina S., Padula C. et al. Mechanisms of imiquimod skin penetra-tion. J. Pharm. 2016; 511 (1): 516–523.
Tillman D. K. Jr., Carroll M. T. Topical imiquimod therapy for basal and squa-mous cell carcinomas: a clinical experience. 2007; 79: 241–248.
Tio D., Van der Woude J., Prinsen C. A. et al. A systematic review on the role of imiquimod in lentigo maligna and lentigo maligna melanoma: need for standardization of treatment schedule and outcome measures. Europ. Acad. Dermatol. Venereol. 2016; doi: 10.1111/jdv.14085.

Traiman P., Bacchi C. E., De Luca L. A. et al. Vulvar carcinoma in young pa-tients and its relationship with genital warts. J. Gynaecol. Oncol. 1999; 20 (3): 191–194.
Triantafi lou K., Orthopoulos G., Vakakis E. et al. Human cardiac inflamma-tory responses triggered by Coxsackie B viruses are mainly Toll-like receptor (TLR) 8-dependent. Microbiol. 2005; 7: 1117–1126.
Tschandl P., Rosendahlb C., Kittlera H. Cutaneous Human Papillomavirus In-fection: Manifestations and Diagnosis. Probl. Dermatol. 2014; 45: 92–97.
Tyring S. Imiquimod applied topically: A novel immune response modifier. Skin Ther. Lett. 2001; 6 (6): 1–4.

Ueyama A., Yamamoto M., Tsujii K. Mechanism of pathogenesis of imiquimod-induced skin inflammation in the mouse: a role for interferon-alpha in dendritic cell activation by imiquimod. Dermatol. 2014; 41 (2): 135–143.

Unger E. R., Fajman N. N., Maloney E. M. et al. Anogenital human papil-lomavirus in sexually abused and nonabused children: a multicenter study. 2011; 128(3): e658–665.

Utada A. S., Bennett R. R., Fong J. C. Vibrio cholerae use pili and flagella syn-ergistically to effect motility switching and conditional surface attachment. Commun. 2014; 5: 4913.
Uthaisangsook S., Day N. K., Bahna S. L. et al. Innate immunity and its role against infections. Allergy Asthma Immunol. 2002; 88(3): 253–264; quiz 265–266, 318.
Van Haalen F. M., Bruggink S. C., Gussekloo J. et al. Warts in primary school-children: prevalence and relation with environmental factors. J. Dermatol. 2009; 161: 148–152.
Vilahur G., Badimon L. Ischemia/reperfusion activates myocardial innate im-mune response: the key role of the toll-like receptor. Physiol. 2014; 5: 496.
Vlahovic T. C., Khan M. T. The human papillomavirus and its role in plantar warts: a comprehensive review of diagnosis and management. Podiat. Med. Surg. 2016; 33 (3): 337–353.
Wagner T. L., Ahonen C. L., Couture A. M. et al. Modulation of TH1 and TH2 citokine production with the immune response modifiers, R-848 and Imiqui-mod. Immunol. 1999; 191: 10–19.
Wang Y., Wang S., Shen J. et al. Genotype distribution of human papillomavirus among women with cervical cytological abnormalities or invasive squamous cell carcinoma in a high-incidence area of esophageal carcinoma in china. Res. Int. 2016; 2016: 1256384.

Wang Y., Zhao B., Wang S. et al. Formulation and evaluation of novel glycyr-rhizic acid micelles for transdermal delivery of podophyllotoxin. Drug Deliv. 2016; 23 (5): 1623–1635.
Weeks C. E., Gibson S. J. Induction of interferon and other cytokines by im-iquimod and its hydroxylated metabolite R-842 in human blood cells in vitro. Interferon Res. 1994; 14 (2): 81–85.
Wei T., Gong J., Jamitzky F. et al. Homology modeling of human Toll-like recep-tors TLR7, 8, and 9 ligand-binding domains. Protein Sci. 2009; 18: 1684 –1691.
Werner R. N., Sammain A., Erdmann R. et al. The natural history of actinic keratosis: a systematic review. J. Dermatol. 2013; 169 (3): 502–518.
Werner R. N., Westfechtel L., Dressler C., Nast A. Self-administered interven-tions for anogenital warts in immunocompetent patients: a systematic review and meta-analysis. Transm. Infect. 2016: 1. pii: sextrans-2016-052768.
Wiedemann G. M., Jacobi S. J., Chaloupka M. et al. A novel TLR7 ago-nist reverses NK cell anergy and cures RMA-S lymphoma-bearing mice. 2016; 5(7): e1189051.
Wieland U., Kreuter A. HPV-induzierte anale Läsionen Hautarzt. 2015; 66: 439– 445.

Wincle G., Osborn D. W. 1Н-imidazo[4,5-с]quinolinamines and antiviral use. US Patent № 4 689 338, 1987.
Wolff F., Loipetzberger A., Gruber W. Imiquimod directly inhibits Hedgehog signalling by stimulating adenosine receptor/protein kinase A-mediated GLI phosphorylation. 2013; 32 (50): 5574–5581.
Woodworth C. D. HPV innate immunity. Biosci. 2002; 7: d2058-d2071.

Wright T. C., Richart R. M. Role of human papillomavirus in the pathogenesis of genital tract warts and cancer. Oncol. 1990; 37 (2): 151–164.
Wulf H. C. Hvorfor og hvornår behandles aktiniske keratoser — en gennem-gang af et Cochranereview. Ugeskr Læger 2014; 176: V07130448.
Yamada S., Jinnin M., Kajihara I. et al. Cytokine expression profiles in the sera of cutaneous squamous cell carcinoma patients. Drug Discov. Ther. 2016; 10 (3): 172–176.
Yang J., Qin N., Zhang H. et al. Cellular uptake of exogenous calcineurin B is dependent on TLR4/MD2/CD14 complexes, and CnB is an endogenous ligand of TLR4. Sci. 2016; 6: 24346.
Young-Zvandasara T., Popiela M., Shuttleworth G. ‘The nodule that disap-peared’ spontaneous regression of an eyelid noduloulcerative lesion mimicking the features of a basal cell carcinoma. med. J. Case Rep. 2015; 2015. pii: bcr2014206566.

Youssef K. K., Lapouge G., Bouvree K. et al. Adult interfollicular tumour-initiating cells are reprogrammed into an embryonic hair follicle progenitor-like fate during basal cell carcinoma initiation. cell biol. 2012; 14 (12): 1282–1294.

Zabawski E. J. Jr., Cockerell C. J. Topical and intralesional cidofovir: a review of pharmacology and therapeutic effects. Amer. Acad. Dermatol. 1998; 39: 741–745.
Zandi S., Ahmad Zadeh R., Yousefi S. R., Gharibi F. Promising New Wart Treat-ment: A Randomized, Placebo-Controlled, Clinical Trial. Red. Crescent Med. J. 2016; (8): e19650.
Zaravinos A., Kanellou P., Spandidos D. A. Viral DNA detection and RAS mu-tations in actinic keratosis and nonmelanoma skin cancers. J. Dermatol. 2010; 162: 325–331.
Zaza M., Grassi C., Mardjonovic A. et al. L’uso di elettrochirurgia nel tratta-mento di genitale extra-cervicale condilomatosi. Minerva Ginec. 1998; 50 (9): 367–371.
Zhang X., Munegowda M. A., Yuan J. Optimal TLR9 signal converts tolero-genic CD4-8-DCs into immunogenic ones capable of stimulating antitumor immunity via activating CD4+ Th1/Th17 and NK cell responses. Leukoc. Biol. 2010; 88 (2): 393–403.

Zhao H., Shu G., Wang S. The risk of non-melanoma skin cancer in HIV-in-fected patients: new data and meta-analysis. J. STD AIDS. 2016; 27 (7): 568–575.

Zhu Y. P., Jia Z. W., Dai B. et al. Relationship between circumcision and hu-man papillomavirus infection: a systematic review and meta-analysis. Asian J. Androl. 2016. doi: 10.4103/1008-682X.175092.