Toll-like receptors as a therapeutic target in cancer, infections and inflammatory diseases
Toll-like receptors (TLRs) are widely expressed pattern recognition receptors that bind to conserved molecular patterns expressed by pathogens and damaged cells. After recognition, activated TLRs induce the expression of various proinflammatory and antiviral molecules. Thus, TLRs are potential targe...
- Autores:
-
Flórez Álvarez, Lizdany
Ruiz Perez, Lanie
Taborda, Natalia Andrea
Hernández López, Juan Carlos
- Tipo de recurso:
- Article of journal
- Fecha de publicación:
- 2020
- Institución:
- Universidad Cooperativa de Colombia
- Repositorio:
- Repositorio UCC
- Idioma:
- OAI Identifier:
- oai:repository.ucc.edu.co:20.500.12494/28267
- Acceso en línea:
- https://hdl.handle.net/20.500.12494/28267
- Palabra clave:
- Toll-like receptors
cancer
vaccines
inflammation
infectious diseases
immune modulators
- Rights
- openAccess
- License
- Atribución
| id |
COOPER2_32dd73940eff5c3309f76514cc59ac64 |
|---|---|
| oai_identifier_str |
oai:repository.ucc.edu.co:20.500.12494/28267 |
| network_acronym_str |
COOPER2 |
| network_name_str |
Repositorio UCC |
| repository_id_str |
|
| dc.title.spa.fl_str_mv |
Toll-like receptors as a therapeutic target in cancer, infections and inflammatory diseases |
| title |
Toll-like receptors as a therapeutic target in cancer, infections and inflammatory diseases |
| spellingShingle |
Toll-like receptors as a therapeutic target in cancer, infections and inflammatory diseases Toll-like receptors cancer vaccines inflammation infectious diseases immune modulators |
| title_short |
Toll-like receptors as a therapeutic target in cancer, infections and inflammatory diseases |
| title_full |
Toll-like receptors as a therapeutic target in cancer, infections and inflammatory diseases |
| title_fullStr |
Toll-like receptors as a therapeutic target in cancer, infections and inflammatory diseases |
| title_full_unstemmed |
Toll-like receptors as a therapeutic target in cancer, infections and inflammatory diseases |
| title_sort |
Toll-like receptors as a therapeutic target in cancer, infections and inflammatory diseases |
| dc.creator.fl_str_mv |
Flórez Álvarez, Lizdany Ruiz Perez, Lanie Taborda, Natalia Andrea Hernández López, Juan Carlos |
| dc.contributor.author.none.fl_str_mv |
Flórez Álvarez, Lizdany Ruiz Perez, Lanie Taborda, Natalia Andrea Hernández López, Juan Carlos |
| dc.subject.spa.fl_str_mv |
Toll-like receptors cancer vaccines inflammation infectious diseases immune modulators |
| topic |
Toll-like receptors cancer vaccines inflammation infectious diseases immune modulators |
| description |
Toll-like receptors (TLRs) are widely expressed pattern recognition receptors that bind to conserved molecular patterns expressed by pathogens and damaged cells. After recognition, activated TLRs induce the expression of various proinflammatory and antiviral molecules. Thus, TLRs are potential targets for treatment strategies aimed at boosting the adaptive immune response to vaccines, controlling infections, enhancing immune responses during tumor treatment and attenuating immune responses in inflammatory disorders. This Special Report examines the potential of TLRs as targets for the treatment of cancer, infections and inflammatory diseases. Here, we make a particular emphasis on molecules capable of modulating TLRs and their therapeutic applications. |
| publishDate |
2020 |
| dc.date.accessioned.none.fl_str_mv |
2020-11-24T22:00:46Z |
| dc.date.available.none.fl_str_mv |
2020-11-24T22:00:46Z |
| dc.date.issued.none.fl_str_mv |
2020-04-02 |
| dc.type.none.fl_str_mv |
Artículo |
| dc.type.coar.fl_str_mv |
http://purl.org/coar/resource_type/c_2df8fbb1 |
| dc.type.coar.none.fl_str_mv |
http://purl.org/coar/resource_type/c_6501 |
| dc.type.coarversion.none.fl_str_mv |
http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| dc.type.driver.none.fl_str_mv |
info:eu-repo/semantics/article |
| dc.type.version.none.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
| format |
http://purl.org/coar/resource_type/c_6501 |
| status_str |
publishedVersion |
| dc.identifier.issn.spa.fl_str_mv |
1750-7448 |
| dc.identifier.uri.none.fl_str_mv |
https://hdl.handle.net/20.500.12494/28267 |
| dc.identifier.uri.spa.fl_str_mv |
10.2217/imt-2019-0096 |
| dc.identifier.bibliographicCitation.spa.fl_str_mv |
Flórez-Álvarez, F., Ruiz-Perez, L., Taborda, N. y Hernandez, J. C. (2020). Toll-like receptors as a therapeutic target in cancer, infections and inflammatory diseases. Immunotherapy, 12 (5), 311-322. Recuperado de https://www.futuremedicine.com/doi/abs/10.2217/imt-2019-0096 |
| identifier_str_mv |
1750-7448 10.2217/imt-2019-0096 Flórez-Álvarez, F., Ruiz-Perez, L., Taborda, N. y Hernandez, J. C. (2020). Toll-like receptors as a therapeutic target in cancer, infections and inflammatory diseases. Immunotherapy, 12 (5), 311-322. Recuperado de https://www.futuremedicine.com/doi/abs/10.2217/imt-2019-0096 |
| url |
https://hdl.handle.net/20.500.12494/28267 |
| dc.relation.isversionof.spa.fl_str_mv |
https://www.futuremedicine.com/doi/pdf/10.2217/imt-2019-0096 |
| dc.relation.ispartofjournal.spa.fl_str_mv |
IMMUNOTHERAPY |
| dc.relation.references.spa.fl_str_mv |
Jin MS, Lee J-O. Structures of the Toll-like Receptor Family and Its Ligand Complexes. Immunity [Internet]. 2008 Aug 15 [cited 2016 Dec 13];29(2):182–91. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18701082 Mogensen TH, Chamberlain G, Sacre S, Mogensen T, Tang D, Kang R, et al. Pathogen Recognition and Inflammatory Signaling in Innate Immune Defenses. Clin Microbiol Rev [Internet]. 2009 Apr 1 [cited 2017 Jan 12];22(2):240–73. Available from: http://cmr.asm.org/cgi/doi/10.1128/CMR.00046-08 Uematsu S, Akira S. Toll-Like Receptors (TLRs) and Their Ligands. In: Handbook of experimental pharmacology [Internet]. 2008 [cited 2016 Dec 20]. p. 1–20. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18071652 Hatai H, Lepelley A, Zeng W, Hayden MS, Ghosh S, West A, et al. Toll-Like Receptor 11 (TLR11) Interacts with Flagellin and Profilin through Disparate Mechanisms. Blader IJ, editor. PLoS One [Internet]. 2016 Feb 9 [cited 2017 Jan 12];11(2):e0148987. Available from: http://dx.plos.org/10.1371/journal.pone.0148987 Abdelsadik A, Trad A. Toll-like receptors on the fork roads between innate and adaptive immunity. Hum Immunol. 2011 Dec;72(12):1188–93. Palsson-McDermott EM, O’Neill LAJ. Building an immune system from nine domains. Biochem Soc Trans [Internet]. 2007 Dec 1 [cited 2016 Dec 20];35(6):1437–44. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18031241 Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol [Internet]. 2010 May 20 [cited 2016 Dec 22];11(5):373–84. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20404851 Kawai T, Akira S. TLR signaling. Cell Death Differ [Internet]. 2006 May 20 [cited 2016 Dec 22];13(5):816–25. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16410796 Dunne A, Marshall NA, Mills KH. TLR based therapeutics. Curr Opin Pharmacol [Internet]. 2011 Aug [cited 2016 Dec 22];11(4):404–11. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21501972 Zhao H, Wang Z, Wu H, Xiao Q, Yao W, Wang E, et al. STAT3 genetic variant, alone and in combination with STAT5b polymorphism, contributes to breast cancer risk and clinical outcomes. Med Oncol [Internet]. 2015 Jan [cited 2019 7 Jan 23];32(1):375. Available from: http://link.springer.com/10.1007/s12032-014- 0375-z Wurfel MM, Park WY, Radella F, Ruzinski J, Sandstrom A, Strout J, et al. Identification of high and low responders to lipopolysaccharide in normal subjects: an unbiased approach to identify modulators of innate immunity. J Immunol [Internet]. 2005 Aug 15 [cited 2017 Jul 4];175(4):2570–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16081831 LaVoie MJ, Card JP, Hastings TG. Microglial activation precedes dopamine terminal pathology in methamphetamine-induced neurotoxicity. Exp Neurol [Internet]. 2004 May [cited 2017 Jul 13];187(1):47–57. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15081587 Worley MJ, Heinzerling KG, Roche DJO, Shoptaw S. Ibudilast attenuates subjective effects of methamphetamine in a placebo-controlled inpatient study. Drug Alcohol Depend [Internet]. 2016 May [cited 2017 Jun 22];162:245–50. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0376871616001204 Aletaha S, Haddad L, Roozbehkia M, Bigdeli R, Asgary V, Mahmoudi M, et al. M2000 -D-Mannuronic Acid) as a Novel Antagonist for Blocking the TLR2 and TLR4 Downstream Signalling Pathway. Scand J Immunol [Internet]. 2017 Feb 1 [cited 2017 Jun 22];85(2):122–9. Available from: http://doi.wiley.com/10.1111/sji.12519 IPH33: anti-TLR3 mAb | Innate Pharma [Internet]. [cited 2017 Jul 12]. Available from: http://www.innate-pharma.com/en/pipeline/iph33-anti-tlr3-mab Lamrani M, Sassi N, Paul C, Yousfi N, Boucher J-L, Gauthier N, et al. TLR4/IFNγ pathways induce tumor regression via NOS II-dependent NO and ROS production in murine breast cancer models. Oncoimmunology [Internet]. 2016 May 3 [cited 2017 Jun 22];5(5):e1123369. Available from: https://www.tandfonline.com/doi/full/10.1080/2162402X.2015.1123369 Isambert N, Fumoleau P, Paul C, Ferrand C, Zanetta S, Bauer J, et al. Phase I study of OM-174, a lipid A analogue, with assessment of immunological response, in patients with refractory solid tumors. BMC Cancer [Internet]. 2013 [cited 2017 Jul 12];13. Available from: http://www.biomedcentral.com/1471-2407/13/172 Sagiv-Barfi I, Lu H, Hewitt J, Hsu FJ, Meulen J ter, Levy R. Intratumoral Injection of TLR4 Agonist (G100) Leads to Tumor Regression of A20 Lymphoma and Induces Abscopal Responses. Blood [Internet]. 2015 [cited 2017 Jun 22];126(23). Available from: http://www.bloodjournal.org/content/126/23/820?sso-checked=true Woller SA, Ravula SB, Tucci FC, Beaton G, Corr M, Isseroff RR, et al. Systemic TAK-242 prevents intrathecal LPS evoked hyperalgesia in male, but not female mice and prevents delayed allodynia following intraplantar formalin in both male and female mice: The role of TLR4 in the evolution of a persistent pain state. Brain Behav Immun [Internet]. 2016 Aug [cited 2017 Jun 22];56:271–80. Available from: http://linkinghub.elsevier.com/retrieve/pii/S088915911630071X Woller SA, Ravula SB, Tucci FC, Beaton G, Corr M, Isseroff RR, et al. Systemic 18 TAK-242 prevents intrathecal LPS evoked hyperalgesia in male, but not female 19 mice and prevents delayed allodynia following intraplantar formalin in both male 20 and female mice: The role of TLR4 in the evolution of a persistent pain state. 21 Brain Behav Immun [Internet]. 2016 Aug [cited 2017 Jun 22];56:271–80. 22 Available from: http://linkinghub.elsevier.com/retrieve/pii/S088915911630071X Huggins CL, Pierce S, Neumann F, Peri F, Cockerill GW, Pirianov G. A novel small mimetic molecule TLR4 antagonist (IAXO-102) modulates TLR4 proinflammatory signalling and inhibits aortic aneurysms development. Atherosclerosis [Internet]. 2015 Jul 1 [cited 2017 Jun 22];241(1). Available from: http://linkinghub.elsevier.com/retrieve/pii/S0021915015004074 Cook DN, Pisetsky DS, Schwartz DA. Toll-like receptors in the pathogenesis of human disease. Nat Immunol [Internet]. 2004 Oct [cited 2017 Jan 28];5(10):975– 9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15454920 Lampe AT, Hain JL, Brown DM. Combination CpG and MPL agonists heighten vaccine-induced protection against Influenza A virus challenge. J Immunol [Internet]. 2017 [cited 2017 Jun 22];198(1 Supplement). Available from: http://www.jimmunol.org/content/198/1_Supplement/147.4 Zhang Y, Chang E, Dutz J. Toll like receptor 7 antagonist IRS661 inhibits insulitis and autoimmune diabetes in non-obese diabetic mice (P5227). J Immunol [Internet]. 2016 [cited 2017 Jun 27];190(1 Supplement). Available from: http://www.jimmunol.org/content/190/1_Supplement/67.10.short Hennessy EJ, Parker AE, O’Neill LAJ. Targeting Toll-like receptors: emerging therapeutics? Nat Rev Drug Discov [Internet]. 2010 Apr 1 [cited 2016 Dec 22];9(4):293–307. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20380038 Misch EA, Hawn TR. Toll-like receptor polymorphisms and susceptibility to human disease. Clin Sci [Internet]. 2008 Mar 1 [cited 2017 Jul 4];114(5):347–60. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18230059 von Bernuth H, Picard C, Jin Z, Pankla R, Xiao H, Ku C-L, et al. Pyogenic bacterial infections in humans with MyD88 deficiency. Science [Internet]. 2008 Aug 1 [cited 2017 Jul 5];321(5889):691–6. Available from: http://www.sciencemag.org/cgi/doi/10.1126/science.1158298 Picard C, von Bernuth H, Ghandil P, Chrabieh M, Levy O, Arkwright PD, et al. Clinical Features and Outcome of Patients With IRAK-4 and MyD88 Deficiency. Medicine (Baltimore) [Internet]. 2010 Nov [cited 2017 Jul 5];89(6):403–25. 18 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21057262 Semlali A, Jalouli M, Parine NR, Al Amri A, Arafah M, Al Naeem A, et al. Toll like receptor 4 as a predictor of clinical outcomes of estrogen receptor-negative breast cancer in Saudi women. Onco Targets Ther [Internet]. 2017 [cited 2017 Jul 5 ];10:1207–16. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28280355 Piaserico S, Michelotto A, Frigo AC, Alaibac M. TLR7 Gln11Leu single nucleotide polymorphism and response to treatment with imiquimod in patients with basal cell carcinoma: a pilot study. Pharmacogenomics [Internet]. 2015 Nov [cited 2017 Jul 5];16(17):1913–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26556041 Stappers MHT, Thys Y, Oosting M, Plantinga TS, Ioana M, Reimnitz P, et al. TLR1, TLR2, and TLR6 Gene Polymorphisms Are Associated With Increased Susceptibility to Complicated Skin and Skin Structure Infections. J Infect Dis [Internet]. 2014 Jul 15 [cited 2017 Jul 5];210(2):311–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24511099 O’Sullivan TETE, Sun JCJCJC, Lanier LLLLL, O’Sullivan TE, Sun JCJCJC, Lanier LLLLL, et al. No Title. Immunity [Internet]. 2015 Oct 20 [cited 2016 Oct 14];43(4). Available from: http://www.ncbi.nlm.nih.gov/pubmed/26488815 Al-Daghri NM, Clerici M, Al-Attas O, Forni D, Alokail MS, Alkharfy KM, et al. A nonsense polymorphism (R392X) in TLR5 protects from obesity but predisposes to diabetes. J Immunol. 2013 Apr 1;190(7):3716–20. Plantinga TS, Johnson MD, Scott WK, van de Vosse E, Velez Edwards DR, Smith PB, et al. Toll-like receptor 1 polymorphisms increase susceptibility to candidemia. J Infect Dis [Internet]. 2012 Mar 15 [cited 2017 Jul 5];205(6):934–43. Available from: https://academic.oup.com/jid/article lookup/doi/10.1093/infdis/jir867 Hahn WO, Harju-Baker S, Erdman LK, Krudsood S, Kain KC, Wurfel MM, et al. A common TLR1 polymorphism is associated with higher parasitaemia in a Southeast Asian population with Plasmodium falciparum malaria. Malar J [Internet]. 2016 Jan 6 [cited 2017 Jul 5];15:12. Available from: 19 1 http://www.ncbi.nlm.nih.gov/pubmed/26738805 Saleh MA, Ramadan MM, Arram EO. Toll-like receptor-2 Arg753Gln and Arg677Trp polymorphisms and susceptibility to pulmonary and peritoneal tuberculosis. APMIS [Internet]. 2017 Jun [cited 2017 Jul 5];125(6):558–64. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28332241 Zeljic K, Supic G, Jovic N, Kozomara R, Brankovic-Magic M, Obrenovic M, et al. Association of TLR2, TLR3, TLR4 and CD14 genes polymorphisms with oral cancer risk and survival. Oral Dis [Internet]. 2014 May [cited 2017 Jul 5];20(4):416–24. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23796347 Taft D, Kottyan L, Lagomarcino A, Schibler C, Yu Z, Gevers D, et al. A pilot study of TLR4 polymorphism in relation to intestinal dysbiosis and risk of necrotizing enterocolitis in preterm infants. FASEB J [Internet]. 2013 Apr 1 [cited 2017 Jul 6];27(1 Supplement). Available from: http://www.fasebj.org/content/27/1_Supplement/866.10.short Lee E, Kwon J-W, Kim H-B, Yu H-S, Kang M-J, Hong K, et al. Association Between Antibiotic Exposure, Bronchiolitis, and TLR4 (rs1927911) Polymorphisms in Childhood Asthma. Allergy Asthma Immunol Res [Internet]. 2015 Mar [cited 2017 Jul 5];7(2):167. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25729624 Jin S-H, Guan X-Y, Liang W-H, Bai G-H, Liu J-G. TLR4 polymorphism and periodontitis susceptibility. Medicine (Baltimore) [Internet]. 2016 Sep [cited 2017 Jul 5];95(36):e4845. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27603404 Sellers RM, Payne JB, Yu F, LeVan TD, Walker C, Mikuls TR. TLR4 Asp299Gly polymorphism may be protective against chronic periodontitis. J Periodontal Res [Internet]. 2016 Apr [cited 2017 Jul 5];51(2):203–11. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26174031 Cheng Y, Zhu Y, Huang X, Zhang W, Han Z, Liu S. Association between TLR2 and TLR4 Gene Polymorphisms and the Susceptibility to Inflammatory Bowel Disease: A Meta-Analysis. Boone DL, editor. PLoS One [Internet]. 2015 May 29 20 [cited 2017 Jul 5];10(5):e0126803. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26023918 S. Belforte F, Coluccio Leskow F, Poskus E, Penas Steinhardt A. Toll-like receptor 4 D299G polymorphism in metabolic disorders: a meta-analysis. Mol Biol Rep [Internet]. 2013 Apr 29 [cited 2017 Jul 5];40(4):3015–20. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23275193 Meena NK, Ahuja V, Meena K, Paul J. Association of TLR5 Gene Polymorphisms in Ulcerative Colitis Patients of North India and Their Role in Cytokine Homeostasis. Speletas M, editor. PLoS One [Internet]. 2015 Mar 19 [cited 2017 Jul 5];10(3):e0120697. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25789623 Sheridan J, Mack DR, Amre DK, Israel DM, Cherkasov A, Li H, et al. A Non Synonymous Coding Variant (L616F) in the TLR5 Gene Is Potentially Associated with Crohn’s Disease and Influences Responses to Bacterial Flagellin. Song Q, editor. PLoS One [Internet]. 2013 Apr 11 [cited 2017 Jul 5];8(4):e61326. Available from: http://dx.plos.org/10.1371/journal.pone.0061326 Misch EA, Verbon A, Prins JM, Skerrett SJ, Hawn TR. A TLR6 polymorphism is associated with increased risk of Legionnaires’ disease. Genes Immun [Internet]. 2013 Oct [cited 2017 Jul 5];14(7):420–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23823019 Sun Q, Zhang Q, Xiao H, Bai C. Toll-like receptor polymorphisms and 22 tuberculosis susceptibility: A comprehensive meta-analysis. J Huazhong Univ Sci 23 Technol Med Sci [Internet]. 2015 Apr 16 [cited 2017 Jul 6];35(2):157–68. 24 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25877346 Wei X, Wei C, Tong Y, Zhu C, Zhang P. Single Nucleotide Polymorphisms of Toll-Like Receptor 7 and Toll-Like Receptor 9 in Hepatitis C Virus Infection Patients from Central China. Yonsei Med J [Internet]. 2014 Mar [cited 2017 Jul 5];55(2):428. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24532514 Gu L, Zhou J, Tan J, Su L, Wei Q, Jiang H, et al. TLR7 rs2897827 Polymorphism Affects TLR7 Gene mRNA Expression and Serum Apolipoprotein A1 Level of 21 Ischemic Stroke Patients in a Chinese Han Population. J Mol Neurosci [Internet]. 2016 Jul 18 [cited 2017 Jul 5];59(3):397–403. Available from: http://link.springer.com/10.1007/s12031-016-0773-0 Lee YH, Choi SJ, Ji JD, Song GG. Association between toll-like receptor polymorphisms and systemic lupus erythematosus: a meta-analysis update. Lupus [Internet]. 2016 May 12 [cited 2017 Jul 5];25(6):593–601. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26762473 Lai Y-F, Lin T-M, Wang C-H, Su P-Y, Wu J-T, Lin M-C, et al. Functional polymorphisms of the TLR7 and TLR8 genes contribute to Mycobacterium tuberculosis infection. Tuberculosis (Edinb) [Internet]. 2016 May [cited 2017 Jul 5];98:125–31. Available from: http://linkinghub.elsevier.com/retrieve/pii/S147297921420566X Torices S, Alvarez-Rodríguez L, Varela I, Muñoz P, Balsa A, López-Hoyos M, et al. Evaluation of Toll-like-receptor gene family variants as prognostic biomarkers in rheumatoid arthritis. Immunol Lett [Internet]. 2017 [cited 2017 Jul 6];187:35– 40. Available from: http://www.sciencedirect.com/science/article/pii/S0165247817300949 Gu L, Zhou J, Tan J, Yang J, Shen T, Jiang H, et al. Association of TLR8 gene rs3764880 polymorphisms with susceptibility and lipid metabolism- and inflammation response-related quantitative traits of ischemic stroke in southern Chinese Han male population. J Neurol Sci [Internet]. 2016 Nov 15 [cited 2017 Jul 5];370:94–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27772795 Okazaki S, Stintzing S, Heinemann V, Cao S, Zhang W, Yang D, et al. Association of TLR9 polymorphism with overall survival in metastatic colorectal cancer patients treated with FOLFIRI plus bevacizumab enrolled in FIRE3. J Clin Oncol [Internet]. 2016 Feb [cited 2017 Jul 5];34(4_suppl):498–498. Available from: http://ascopubs.org/doi/10.1200/jco.2016.34.4_suppl.498 Casale TB, Cole J, Beck E, Vogelmeier CF, Willers J, Lassen C, et al. CYT003, a TLR9 agonist, in persistent allergic asthma - a randomized placebo-controlled Phase 2b study. Allergy [Internet]. 2015 Sep 1 [cited 2017 Jun 27];70(9):1160–8. Available from: http://doi.wiley.com/10.1111/all.12663 Cunningham D, Zurlo A, Salazar R, Ducreux M, Waddell TS, Stein A, et al. IMPALA, a randomized phase III study in patients with metastatic colorectal carcinoma: Immunomodulatory maintenance therapy with TLR-9 agonist MGN1703. J Clin Oncol [Internet]. 2015 Jan 20 [cited 2017 Jun 27];33:TPS791- TPS791. Available from: http://ascopubs.org/doi/10.1200/jco.2015.33.3_suppl.tps791 Reilly M, Miller RM, Thomson MH, Patris V, Ryle P, McLoughlin L, et al. Randomized, Double-Blind, Placebo-Controlled, Dose-Escalating Phase I, Healthy Subjects Study of Intravenous OPN-305, a Humanized Anti-TLR2 Antibody. Clin Pharmacol Ther [Internet]. 2013 Oct 23 [cited 2017 Jun 22];94(5):593–600. Available from: http://doi.wiley.com/10.1038/clpt.2013.150 Monnet E, Lapeyre G, Poelgeest E van, Jacqmin P, Graaf K de, Reijers J, et al. Evidence of NI-0101 pharmacological activity, an anti-TLR4 antibody, in a randomized phase I dose escalation study in healthy volunteers receiving LPS. Clin Pharmacol Ther [Internet]. 2017 Feb 1 [cited 2017 Jun 22];101(2):200–8. Available from: http://doi.wiley.com/10.1002/cpt.522 Wipf P, Eyer BR, Yamaguchi Y, Zhang F, Neal MD, Sodhi CP, et al. Synthesis of anti -inflammatory α-and β-linked acetamidopyranosides as inhibitors of toll-like receptor 4 (TLR4). Tetrahedron Lett [Internet]. 2015 Jun [cited 2017 Jun 22];56(23):3097–100. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0040403914019418 Coley WB. The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. 1893. Clin Orthop Relat Res [Internet]. 1991 Jan [cited 2017 Jul 6];(262):3–11. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1984929 Wiemann B, Starnes CO. Coley’s toxins, tumor necrosis factor and cancer research: A historical perspective. Pharmacol Ther [Internet]. 1994 Jan [cited 2017 Jul 6];64(3):529–64. Available from: http://linkinghub.elsevier.com/retrieve/pii/016372589490023X Fried S, Tosun S, Troost G, Keil S, Zaenker KS, Dittmar T. Lipopolysaccharide (LPS) Promotes Apoptosis in Human Breast Epithelial × Breast Cancer Hybrids, 23 but Not in Parental Cells. PLoS One [Internet]. 2016 [cited 2018 Mar 18];11(2):e0148438. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26863029 Kaczanowska S, Joseph AM, Davila E. TLR agonists: our best frenemy in cancer immunotherapy. J Leukoc Biol [Internet]. 2013 Jun [cited 2018 Mar 18];93(6):847–63. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23475577 Miyauchi M, Murata M, Fukushima A, Sato T, Nakagawa M, Fujii T, et al. Optimization of cell-wall skeleton derived from Mycobacterium bovis BCG Tokyo 172 (SMP-105) emulsion in delayed-type hypersensitivity and antitumor models. Drug Discov Ther [Internet]. 2012 Aug [cited 2017 Jul 6];6(4):218–25. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23006993 Yamazaki S, Okada K, Maruyama A, Matsumoto M, Yagita H, Seya T. TLR2- Dependent Induction of IL-10 and Foxp3+CD25+CD4+ Regulatory T Cells Prevents Effective Anti-Tumor Immunity Induced by Pam2 Lipopeptides In Vivo. Zimmer J, editor. PLoS One [Internet]. 2011 Apr 20 [cited 2019 Jun 7];6(4):e18833. Available from: http://dx.plos.org/10.1371/journal.pone.0018833 Martins KA, Bavari S, Salazar AM. Vaccine adjuvant uses of poly-IC and derivatives. Expert Rev Vaccines [Internet]. 2015 Mar 4 [cited 2019 Jun 7];14(3):447–59. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25308798 Sabbatini P, Tsuji T, Ferran L, Ritter E, Sedrak C, Tuballes K, et al. Phase I Trial of Overlapping Long Peptides from a Tumor Self-Antigen and Poly-ICLC Shows Rapid Induction of Integrated Immune Response in Ovarian Cancer Patients. Clin Cancer Res [Internet]. 2012 Dec 1 [cited 2019 Jun 7];18(23):6497–508. Available from: http://clincancerres.aacrjournals.org/cgi/doi/10.1158/1078-0432.CCR-12- 2189 Faham A, Altin JG. Antigen-Containing Liposomes Engrafted with Flagellin Related Peptides Are Effective Vaccines That Can Induce Potent Antitumor Immunity and Immunotherapeutic Effect. J Immunol [Internet]. 2010 Aug 1 [cited 2019 Jun 7];185(3):1744–54. Available from: http://www.jimmunol.org/cgi/doi/10.4049/jimmunol.1000027 Brackett CM, Kojouharov B, Greene K, Trageser N, Gollnick S, Burdelya L, et al. Entolimod, a clinical-stage TLR5 agonist, activates antitumor T cell immunity against liver and lung metastases through distinct mechanisms. J Immunol [Internet]. 2017 [cited 2017 Jun 22];198(1 Supplement). Available from: http://www.jimmunol.org/content/198/1_Supplement/79.12 Chiron D, Pellat-Deceunynck C, Amiot M, Bataille R, Jego G. TLR3 Ligand Induces NF-κB Activation and Various Fates of Multiple Myeloma Cells Depending on IFN-α Production. J Immunol [Internet]. 2009 [cited 2017 Jun 22];182(7):4471–8. Available from: http://www.jimmunol.org/content/182/7/4471.short Mett V, Komarova EA, Greene K, Bespalov I, Brackett C, Gillard B, et al. Mobilan: a recombinant adenovirus carrying Toll-like receptor 5 self-activating cassette for cancer immunotherapy. Oncogene [Internet]. 2018 Jan 2 [cited 2019 Jun 7];37(4):439–49. Available from: http://www.nature.com/articles/onc2017346 Vacchelli E, Galluzzi L, Eggermont A, Fridman WH, Galon J, Sautès-Fridman C, et al. Trial watch: FDA-approved Toll-like receptor agonists for cancer therapy. Oncoimmunology [Internet]. 2012 Sep 1 [cited 2019 Jun 7];1(6):894–907. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23162757 Spaner DE, Shi Y, White D, Shaha S, He L, Masellis A, et al. A phase I/II trial of TLR-7 agonist immunotherapy in chronic lymphocytic leukemia. Leukemia [Internet]. 2010 Jan 17 [cited 2017 Jun 22];24(1):222–6. Available from: http://www.nature.com/doifinder/10.1038/leu.2009.195 Cho JH, Lee H-J, Ko H-J, Yoon B-I, Choe J, Kim K-C, et al. The TLR7 agonist imiquimod induces anti-cancer effects via autophagic cell death and enhances anti tumoral and systemic immunity during radiotherapy for melanoma. Oncotarget [Internet]. 2017 Apr 11 [cited 2017 Jun 22];8(15):24932–48. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28212561 Rook AH, Gelfand JM, Wysocka M, Troxel AB, Benoit B, Surber C, et al. Topical resiquimod can induce disease regression and enhance T-cell effector functions in cutaneous T-cell lymphoma. Blood [Internet]. 2015 [cited 2017 Jul 6];126(12):1452–61. Available from: 25 http://www.bloodjournal.org/content/126/12/1452?sso-checked=true Wittig B, Schmidt M, Scheithauer W, Schmoll H-J. MGN1703, an immunomodulator and toll-like receptor 9 (TLR-9) agonist: From bench to bedside. Crit Rev Oncol Hematol [Internet]. 2015 Apr [cited 2017 Jul 10];94(1):31–44. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1040842814002108 Kapp K, Kleuss C, Schroff M, Wittig B. Genuine Immunomodulation With dSLIM. Mol Ther - Nucleic Acids [Internet]. 2014 Jan [cited 2017 Jul 10];3:e170. Available from: http://linkinghub.elsevier.com/retrieve/pii/S2162253116303110 Srivastava AK, Dinc G, Sharma RK, Yolcu ES, Zhao H, Shirwan H. SA-4-1BBL and Monophosphoryl Lipid A Constitute an Efficacious Combination Adjuvant for Cancer Vaccines. Cancer Res [Internet]. 2014 Nov 15 [cited 2019 Jun 7];74(22):6441–51. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25252915 Study of Immune Response Modifier in the Treatment of Breast, Ovarian, Endometrial and Cervical Cancers - Full Text View - ClinicalTrials.gov [Internet]. [cited 2019 Jun 7]. Available from: https://clinicaltrials.gov/ct2/show/NCT00319748 Study of Immune Response Modifier in the Treatment of Hematologic Malignancies - Full Text View - ClinicalTrials.gov [Internet]. [cited 2019 Jun 7]. Available from: https://clinicaltrials.gov/ct2/show/NCT00276159 Smith DA, Conkling P, Richards DA, Nemunaitis JJ, Boyd TE, Mita AC, et al. Antitumor activity and safety of combination therapy with the Toll-like receptor 9 agonist IMO-2055, erlotinib, and bevacizumab in advanced or metastatic non small cell lung cancer patients who have progressed following chemotherapy. Cancer Immunol Immunother [Internet]. 2014 Aug [cited 2017 Jun 27 27];63(8):787–96. Available from: http://link.springer.com/10.1007/s00262-014- 1547-6 Wang D, Jiang W, Lakshmi B, DiMuzio J, Zhu F, Agrawal S. Creating the tumor microenvironment for effective immunotherapy: Antitumor activity of 26 intratumoral IMO-2125, a TLR9 agonist is further enhanced by inhibition of indoleamine-pyrrole 2,3-dioxygenase (IDO). Cancer Res [Internet]. 2016 [cited 2017 Jul 6];76(14 Supplement):Abstract nr 3847. Available from: http://cancerres.aacrjournals.org/content/76/14_Supplement/3847.short Levy R, Reagan PM, Friedberg JW, Bartlett NL, Gordon LI, Leung A, et al. SD 101, a Novel Class C CpG-Oligodeoxynucleotide (ODN) Toll-like Receptor 9 (TLR9) Agonist, Given with Low Dose Radiation for Untreated Low Grade B Cell Lymphoma: Interim Results of a Phase 1/2 Trial. Blood [Internet]. 2016 [cited 2017 Jun 27];128(22). Available from: http://www.bloodjournal.org/content/128/22/2974?sso-checked=true Rosewich M, Lee D, Zielen S. Pollinex Quattro: An innovative four injections immunotherapy In allergic rhinitis. Hum Vaccin Immunother [Internet]. 2013 Jul 13 [cited 2017 Jun 22];9(7):1523–31. Available from: http://www.tandfonline.com/doi/abs/10.4161/hv.24631 Strayer DR, Stouch BC, Stevens SR, Bateman L, Lapp CW, Peterson DL, et al. Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME): Characteristics of Responders to Rintatolimod. J Drug Res Dev [Internet]. 2015 [cited 2017 Jun 22];1(1). Available from: http://sciforschenonline.org/journals/drug/article data/JDRD-1-103/JDRD-1-103.pdf Xu Y, Dong H, Ge C, Gao Y, Liu H, Li W, et al. CBLB502 administration protects gut mucosal tissue in ulcerative colitis by inhibiting inflammation. Ann Transl Med [Internet]. 2016 Aug [cited 2017 Jun 22];4(16):301. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27668221 Tsitoura D, Ambery C, Price M, Powley W, Garthside S, Biggadike K, et al. Early clinical evaluation of the intranasal TLR7 agonist GSK2245035: Use of translational biomarkers to guide dosing and confirm target engagement. Clin Pharmacol Ther [Internet]. 2015 Oct 1 [cited 2017 Jun 27];98(4):369–80. Available from: http://doi.wiley.com/10.1002/cpt.157 Delaney S, Biffen M, Maltby J, Bell J, Asimus S, Aggarwal A, et al. Tolerability in man following inhalation dosing of the selective TLR7 agonist, AZD8848. BMJ Open Resp Res [Internet]. 2016 [cited 2017 Jul 11];3. Available from: 27 http://bmjopenrespres.bmj.com/content/bmjresp/3/1/e000113.full.pdf Daluge K, Jirmo AC, Busse M, Hansen G. TLR 7/8 agonist resiquimod alleviates murine allergic asthma through IL-27 production and up regulation of B7-H1 on antigen presenting cells. Eur Respir J [Internet]. 2015 [cited 2017 Jul 11];46(suppl 59). Available from: http://erj.ersjournals.com/content/46/suppl_59/PA1896 Barrett EG, Rudolph K, Matthews M, Dietsch G, Hershberg R. A novel TLR-8 agonist attenuates nasal symptoms/congestion in both dog and human allergen challenge studies. J Inflamm [Internet]. 2013 [cited 2017 Jun 27];10(S1). Available from: https://link.springer.com/article/10.1186/1476-9255-10-S1-P14 Atreya R, Reinisch W, Peyrin-Biroulet L, Scaldaferri F, Admyre C, Knittel T, et al. Clinical efficacy of the Toll-like receptor 9 agonist cobitolimod using patient reported-outcomes defined clinical endpoints in patients with ulcerative colitis. Dig Liver Dis [Internet]. 2018 Oct [cited 2019 Jun 7];50(10):1019–29. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1590865818307977 Hossain MS, Ramachandiran S, Gewirtz AT, Waller EK, McCarthy P. Recombinant TLR5 Agonist CBLB502 Promotes NK Cell-Mediated Anti-CMV Immunity in Mice. Heimesaat MM, editor. PLoS One [Internet]. 2014 May 30 [cited 2017 Jun 22];9(5):e96165. Available from: http://dx.plos.org/10.1371/journal.pone.0096165 Admyre C, Zargari A, Atreya R, Knittel T. IL-10 Induction Properties of the TLR 9 Agonist Cobitolimod and a Candidate for Treatment of Active Ulcerative Colitis in Late Stage of Clinical Development. Gastroenterology [Internet]. 2017 Apr 1 [cited 2017 Jul 11];152(5):S766. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0016508517326604 Bergmann JF, de Bruijne J, Hotho DM, de Knegt RJ, Boonstra A, Weegink CJ, et al. Randomised clinical trial: anti-viral activity of ANA773, an oral inducer of endogenous interferons acting via TLR7, in chronic HCV. Aliment Pharmacol Ther [Internet]. 2011 Aug 1 [cited 2016 Dec 22];34(4):443–53. Available from: http://doi.wiley.com/10.1111/j.1365-2036.2011.04745.x Fidock MD, Souberbielle BE, Laxton C, Rawal J, Delpuech-Adams O, Corey TP, 28 et al. The Innate Immune Response, Clinical Outcomes, and Ex Vivo HCV Antiviral Efficacy of a TLR7 Agonist (PF-4878691). Clin Pharmacol Ther [Internet]. 2011 Jun 30 [cited 2017 Jun 27];89(6):821–9. Available from: http://doi.wiley.com/10.1038/clpt.2011.60 Bam RA, Hansen D, Irrinki A, Mulato A, Jones GS, Hesselgesser J, et al. TLR7 Agonist GS-9620 Is a Potent Inhibitor of Acute HIV-1 Infection in Human Peripheral Blood Mononuclear Cells. Antimicrob Agents Chemother [Internet]. 2017 Jan 1 [cited 2017 Jun 27];61(1):e01369-16. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27799218 Tan ZY, Khah AKL, Sim SH, Novem V, Liu Y, Tan G-YG. Synthetic TLR4 agonist as a potential immunotherapy for melioidosis. Open J Immunol [Internet]. 2013 Mar 13 [cited 2017 Jun 22];3(1):1–9. Available from: http://www.scirp.org/journal/PaperDownload.aspx?DOI=10.4236/oji.2013.31001 Talbot HK, Rock MT, Johnson C, Tussey L, Kavita U, Shanker A, et al. Immunopotentiation of Trivalent Influenza Vaccine When Given with VAX102, a Recombinant Influenza M2e Vaccine Fused to the TLR5 Ligand Flagellin. Montgomery JM, editor. PLoS One [Internet]. 2010 Dec 28 [cited 2017 Jun 22];5(12):e14442. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21203437 Gupta RK, Relyveld EH, Lindblad EB, Bizzini B, Ben-Efraim S, Gupta CK. Adjuvants--a balance between toxicity and adjuvanticity. Vaccine [Internet]. 1993 [cited 2017 Jul 14];11(3):293–306. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8447157 Maisonneuve C, Bertholet S, Philpott DJ, De Gregorio E. Unleashing the potential of NOD- and Toll-like agonists as vaccine adjuvants. Proc Natl Acad Sci U S A [Internet]. 2014 Aug 26 [cited 2017 Jul 13];111(34):12294–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25136133 Mohr E, Siegrist C-A. Vaccination in early life: standing up to the challenges. Curr Opin Immunol [Internet]. 2016 [cited 2017 Jul 13];41:1–8. Available from: http://dx.doi.org/10.1016/j.coi.2016.04.004 Clem AS. Fundamentals of vaccine immunology. J Glob Infect Dis [Internet]. 2011 Jan [cited 2017 Jul 14];3(1):73–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21572612 Blander JM, Medzhitov R. Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature [Internet]. 2006 Apr 6 [cited 2017 Jul 14];440(7085):808–12. Available from: http://www.nature.com/doifinder/10.1038/nature04596 GIANNINI S, HANON E, MORIS P, VANMECHELEN M, MOREL S, DESSY F, et al. Enhanced humoral and memory B cellular immunity using HPV16/18 L1 VLP vaccine formulated with the MPL/aluminium salt combination (AS04) compared to aluminium salt only. Vaccine [Internet]. 2006 Aug 14 [cited 2017 Jul 14];24(33–34):5937–49. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16828940 Orr MT, Beebe EA, Hudson TE, Moon JJ, Fox CB, Reed SG, et al. A Dual TLR Agonist Adjuvant Enhances the Immunogenicity and Protective Efficacy of the Tuberculosis Vaccine Antigen ID93. Tyagi AK, editor. PLoS One [Internet]. 2014 Jan 3 [cited 2017 Jul 13];9(1):e83884. Available from: http://dx.plos.org/10.1371/journal.pone.0083884 Caproni E, Tritto E, Cortese M, Muzzi A, Mosca F, Monaci E, et al. MF59 and Pam3CSK4 Boost Adaptive Responses to Influenza Subunit Vaccine through an IFN Type I-Independent Mechanism of Action. J Immunol [Internet]. 2012 Apr 1 [cited 2016 Dec 22];188(7):3088–98. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22351935 Napolitani G, Rinaldi A, Bertoni F, Sallusto F, Lanzavecchia A. Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1-polarizing program in dendritic cells. Nat Immunol [Internet]. 2005 Aug [cited 2017 Jul 14];6(8):769–76. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15995707 Placebo-Controlled Study to Evaluate the Safety and Efficacy of OPN-305 in Preventing Delayed Renal Graft Function - Full Text View - ClinicalTrials.gov [Internet]. NCT01794663, 2017 [cited 2017 Jul 12]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT01794663?term=opsona&rank=1 Liu M, Gu M, Xu D, Lv Q, Zhang W, Wu Y. Protective Effects of Toll-like Receptor 4 Inhibitor Eritoran on Renal Ischemia-Reperfusion Injury. Transplant Proc [Internet]. 2010 Jun [cited 2017 Jun 22];42(5):1539–44. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0041134510004914 Opal SM, Laterre P-F, Francois B, LaRosa SP, Angus DC, Mira J-P, et al. Effect of Eritoran, an Antagonist of MD2-TLR4, on Mortality in Patients With Severe Sepsis. JAMA [Internet]. 2013 Mar 20 [cited 2017 Jul 12];309(11):1154. Available from: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2013.2194 Lima CX, Souza DG, Amaral FA, Fagundes CT, Rodrigues IPS, Alves-Filho JC, et al. Therapeutic Effects of Treatment with Anti-TLR2 and Anti-TLR4 Monoclonal Antibodies in Polymicrobial Sepsis. Ryffel B, editor. PLoS One [Internet]. 2015 Jul 6 [cited 2017 Jul 12];10(7):e0132336. Available from: http://dx.plos.org/10.1371/journal.pone.0132336 Narita M, Suzuki M, Kuzumaki N, Miyatake M, Suzuki T. Implication of Activated Astrocytes in the Development of Drug Dependence. Ann N Y Acad Sci [Internet]. 2008 Oct [cited 2017 Jul 13];1141(1):96–104. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18991953 |
| dc.rights.license.none.fl_str_mv |
Atribución |
| dc.rights.accessrights.none.fl_str_mv |
info:eu-repo/semantics/openAccess |
| dc.rights.coar.none.fl_str_mv |
http://purl.org/coar/access_right/c_abf2 |
| rights_invalid_str_mv |
Atribución http://purl.org/coar/access_right/c_abf2 |
| eu_rights_str_mv |
openAccess |
| dc.format.extent.spa.fl_str_mv |
311-322 |
| dc.coverage.temporal.spa.fl_str_mv |
12 (5) |
| dc.publisher.spa.fl_str_mv |
Universidad Cooperativa de Colombia, Facultad de Ciencias de la Salud, Programa de Medicina, Medellín y Envigado, Colombia, 00000 future science group |
| dc.publisher.program.spa.fl_str_mv |
Medicina |
| dc.publisher.place.spa.fl_str_mv |
Medellín |
| institution |
Universidad Cooperativa de Colombia |
| bitstream.url.fl_str_mv |
https://repository.ucc.edu.co/bitstreams/3b3d84ab-e329-4e3b-8dea-228728371685/download https://repository.ucc.edu.co/bitstreams/95cfbe46-b09a-4c57-ab57-18cddc812e18/download https://repository.ucc.edu.co/bitstreams/8a0ef135-1852-47e3-b9c0-eaa3caa90ee8/download https://repository.ucc.edu.co/bitstreams/aa022284-64e5-4731-b278-dc835a63d978/download |
| bitstream.checksum.fl_str_mv |
3bce4f7ab09dfc588f126e1e36e98a45 ab1419a03c81ab22b1a331e3f023a10a fe1df1a99c364e9c1311fb12fed326a1 f1bb0b5e1f7f9e498ad2b5480c7160f4 |
| bitstream.checksumAlgorithm.fl_str_mv |
MD5 MD5 MD5 MD5 |
| repository.name.fl_str_mv |
Repositorio Institucional Universidad Cooperativa de Colombia |
| repository.mail.fl_str_mv |
bdigital@metabiblioteca.com |
| _version_ |
1814246699438178304 |
| spelling |
Flórez Álvarez, LizdanyRuiz Perez, LanieTaborda, Natalia AndreaHernández López, Juan Carlos12 (5)2020-11-24T22:00:46Z2020-11-24T22:00:46Z2020-04-021750-7448https://hdl.handle.net/20.500.12494/2826710.2217/imt-2019-0096Flórez-Álvarez, F., Ruiz-Perez, L., Taborda, N. y Hernandez, J. C. (2020). Toll-like receptors as a therapeutic target in cancer, infections and inflammatory diseases. Immunotherapy, 12 (5), 311-322. Recuperado de https://www.futuremedicine.com/doi/abs/10.2217/imt-2019-0096Toll-like receptors (TLRs) are widely expressed pattern recognition receptors that bind to conserved molecular patterns expressed by pathogens and damaged cells. After recognition, activated TLRs induce the expression of various proinflammatory and antiviral molecules. Thus, TLRs are potential targets for treatment strategies aimed at boosting the adaptive immune response to vaccines, controlling infections, enhancing immune responses during tumor treatment and attenuating immune responses in inflammatory disorders. This Special Report examines the potential of TLRs as targets for the treatment of cancer, infections and inflammatory diseases. Here, we make a particular emphasis on molecules capable of modulating TLRs and their therapeutic applications.Toll-like receptors (TLRs) are widely expressed pattern recognition receptors that bind to conserved molecular patterns expressed by pathogens and damaged cells. After recognition, activated TLRs induce the expression of various proinflammatory and antiviral molecules. Thus, TLRs are potential targets for treatment strategies aimed at boosting the adaptive immune response to vaccines, controlling infections, enhancing immune responses during tumor treatment and attenuating immune responses in inflammatory disorders. This Special Report examines the potential of TLRs as targets for the treatment of cancer, infections and inflammatory diseases. Here, we make a particular emphasis on molecules capable of modulating TLRs and their therapeutic applications.https://scienti.colciencias.gov.co/cvlac/visualizador/generarCurriculoCv.do?cod_rh=0000283088http://orcid.org/0000-0002-9200-5698https://scienti.colciencias.gov.co/gruplac/jsp/visualiza/visualizagr.jsp?nro=00000000011355juanc.hernandezl@campusucc.edu.co311-322Universidad Cooperativa de Colombia, Facultad de Ciencias de la Salud, Programa de Medicina, Medellín y Envigado, Colombia, 00000future science groupMedicinaMedellínhttps://www.futuremedicine.com/doi/pdf/10.2217/imt-2019-0096IMMUNOTHERAPYJin MS, Lee J-O. Structures of the Toll-like Receptor Family and Its Ligand Complexes. Immunity [Internet]. 2008 Aug 15 [cited 2016 Dec 13];29(2):182–91. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18701082Mogensen TH, Chamberlain G, Sacre S, Mogensen T, Tang D, Kang R, et al. Pathogen Recognition and Inflammatory Signaling in Innate Immune Defenses. Clin Microbiol Rev [Internet]. 2009 Apr 1 [cited 2017 Jan 12];22(2):240–73. Available from: http://cmr.asm.org/cgi/doi/10.1128/CMR.00046-08Uematsu S, Akira S. Toll-Like Receptors (TLRs) and Their Ligands. In: Handbook of experimental pharmacology [Internet]. 2008 [cited 2016 Dec 20]. p. 1–20. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18071652Hatai H, Lepelley A, Zeng W, Hayden MS, Ghosh S, West A, et al. Toll-Like Receptor 11 (TLR11) Interacts with Flagellin and Profilin through Disparate Mechanisms. Blader IJ, editor. PLoS One [Internet]. 2016 Feb 9 [cited 2017 Jan 12];11(2):e0148987. Available from: http://dx.plos.org/10.1371/journal.pone.0148987Abdelsadik A, Trad A. Toll-like receptors on the fork roads between innate and adaptive immunity. Hum Immunol. 2011 Dec;72(12):1188–93.Palsson-McDermott EM, O’Neill LAJ. Building an immune system from nine domains. Biochem Soc Trans [Internet]. 2007 Dec 1 [cited 2016 Dec 20];35(6):1437–44. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18031241Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol [Internet]. 2010 May 20 [cited 2016 Dec 22];11(5):373–84. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20404851Kawai T, Akira S. TLR signaling. Cell Death Differ [Internet]. 2006 May 20 [cited 2016 Dec 22];13(5):816–25. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16410796Dunne A, Marshall NA, Mills KH. TLR based therapeutics. Curr Opin Pharmacol [Internet]. 2011 Aug [cited 2016 Dec 22];11(4):404–11. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21501972Zhao H, Wang Z, Wu H, Xiao Q, Yao W, Wang E, et al. STAT3 genetic variant, alone and in combination with STAT5b polymorphism, contributes to breast cancer risk and clinical outcomes. Med Oncol [Internet]. 2015 Jan [cited 2019 7 Jan 23];32(1):375. Available from: http://link.springer.com/10.1007/s12032-014- 0375-zWurfel MM, Park WY, Radella F, Ruzinski J, Sandstrom A, Strout J, et al. Identification of high and low responders to lipopolysaccharide in normal subjects: an unbiased approach to identify modulators of innate immunity. J Immunol [Internet]. 2005 Aug 15 [cited 2017 Jul 4];175(4):2570–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16081831LaVoie MJ, Card JP, Hastings TG. Microglial activation precedes dopamine terminal pathology in methamphetamine-induced neurotoxicity. Exp Neurol [Internet]. 2004 May [cited 2017 Jul 13];187(1):47–57. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15081587Worley MJ, Heinzerling KG, Roche DJO, Shoptaw S. Ibudilast attenuates subjective effects of methamphetamine in a placebo-controlled inpatient study. Drug Alcohol Depend [Internet]. 2016 May [cited 2017 Jun 22];162:245–50. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0376871616001204Aletaha S, Haddad L, Roozbehkia M, Bigdeli R, Asgary V, Mahmoudi M, et al. M2000 -D-Mannuronic Acid) as a Novel Antagonist for Blocking the TLR2 and TLR4 Downstream Signalling Pathway. Scand J Immunol [Internet]. 2017 Feb 1 [cited 2017 Jun 22];85(2):122–9. Available from: http://doi.wiley.com/10.1111/sji.12519IPH33: anti-TLR3 mAb | Innate Pharma [Internet]. [cited 2017 Jul 12]. Available from: http://www.innate-pharma.com/en/pipeline/iph33-anti-tlr3-mabLamrani M, Sassi N, Paul C, Yousfi N, Boucher J-L, Gauthier N, et al. TLR4/IFNγ pathways induce tumor regression via NOS II-dependent NO and ROS production in murine breast cancer models. Oncoimmunology [Internet]. 2016 May 3 [cited 2017 Jun 22];5(5):e1123369. Available from: https://www.tandfonline.com/doi/full/10.1080/2162402X.2015.1123369Isambert N, Fumoleau P, Paul C, Ferrand C, Zanetta S, Bauer J, et al. Phase I study of OM-174, a lipid A analogue, with assessment of immunological response, in patients with refractory solid tumors. BMC Cancer [Internet]. 2013 [cited 2017 Jul 12];13. Available from: http://www.biomedcentral.com/1471-2407/13/172Sagiv-Barfi I, Lu H, Hewitt J, Hsu FJ, Meulen J ter, Levy R. Intratumoral Injection of TLR4 Agonist (G100) Leads to Tumor Regression of A20 Lymphoma and Induces Abscopal Responses. Blood [Internet]. 2015 [cited 2017 Jun 22];126(23). Available from: http://www.bloodjournal.org/content/126/23/820?sso-checked=trueWoller SA, Ravula SB, Tucci FC, Beaton G, Corr M, Isseroff RR, et al. Systemic TAK-242 prevents intrathecal LPS evoked hyperalgesia in male, but not female mice and prevents delayed allodynia following intraplantar formalin in both male and female mice: The role of TLR4 in the evolution of a persistent pain state. Brain Behav Immun [Internet]. 2016 Aug [cited 2017 Jun 22];56:271–80. Available from: http://linkinghub.elsevier.com/retrieve/pii/S088915911630071XWoller SA, Ravula SB, Tucci FC, Beaton G, Corr M, Isseroff RR, et al. Systemic 18 TAK-242 prevents intrathecal LPS evoked hyperalgesia in male, but not female 19 mice and prevents delayed allodynia following intraplantar formalin in both male 20 and female mice: The role of TLR4 in the evolution of a persistent pain state. 21 Brain Behav Immun [Internet]. 2016 Aug [cited 2017 Jun 22];56:271–80. 22 Available from: http://linkinghub.elsevier.com/retrieve/pii/S088915911630071XHuggins CL, Pierce S, Neumann F, Peri F, Cockerill GW, Pirianov G. A novel small mimetic molecule TLR4 antagonist (IAXO-102) modulates TLR4 proinflammatory signalling and inhibits aortic aneurysms development. Atherosclerosis [Internet]. 2015 Jul 1 [cited 2017 Jun 22];241(1). Available from: http://linkinghub.elsevier.com/retrieve/pii/S0021915015004074Cook DN, Pisetsky DS, Schwartz DA. Toll-like receptors in the pathogenesis of human disease. Nat Immunol [Internet]. 2004 Oct [cited 2017 Jan 28];5(10):975– 9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15454920Lampe AT, Hain JL, Brown DM. Combination CpG and MPL agonists heighten vaccine-induced protection against Influenza A virus challenge. J Immunol [Internet]. 2017 [cited 2017 Jun 22];198(1 Supplement). Available from: http://www.jimmunol.org/content/198/1_Supplement/147.4Zhang Y, Chang E, Dutz J. Toll like receptor 7 antagonist IRS661 inhibits insulitis and autoimmune diabetes in non-obese diabetic mice (P5227). J Immunol [Internet]. 2016 [cited 2017 Jun 27];190(1 Supplement). Available from: http://www.jimmunol.org/content/190/1_Supplement/67.10.shortHennessy EJ, Parker AE, O’Neill LAJ. Targeting Toll-like receptors: emerging therapeutics? Nat Rev Drug Discov [Internet]. 2010 Apr 1 [cited 2016 Dec 22];9(4):293–307. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20380038Misch EA, Hawn TR. Toll-like receptor polymorphisms and susceptibility to human disease. Clin Sci [Internet]. 2008 Mar 1 [cited 2017 Jul 4];114(5):347–60. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18230059von Bernuth H, Picard C, Jin Z, Pankla R, Xiao H, Ku C-L, et al. Pyogenic bacterial infections in humans with MyD88 deficiency. Science [Internet]. 2008 Aug 1 [cited 2017 Jul 5];321(5889):691–6. Available from: http://www.sciencemag.org/cgi/doi/10.1126/science.1158298Picard C, von Bernuth H, Ghandil P, Chrabieh M, Levy O, Arkwright PD, et al. Clinical Features and Outcome of Patients With IRAK-4 and MyD88 Deficiency. Medicine (Baltimore) [Internet]. 2010 Nov [cited 2017 Jul 5];89(6):403–25. 18 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21057262Semlali A, Jalouli M, Parine NR, Al Amri A, Arafah M, Al Naeem A, et al. Toll like receptor 4 as a predictor of clinical outcomes of estrogen receptor-negative breast cancer in Saudi women. Onco Targets Ther [Internet]. 2017 [cited 2017 Jul 5 ];10:1207–16. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28280355Piaserico S, Michelotto A, Frigo AC, Alaibac M. TLR7 Gln11Leu single nucleotide polymorphism and response to treatment with imiquimod in patients with basal cell carcinoma: a pilot study. Pharmacogenomics [Internet]. 2015 Nov [cited 2017 Jul 5];16(17):1913–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26556041Stappers MHT, Thys Y, Oosting M, Plantinga TS, Ioana M, Reimnitz P, et al. TLR1, TLR2, and TLR6 Gene Polymorphisms Are Associated With Increased Susceptibility to Complicated Skin and Skin Structure Infections. J Infect Dis [Internet]. 2014 Jul 15 [cited 2017 Jul 5];210(2):311–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24511099O’Sullivan TETE, Sun JCJCJC, Lanier LLLLL, O’Sullivan TE, Sun JCJCJC, Lanier LLLLL, et al. No Title. Immunity [Internet]. 2015 Oct 20 [cited 2016 Oct 14];43(4). Available from: http://www.ncbi.nlm.nih.gov/pubmed/26488815Al-Daghri NM, Clerici M, Al-Attas O, Forni D, Alokail MS, Alkharfy KM, et al. A nonsense polymorphism (R392X) in TLR5 protects from obesity but predisposes to diabetes. J Immunol. 2013 Apr 1;190(7):3716–20.Plantinga TS, Johnson MD, Scott WK, van de Vosse E, Velez Edwards DR, Smith PB, et al. Toll-like receptor 1 polymorphisms increase susceptibility to candidemia. J Infect Dis [Internet]. 2012 Mar 15 [cited 2017 Jul 5];205(6):934–43. Available from: https://academic.oup.com/jid/article lookup/doi/10.1093/infdis/jir867Hahn WO, Harju-Baker S, Erdman LK, Krudsood S, Kain KC, Wurfel MM, et al. A common TLR1 polymorphism is associated with higher parasitaemia in a Southeast Asian population with Plasmodium falciparum malaria. Malar J [Internet]. 2016 Jan 6 [cited 2017 Jul 5];15:12. Available from: 19 1 http://www.ncbi.nlm.nih.gov/pubmed/26738805Saleh MA, Ramadan MM, Arram EO. Toll-like receptor-2 Arg753Gln and Arg677Trp polymorphisms and susceptibility to pulmonary and peritoneal tuberculosis. APMIS [Internet]. 2017 Jun [cited 2017 Jul 5];125(6):558–64. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28332241Zeljic K, Supic G, Jovic N, Kozomara R, Brankovic-Magic M, Obrenovic M, et al. Association of TLR2, TLR3, TLR4 and CD14 genes polymorphisms with oral cancer risk and survival. Oral Dis [Internet]. 2014 May [cited 2017 Jul 5];20(4):416–24. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23796347Taft D, Kottyan L, Lagomarcino A, Schibler C, Yu Z, Gevers D, et al. A pilot study of TLR4 polymorphism in relation to intestinal dysbiosis and risk of necrotizing enterocolitis in preterm infants. FASEB J [Internet]. 2013 Apr 1 [cited 2017 Jul 6];27(1 Supplement). Available from: http://www.fasebj.org/content/27/1_Supplement/866.10.shortLee E, Kwon J-W, Kim H-B, Yu H-S, Kang M-J, Hong K, et al. Association Between Antibiotic Exposure, Bronchiolitis, and TLR4 (rs1927911) Polymorphisms in Childhood Asthma. Allergy Asthma Immunol Res [Internet]. 2015 Mar [cited 2017 Jul 5];7(2):167. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25729624Jin S-H, Guan X-Y, Liang W-H, Bai G-H, Liu J-G. TLR4 polymorphism and periodontitis susceptibility. Medicine (Baltimore) [Internet]. 2016 Sep [cited 2017 Jul 5];95(36):e4845. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27603404Sellers RM, Payne JB, Yu F, LeVan TD, Walker C, Mikuls TR. TLR4 Asp299Gly polymorphism may be protective against chronic periodontitis. J Periodontal Res [Internet]. 2016 Apr [cited 2017 Jul 5];51(2):203–11. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26174031Cheng Y, Zhu Y, Huang X, Zhang W, Han Z, Liu S. Association between TLR2 and TLR4 Gene Polymorphisms and the Susceptibility to Inflammatory Bowel Disease: A Meta-Analysis. Boone DL, editor. PLoS One [Internet]. 2015 May 29 20 [cited 2017 Jul 5];10(5):e0126803. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26023918S. Belforte F, Coluccio Leskow F, Poskus E, Penas Steinhardt A. Toll-like receptor 4 D299G polymorphism in metabolic disorders: a meta-analysis. Mol Biol Rep [Internet]. 2013 Apr 29 [cited 2017 Jul 5];40(4):3015–20. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23275193Meena NK, Ahuja V, Meena K, Paul J. Association of TLR5 Gene Polymorphisms in Ulcerative Colitis Patients of North India and Their Role in Cytokine Homeostasis. Speletas M, editor. PLoS One [Internet]. 2015 Mar 19 [cited 2017 Jul 5];10(3):e0120697. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25789623Sheridan J, Mack DR, Amre DK, Israel DM, Cherkasov A, Li H, et al. A Non Synonymous Coding Variant (L616F) in the TLR5 Gene Is Potentially Associated with Crohn’s Disease and Influences Responses to Bacterial Flagellin. Song Q, editor. PLoS One [Internet]. 2013 Apr 11 [cited 2017 Jul 5];8(4):e61326. Available from: http://dx.plos.org/10.1371/journal.pone.0061326Misch EA, Verbon A, Prins JM, Skerrett SJ, Hawn TR. A TLR6 polymorphism is associated with increased risk of Legionnaires’ disease. Genes Immun [Internet]. 2013 Oct [cited 2017 Jul 5];14(7):420–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23823019Sun Q, Zhang Q, Xiao H, Bai C. Toll-like receptor polymorphisms and 22 tuberculosis susceptibility: A comprehensive meta-analysis. J Huazhong Univ Sci 23 Technol Med Sci [Internet]. 2015 Apr 16 [cited 2017 Jul 6];35(2):157–68. 24 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25877346Wei X, Wei C, Tong Y, Zhu C, Zhang P. Single Nucleotide Polymorphisms of Toll-Like Receptor 7 and Toll-Like Receptor 9 in Hepatitis C Virus Infection Patients from Central China. Yonsei Med J [Internet]. 2014 Mar [cited 2017 Jul 5];55(2):428. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24532514Gu L, Zhou J, Tan J, Su L, Wei Q, Jiang H, et al. TLR7 rs2897827 Polymorphism Affects TLR7 Gene mRNA Expression and Serum Apolipoprotein A1 Level of 21 Ischemic Stroke Patients in a Chinese Han Population. J Mol Neurosci [Internet]. 2016 Jul 18 [cited 2017 Jul 5];59(3):397–403. Available from: http://link.springer.com/10.1007/s12031-016-0773-0Lee YH, Choi SJ, Ji JD, Song GG. Association between toll-like receptor polymorphisms and systemic lupus erythematosus: a meta-analysis update. Lupus [Internet]. 2016 May 12 [cited 2017 Jul 5];25(6):593–601. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26762473Lai Y-F, Lin T-M, Wang C-H, Su P-Y, Wu J-T, Lin M-C, et al. Functional polymorphisms of the TLR7 and TLR8 genes contribute to Mycobacterium tuberculosis infection. Tuberculosis (Edinb) [Internet]. 2016 May [cited 2017 Jul 5];98:125–31. Available from: http://linkinghub.elsevier.com/retrieve/pii/S147297921420566XTorices S, Alvarez-Rodríguez L, Varela I, Muñoz P, Balsa A, López-Hoyos M, et al. Evaluation of Toll-like-receptor gene family variants as prognostic biomarkers in rheumatoid arthritis. Immunol Lett [Internet]. 2017 [cited 2017 Jul 6];187:35– 40. Available from: http://www.sciencedirect.com/science/article/pii/S0165247817300949Gu L, Zhou J, Tan J, Yang J, Shen T, Jiang H, et al. Association of TLR8 gene rs3764880 polymorphisms with susceptibility and lipid metabolism- and inflammation response-related quantitative traits of ischemic stroke in southern Chinese Han male population. J Neurol Sci [Internet]. 2016 Nov 15 [cited 2017 Jul 5];370:94–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27772795Okazaki S, Stintzing S, Heinemann V, Cao S, Zhang W, Yang D, et al. Association of TLR9 polymorphism with overall survival in metastatic colorectal cancer patients treated with FOLFIRI plus bevacizumab enrolled in FIRE3. J Clin Oncol [Internet]. 2016 Feb [cited 2017 Jul 5];34(4_suppl):498–498. Available from: http://ascopubs.org/doi/10.1200/jco.2016.34.4_suppl.498Casale TB, Cole J, Beck E, Vogelmeier CF, Willers J, Lassen C, et al. CYT003, a TLR9 agonist, in persistent allergic asthma - a randomized placebo-controlled Phase 2b study. Allergy [Internet]. 2015 Sep 1 [cited 2017 Jun 27];70(9):1160–8. Available from: http://doi.wiley.com/10.1111/all.12663Cunningham D, Zurlo A, Salazar R, Ducreux M, Waddell TS, Stein A, et al. IMPALA, a randomized phase III study in patients with metastatic colorectal carcinoma: Immunomodulatory maintenance therapy with TLR-9 agonist MGN1703. J Clin Oncol [Internet]. 2015 Jan 20 [cited 2017 Jun 27];33:TPS791- TPS791. Available from: http://ascopubs.org/doi/10.1200/jco.2015.33.3_suppl.tps791Reilly M, Miller RM, Thomson MH, Patris V, Ryle P, McLoughlin L, et al. Randomized, Double-Blind, Placebo-Controlled, Dose-Escalating Phase I, Healthy Subjects Study of Intravenous OPN-305, a Humanized Anti-TLR2 Antibody. Clin Pharmacol Ther [Internet]. 2013 Oct 23 [cited 2017 Jun 22];94(5):593–600. Available from: http://doi.wiley.com/10.1038/clpt.2013.150Monnet E, Lapeyre G, Poelgeest E van, Jacqmin P, Graaf K de, Reijers J, et al. Evidence of NI-0101 pharmacological activity, an anti-TLR4 antibody, in a randomized phase I dose escalation study in healthy volunteers receiving LPS. Clin Pharmacol Ther [Internet]. 2017 Feb 1 [cited 2017 Jun 22];101(2):200–8. Available from: http://doi.wiley.com/10.1002/cpt.522Wipf P, Eyer BR, Yamaguchi Y, Zhang F, Neal MD, Sodhi CP, et al. Synthesis of anti -inflammatory α-and β-linked acetamidopyranosides as inhibitors of toll-like receptor 4 (TLR4). Tetrahedron Lett [Internet]. 2015 Jun [cited 2017 Jun 22];56(23):3097–100. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0040403914019418Coley WB. The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. 1893. Clin Orthop Relat Res [Internet]. 1991 Jan [cited 2017 Jul 6];(262):3–11. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1984929Wiemann B, Starnes CO. Coley’s toxins, tumor necrosis factor and cancer research: A historical perspective. Pharmacol Ther [Internet]. 1994 Jan [cited 2017 Jul 6];64(3):529–64. Available from: http://linkinghub.elsevier.com/retrieve/pii/016372589490023XFried S, Tosun S, Troost G, Keil S, Zaenker KS, Dittmar T. Lipopolysaccharide (LPS) Promotes Apoptosis in Human Breast Epithelial × Breast Cancer Hybrids, 23 but Not in Parental Cells. PLoS One [Internet]. 2016 [cited 2018 Mar 18];11(2):e0148438. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26863029Kaczanowska S, Joseph AM, Davila E. TLR agonists: our best frenemy in cancer immunotherapy. J Leukoc Biol [Internet]. 2013 Jun [cited 2018 Mar 18];93(6):847–63. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23475577Miyauchi M, Murata M, Fukushima A, Sato T, Nakagawa M, Fujii T, et al. Optimization of cell-wall skeleton derived from Mycobacterium bovis BCG Tokyo 172 (SMP-105) emulsion in delayed-type hypersensitivity and antitumor models. Drug Discov Ther [Internet]. 2012 Aug [cited 2017 Jul 6];6(4):218–25. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23006993Yamazaki S, Okada K, Maruyama A, Matsumoto M, Yagita H, Seya T. TLR2- Dependent Induction of IL-10 and Foxp3+CD25+CD4+ Regulatory T Cells Prevents Effective Anti-Tumor Immunity Induced by Pam2 Lipopeptides In Vivo. Zimmer J, editor. PLoS One [Internet]. 2011 Apr 20 [cited 2019 Jun 7];6(4):e18833. Available from: http://dx.plos.org/10.1371/journal.pone.0018833Martins KA, Bavari S, Salazar AM. Vaccine adjuvant uses of poly-IC and derivatives. Expert Rev Vaccines [Internet]. 2015 Mar 4 [cited 2019 Jun 7];14(3):447–59. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25308798Sabbatini P, Tsuji T, Ferran L, Ritter E, Sedrak C, Tuballes K, et al. Phase I Trial of Overlapping Long Peptides from a Tumor Self-Antigen and Poly-ICLC Shows Rapid Induction of Integrated Immune Response in Ovarian Cancer Patients. Clin Cancer Res [Internet]. 2012 Dec 1 [cited 2019 Jun 7];18(23):6497–508. Available from: http://clincancerres.aacrjournals.org/cgi/doi/10.1158/1078-0432.CCR-12- 2189Faham A, Altin JG. Antigen-Containing Liposomes Engrafted with Flagellin Related Peptides Are Effective Vaccines That Can Induce Potent Antitumor Immunity and Immunotherapeutic Effect. J Immunol [Internet]. 2010 Aug 1 [cited 2019 Jun 7];185(3):1744–54. Available from: http://www.jimmunol.org/cgi/doi/10.4049/jimmunol.1000027Brackett CM, Kojouharov B, Greene K, Trageser N, Gollnick S, Burdelya L, et al. Entolimod, a clinical-stage TLR5 agonist, activates antitumor T cell immunity against liver and lung metastases through distinct mechanisms. J Immunol [Internet]. 2017 [cited 2017 Jun 22];198(1 Supplement). Available from: http://www.jimmunol.org/content/198/1_Supplement/79.12Chiron D, Pellat-Deceunynck C, Amiot M, Bataille R, Jego G. TLR3 Ligand Induces NF-κB Activation and Various Fates of Multiple Myeloma Cells Depending on IFN-α Production. J Immunol [Internet]. 2009 [cited 2017 Jun 22];182(7):4471–8. Available from: http://www.jimmunol.org/content/182/7/4471.shortMett V, Komarova EA, Greene K, Bespalov I, Brackett C, Gillard B, et al. Mobilan: a recombinant adenovirus carrying Toll-like receptor 5 self-activating cassette for cancer immunotherapy. Oncogene [Internet]. 2018 Jan 2 [cited 2019 Jun 7];37(4):439–49. Available from: http://www.nature.com/articles/onc2017346Vacchelli E, Galluzzi L, Eggermont A, Fridman WH, Galon J, Sautès-Fridman C, et al. Trial watch: FDA-approved Toll-like receptor agonists for cancer therapy. Oncoimmunology [Internet]. 2012 Sep 1 [cited 2019 Jun 7];1(6):894–907. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23162757Spaner DE, Shi Y, White D, Shaha S, He L, Masellis A, et al. A phase I/II trial of TLR-7 agonist immunotherapy in chronic lymphocytic leukemia. Leukemia [Internet]. 2010 Jan 17 [cited 2017 Jun 22];24(1):222–6. Available from: http://www.nature.com/doifinder/10.1038/leu.2009.195Cho JH, Lee H-J, Ko H-J, Yoon B-I, Choe J, Kim K-C, et al. The TLR7 agonist imiquimod induces anti-cancer effects via autophagic cell death and enhances anti tumoral and systemic immunity during radiotherapy for melanoma. Oncotarget [Internet]. 2017 Apr 11 [cited 2017 Jun 22];8(15):24932–48. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28212561Rook AH, Gelfand JM, Wysocka M, Troxel AB, Benoit B, Surber C, et al. Topical resiquimod can induce disease regression and enhance T-cell effector functions in cutaneous T-cell lymphoma. Blood [Internet]. 2015 [cited 2017 Jul 6];126(12):1452–61. Available from: 25 http://www.bloodjournal.org/content/126/12/1452?sso-checked=trueWittig B, Schmidt M, Scheithauer W, Schmoll H-J. MGN1703, an immunomodulator and toll-like receptor 9 (TLR-9) agonist: From bench to bedside. Crit Rev Oncol Hematol [Internet]. 2015 Apr [cited 2017 Jul 10];94(1):31–44. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1040842814002108Kapp K, Kleuss C, Schroff M, Wittig B. Genuine Immunomodulation With dSLIM. Mol Ther - Nucleic Acids [Internet]. 2014 Jan [cited 2017 Jul 10];3:e170. Available from: http://linkinghub.elsevier.com/retrieve/pii/S2162253116303110Srivastava AK, Dinc G, Sharma RK, Yolcu ES, Zhao H, Shirwan H. SA-4-1BBL and Monophosphoryl Lipid A Constitute an Efficacious Combination Adjuvant for Cancer Vaccines. Cancer Res [Internet]. 2014 Nov 15 [cited 2019 Jun 7];74(22):6441–51. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25252915Study of Immune Response Modifier in the Treatment of Breast, Ovarian, Endometrial and Cervical Cancers - Full Text View - ClinicalTrials.gov [Internet]. [cited 2019 Jun 7]. Available from: https://clinicaltrials.gov/ct2/show/NCT00319748Study of Immune Response Modifier in the Treatment of Hematologic Malignancies - Full Text View - ClinicalTrials.gov [Internet]. [cited 2019 Jun 7]. Available from: https://clinicaltrials.gov/ct2/show/NCT00276159Smith DA, Conkling P, Richards DA, Nemunaitis JJ, Boyd TE, Mita AC, et al. Antitumor activity and safety of combination therapy with the Toll-like receptor 9 agonist IMO-2055, erlotinib, and bevacizumab in advanced or metastatic non small cell lung cancer patients who have progressed following chemotherapy. Cancer Immunol Immunother [Internet]. 2014 Aug [cited 2017 Jun 27 27];63(8):787–96. Available from: http://link.springer.com/10.1007/s00262-014- 1547-6Wang D, Jiang W, Lakshmi B, DiMuzio J, Zhu F, Agrawal S. Creating the tumor microenvironment for effective immunotherapy: Antitumor activity of 26 intratumoral IMO-2125, a TLR9 agonist is further enhanced by inhibition of indoleamine-pyrrole 2,3-dioxygenase (IDO). Cancer Res [Internet]. 2016 [cited 2017 Jul 6];76(14 Supplement):Abstract nr 3847. Available from: http://cancerres.aacrjournals.org/content/76/14_Supplement/3847.shortLevy R, Reagan PM, Friedberg JW, Bartlett NL, Gordon LI, Leung A, et al. SD 101, a Novel Class C CpG-Oligodeoxynucleotide (ODN) Toll-like Receptor 9 (TLR9) Agonist, Given with Low Dose Radiation for Untreated Low Grade B Cell Lymphoma: Interim Results of a Phase 1/2 Trial. Blood [Internet]. 2016 [cited 2017 Jun 27];128(22). Available from: http://www.bloodjournal.org/content/128/22/2974?sso-checked=trueRosewich M, Lee D, Zielen S. Pollinex Quattro: An innovative four injections immunotherapy In allergic rhinitis. Hum Vaccin Immunother [Internet]. 2013 Jul 13 [cited 2017 Jun 22];9(7):1523–31. Available from: http://www.tandfonline.com/doi/abs/10.4161/hv.24631Strayer DR, Stouch BC, Stevens SR, Bateman L, Lapp CW, Peterson DL, et al. Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME): Characteristics of Responders to Rintatolimod. J Drug Res Dev [Internet]. 2015 [cited 2017 Jun 22];1(1). Available from: http://sciforschenonline.org/journals/drug/article data/JDRD-1-103/JDRD-1-103.pdfXu Y, Dong H, Ge C, Gao Y, Liu H, Li W, et al. CBLB502 administration protects gut mucosal tissue in ulcerative colitis by inhibiting inflammation. Ann Transl Med [Internet]. 2016 Aug [cited 2017 Jun 22];4(16):301. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27668221Tsitoura D, Ambery C, Price M, Powley W, Garthside S, Biggadike K, et al. Early clinical evaluation of the intranasal TLR7 agonist GSK2245035: Use of translational biomarkers to guide dosing and confirm target engagement. Clin Pharmacol Ther [Internet]. 2015 Oct 1 [cited 2017 Jun 27];98(4):369–80. Available from: http://doi.wiley.com/10.1002/cpt.157Delaney S, Biffen M, Maltby J, Bell J, Asimus S, Aggarwal A, et al. Tolerability in man following inhalation dosing of the selective TLR7 agonist, AZD8848. BMJ Open Resp Res [Internet]. 2016 [cited 2017 Jul 11];3. Available from: 27 http://bmjopenrespres.bmj.com/content/bmjresp/3/1/e000113.full.pdfDaluge K, Jirmo AC, Busse M, Hansen G. TLR 7/8 agonist resiquimod alleviates murine allergic asthma through IL-27 production and up regulation of B7-H1 on antigen presenting cells. Eur Respir J [Internet]. 2015 [cited 2017 Jul 11];46(suppl 59). Available from: http://erj.ersjournals.com/content/46/suppl_59/PA1896Barrett EG, Rudolph K, Matthews M, Dietsch G, Hershberg R. A novel TLR-8 agonist attenuates nasal symptoms/congestion in both dog and human allergen challenge studies. J Inflamm [Internet]. 2013 [cited 2017 Jun 27];10(S1). Available from: https://link.springer.com/article/10.1186/1476-9255-10-S1-P14Atreya R, Reinisch W, Peyrin-Biroulet L, Scaldaferri F, Admyre C, Knittel T, et al. Clinical efficacy of the Toll-like receptor 9 agonist cobitolimod using patient reported-outcomes defined clinical endpoints in patients with ulcerative colitis. Dig Liver Dis [Internet]. 2018 Oct [cited 2019 Jun 7];50(10):1019–29. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1590865818307977Hossain MS, Ramachandiran S, Gewirtz AT, Waller EK, McCarthy P. Recombinant TLR5 Agonist CBLB502 Promotes NK Cell-Mediated Anti-CMV Immunity in Mice. Heimesaat MM, editor. PLoS One [Internet]. 2014 May 30 [cited 2017 Jun 22];9(5):e96165. Available from: http://dx.plos.org/10.1371/journal.pone.0096165Admyre C, Zargari A, Atreya R, Knittel T. IL-10 Induction Properties of the TLR 9 Agonist Cobitolimod and a Candidate for Treatment of Active Ulcerative Colitis in Late Stage of Clinical Development. Gastroenterology [Internet]. 2017 Apr 1 [cited 2017 Jul 11];152(5):S766. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0016508517326604Bergmann JF, de Bruijne J, Hotho DM, de Knegt RJ, Boonstra A, Weegink CJ, et al. Randomised clinical trial: anti-viral activity of ANA773, an oral inducer of endogenous interferons acting via TLR7, in chronic HCV. Aliment Pharmacol Ther [Internet]. 2011 Aug 1 [cited 2016 Dec 22];34(4):443–53. Available from: http://doi.wiley.com/10.1111/j.1365-2036.2011.04745.xFidock MD, Souberbielle BE, Laxton C, Rawal J, Delpuech-Adams O, Corey TP, 28 et al. The Innate Immune Response, Clinical Outcomes, and Ex Vivo HCV Antiviral Efficacy of a TLR7 Agonist (PF-4878691). Clin Pharmacol Ther [Internet]. 2011 Jun 30 [cited 2017 Jun 27];89(6):821–9. Available from: http://doi.wiley.com/10.1038/clpt.2011.60Bam RA, Hansen D, Irrinki A, Mulato A, Jones GS, Hesselgesser J, et al. TLR7 Agonist GS-9620 Is a Potent Inhibitor of Acute HIV-1 Infection in Human Peripheral Blood Mononuclear Cells. Antimicrob Agents Chemother [Internet]. 2017 Jan 1 [cited 2017 Jun 27];61(1):e01369-16. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27799218Tan ZY, Khah AKL, Sim SH, Novem V, Liu Y, Tan G-YG. Synthetic TLR4 agonist as a potential immunotherapy for melioidosis. Open J Immunol [Internet]. 2013 Mar 13 [cited 2017 Jun 22];3(1):1–9. Available from: http://www.scirp.org/journal/PaperDownload.aspx?DOI=10.4236/oji.2013.31001Talbot HK, Rock MT, Johnson C, Tussey L, Kavita U, Shanker A, et al. Immunopotentiation of Trivalent Influenza Vaccine When Given with VAX102, a Recombinant Influenza M2e Vaccine Fused to the TLR5 Ligand Flagellin. Montgomery JM, editor. PLoS One [Internet]. 2010 Dec 28 [cited 2017 Jun 22];5(12):e14442. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21203437Gupta RK, Relyveld EH, Lindblad EB, Bizzini B, Ben-Efraim S, Gupta CK. Adjuvants--a balance between toxicity and adjuvanticity. Vaccine [Internet]. 1993 [cited 2017 Jul 14];11(3):293–306. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8447157Maisonneuve C, Bertholet S, Philpott DJ, De Gregorio E. Unleashing the potential of NOD- and Toll-like agonists as vaccine adjuvants. Proc Natl Acad Sci U S A [Internet]. 2014 Aug 26 [cited 2017 Jul 13];111(34):12294–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25136133Mohr E, Siegrist C-A. Vaccination in early life: standing up to the challenges. Curr Opin Immunol [Internet]. 2016 [cited 2017 Jul 13];41:1–8. Available from: http://dx.doi.org/10.1016/j.coi.2016.04.004Clem AS. Fundamentals of vaccine immunology. J Glob Infect Dis [Internet]. 2011 Jan [cited 2017 Jul 14];3(1):73–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21572612Blander JM, Medzhitov R. Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature [Internet]. 2006 Apr 6 [cited 2017 Jul 14];440(7085):808–12. Available from: http://www.nature.com/doifinder/10.1038/nature04596GIANNINI S, HANON E, MORIS P, VANMECHELEN M, MOREL S, DESSY F, et al. Enhanced humoral and memory B cellular immunity using HPV16/18 L1 VLP vaccine formulated with the MPL/aluminium salt combination (AS04) compared to aluminium salt only. Vaccine [Internet]. 2006 Aug 14 [cited 2017 Jul 14];24(33–34):5937–49. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16828940Orr MT, Beebe EA, Hudson TE, Moon JJ, Fox CB, Reed SG, et al. A Dual TLR Agonist Adjuvant Enhances the Immunogenicity and Protective Efficacy of the Tuberculosis Vaccine Antigen ID93. Tyagi AK, editor. PLoS One [Internet]. 2014 Jan 3 [cited 2017 Jul 13];9(1):e83884. Available from: http://dx.plos.org/10.1371/journal.pone.0083884Caproni E, Tritto E, Cortese M, Muzzi A, Mosca F, Monaci E, et al. MF59 and Pam3CSK4 Boost Adaptive Responses to Influenza Subunit Vaccine through an IFN Type I-Independent Mechanism of Action. J Immunol [Internet]. 2012 Apr 1 [cited 2016 Dec 22];188(7):3088–98. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22351935Napolitani G, Rinaldi A, Bertoni F, Sallusto F, Lanzavecchia A. Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1-polarizing program in dendritic cells. Nat Immunol [Internet]. 2005 Aug [cited 2017 Jul 14];6(8):769–76. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15995707Placebo-Controlled Study to Evaluate the Safety and Efficacy of OPN-305 in Preventing Delayed Renal Graft Function - Full Text View - ClinicalTrials.gov [Internet]. NCT01794663, 2017 [cited 2017 Jul 12]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT01794663?term=opsona&rank=1Liu M, Gu M, Xu D, Lv Q, Zhang W, Wu Y. Protective Effects of Toll-like Receptor 4 Inhibitor Eritoran on Renal Ischemia-Reperfusion Injury. Transplant Proc [Internet]. 2010 Jun [cited 2017 Jun 22];42(5):1539–44. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0041134510004914Opal SM, Laterre P-F, Francois B, LaRosa SP, Angus DC, Mira J-P, et al. Effect of Eritoran, an Antagonist of MD2-TLR4, on Mortality in Patients With Severe Sepsis. JAMA [Internet]. 2013 Mar 20 [cited 2017 Jul 12];309(11):1154. Available from: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2013.2194Lima CX, Souza DG, Amaral FA, Fagundes CT, Rodrigues IPS, Alves-Filho JC, et al. Therapeutic Effects of Treatment with Anti-TLR2 and Anti-TLR4 Monoclonal Antibodies in Polymicrobial Sepsis. Ryffel B, editor. PLoS One [Internet]. 2015 Jul 6 [cited 2017 Jul 12];10(7):e0132336. Available from: http://dx.plos.org/10.1371/journal.pone.0132336Narita M, Suzuki M, Kuzumaki N, Miyatake M, Suzuki T. Implication of Activated Astrocytes in the Development of Drug Dependence. Ann N Y Acad Sci [Internet]. 2008 Oct [cited 2017 Jul 13];1141(1):96–104. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18991953Toll-like receptorscancervaccinesinflammationinfectious diseasesimmune modulatorsToll-like receptors as a therapeutic target in cancer, infections and inflammatory diseasesArtículohttp://purl.org/coar/resource_type/c_6501http://purl.org/coar/resource_type/c_2df8fbb1http://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionAtribucióninfo:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2PublicationLICENSElicense.txtlicense.txttext/plain; charset=utf-84334https://repository.ucc.edu.co/bitstreams/3b3d84ab-e329-4e3b-8dea-228728371685/download3bce4f7ab09dfc588f126e1e36e98a45MD52ORIGINALPRE-PRINT.pdfPRE-PRINT.pdfapplication/pdf1103306https://repository.ucc.edu.co/bitstreams/95cfbe46-b09a-4c57-ab57-18cddc812e18/downloadab1419a03c81ab22b1a331e3f023a10aMD51THUMBNAILPRE-PRINT.pdf.jpgPRE-PRINT.pdf.jpgGenerated Thumbnailimage/jpeg3857https://repository.ucc.edu.co/bitstreams/8a0ef135-1852-47e3-b9c0-eaa3caa90ee8/downloadfe1df1a99c364e9c1311fb12fed326a1MD53TEXTPRE-PRINT.pdf.txtPRE-PRINT.pdf.txtExtracted texttext/plain65919https://repository.ucc.edu.co/bitstreams/aa022284-64e5-4731-b278-dc835a63d978/downloadf1bb0b5e1f7f9e498ad2b5480c7160f4MD5420.500.12494/28267oai:repository.ucc.edu.co:20.500.12494/282672024-08-10 22:40:55.644restrictedhttps://repository.ucc.edu.coRepositorio Institucional Universidad Cooperativa de Colombiabdigital@metabiblioteca.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 |