Table of Contents Author Guidelines Submit a Manuscript
Mediators of Inflammation
Volume 2015 (2015), Article ID 290657, 11 pages
http://dx.doi.org/10.1155/2015/290657
Review Article

Targeting Th17 Cells with Small Molecules and Small Interference RNA

1Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
2Division of Arthritis and Rheumatic Diseases, Oregon Health & Science University and VA Portland Health Care System, Portland, OR 97239, USA

Received 25 September 2015; Accepted 30 November 2015

Academic Editor: Nina Ivanovska

Copyright © 2015 Hui Lin et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. T. R. Mosmann, H. Cherwinski, M. W. Bond, M. A. Giedlin, and R. L. Coffman, “Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins,” The Journal of Immunology, vol. 136, no. 7, pp. 2348–2357, 1986. View at Google Scholar · View at Scopus
  2. D. Agnello, C. S. R. Lankford, J. Bream et al., “Cytokines and transcription factors that regulate T helper cell differentiation: new players and new insights,” Journal of Clinical Immunology, vol. 23, no. 3, pp. 147–161, 2003. View at Publisher · View at Google Scholar · View at Scopus
  3. K. A. Mowen and L. H. Glimcher, “Signaling pathways in Th2 development,” Immunological Reviews, vol. 202, pp. 203–222, 2004. View at Publisher · View at Google Scholar · View at Scopus
  4. M. Veldhoen, C. Uyttenhove, J. van Snick et al., “Transforming growth factor-β ‘ reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset,” Nature Immunology, vol. 9, no. 12, pp. 1341–1346, 2008. View at Publisher · View at Google Scholar · View at Scopus
  5. D. Breitfeld, L. Ohl, E. Kremmer et al., “Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production,” Journal of Experimental Medicine, vol. 192, no. 11, pp. 1545–1551, 2000. View at Publisher · View at Google Scholar · View at Scopus
  6. S. Sakaguchi, T. Yamaguchi, T. Nomura, and M. Ono, “Regulatory T cells and immune tolerance,” Cell, vol. 133, no. 5, pp. 775–787, 2008. View at Publisher · View at Google Scholar · View at Scopus
  7. H. Park, Z. Li, X. O. Yang et al., “A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17,” Nature Immunology, vol. 6, no. 11, pp. 1133–1141, 2005. View at Publisher · View at Google Scholar · View at Scopus
  8. L. E. Harrington, R. D. Hatton, P. R. Mangan et al., “Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages,” Nature Immunology, vol. 6, no. 11, pp. 1123–1132, 2005. View at Publisher · View at Google Scholar · View at Scopus
  9. I. I. Ivanov, B. S. McKenzie, L. Zhou et al., “The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells,” Cell, vol. 126, no. 6, pp. 1121–1133, 2006. View at Publisher · View at Google Scholar · View at Scopus
  10. C. Dong, “TH17 cells in development: an updated view of their molecular identity and genetic programming,” Nature Reviews Immunology, vol. 8, no. 5, pp. 337–348, 2008. View at Publisher · View at Google Scholar · View at Scopus
  11. F. Annunziato, L. Cosmi, F. Liotta, E. Maggi, and S. Romagnani, “Type 17 T helper cells—origins, features and possible roles in rheumatic disease,” Nature Reviews Rheumatology, vol. 5, no. 6, pp. 325–331, 2009. View at Publisher · View at Google Scholar · View at Scopus
  12. L. Steinman, “Mixed results with modulation of T H-17 cells in human autoimmune diseases,” Nature Immunology, vol. 11, no. 1, pp. 41–44, 2010. View at Publisher · View at Google Scholar · View at Scopus
  13. W. Hueber, D. D. Patel, T. Dryja et al., “Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis,” Science Translational Medicine, vol. 2, no. 52, Article ID 52ra72, 2010. View at Publisher · View at Google Scholar · View at Scopus
  14. C. Leonardi, R. Matheson, C. Zachariae et al., “Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis,” The New England Journal of Medicine, vol. 366, no. 13, pp. 1190–1191, 2012. View at Publisher · View at Google Scholar · View at Scopus
  15. P. Gisondi, C. Dalle Vedove, and G. Girolomoni, “Efficacy and safety of secukinumab in chronic plaque psoriasis and psoriatic arthritis therapy,” Dermatology and Therapy, vol. 4, no. 1, pp. 1–9, 2014. View at Publisher · View at Google Scholar
  16. D. D. Patel, D. M. Lee, F. Kolbinger, and C. Antoni, “Effect of IL-17A blockade with secukinumab in autoimmune diseases,” Annals of the Rheumatic Diseases, vol. 72, supplement 2, pp. ii116–ii123, 2013. View at Publisher · View at Google Scholar · View at Scopus
  17. K. A. Papp, C. Leonardi, A. Menter et al., “Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis,” The New England Journal of Medicine, vol. 366, no. 13, pp. 1181–1189, 2012. View at Publisher · View at Google Scholar · View at Scopus
  18. S. Coimbra, A. Figueiredo, and A. Santos-Silva, “Brodalumab: an evidence-based review of its potential in the treatment of moderate-to-severe psoriasis,” Core Evidence, vol. 9, pp. 89–97, 2014. View at Publisher · View at Google Scholar · View at Scopus
  19. D. A. Martin, M. Churchill, L. F. Flores-Suarez et al., “A phase Ib multiple ascending dose study evaluating safety, pharmacokinetics, and early clinical response of brodalumab, a human anti-IL-17R antibody, in methotrexate-resistant rheumatoid arthritis,” Arthritis Research and Therapy, vol. 15, no. 5, article R164, 2013. View at Publisher · View at Google Scholar · View at Scopus
  20. M. C. Genovese, P. Durez, H. B. Richards et al., “Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study,” Annals of the Rheumatic Diseases, vol. 72, no. 6, pp. 863–869, 2013. View at Publisher · View at Google Scholar · View at Scopus
  21. W. Hueber, B. E. Sands, S. Lewitzky et al., “Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial,” Gut, vol. 61, no. 12, pp. 1693–1700, 2012. View at Publisher · View at Google Scholar
  22. J. Yang, M. S. Sundrud, J. Skepner, and T. Yamagata, “Targeting Th17 cells in autoimmune diseases,” Trends in Pharmacological Sciences, vol. 35, no. 10, pp. 493–500, 2014. View at Publisher · View at Google Scholar · View at Scopus
  23. T. Korn, E. Bettelli, M. Oukka, and V. K. Kuchroo, “IL-17 and Th17 cells,” Annual Review of Immunology, vol. 27, pp. 485–517, 2009. View at Publisher · View at Google Scholar · View at Scopus
  24. E. H. Tran, E. N. Prince, and T. Owens, “IFN-γ shapes immune invasion of the central nervous system via regulation of chemokines,” The Journal of Immunology, vol. 164, no. 5, pp. 2759–2768, 2000. View at Publisher · View at Google Scholar · View at Scopus
  25. B. Gran, G.-X. Zhang, S. Yu et al., “IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination,” Journal of Immunology, vol. 169, no. 12, pp. 7104–7110, 2002. View at Publisher · View at Google Scholar · View at Scopus
  26. C.-Q. Chu, Z. Song, L. Mayton, B. Wu, and P. H. Wooley, “IFNgamma deficient C57BL/6 (H-2b) mice develop collagen induced arthritis with predominant usage of T cell receptor Vbeta6 and Vbeta8 in arthritic joints,” Annals of the Rheumatic Diseases, vol. 62, no. 10, pp. 983–990, 2003. View at Publisher · View at Google Scholar · View at Scopus
  27. C.-Q. Chu, S. Wittmer, and D. K. Dalton, “Failure to suppress the expansion of the activated CD4 T cell population in interferon γ-deficient mice leads to exacerbation of experimental autoimnaune encephalomyelitis,” The Journal of Experimental Medicine, vol. 192, no. 1, pp. 123–128, 2000. View at Publisher · View at Google Scholar · View at Scopus
  28. B. Oppmann, R. Lesley, B. Blom et al., “Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12,” Immunity, vol. 13, no. 5, pp. 715–725, 2000. View at Publisher · View at Google Scholar · View at Scopus
  29. D. J. Cua, J. Sherlock, Y. Chen et al., “Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain,” Nature, vol. 421, no. 6924, pp. 744–748, 2003. View at Publisher · View at Google Scholar · View at Scopus
  30. C. L. Langrish, Y. Chen, W. M. Blumenschein et al., “IL-23 drives a pathogenic T cell population that induces autoimmune inflammation,” Journal of Experimental Medicine, vol. 201, no. 2, pp. 233–240, 2005. View at Publisher · View at Google Scholar · View at Scopus
  31. M. O. Li, Y. Y. Wan, S. Sanjabi, A.-K. L. Robertson, and R. A. Flavell, “Transforming growth factor-β regulation of immune responses,” Annual Review of Immunology, vol. 24, pp. 99–146, 2006. View at Publisher · View at Google Scholar · View at Scopus
  32. M. Veldhoen, R. J. Hocking, R. A. Flavell, and B. Stockinger, “Signals mediated by transforming growth factor-β initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease,” Nature Immunology, vol. 7, no. 11, pp. 1151–1156, 2006. View at Publisher · View at Google Scholar · View at Scopus
  33. E. Bettelli, Y. Carrier, W. Gao et al., “Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells,” Nature, vol. 441, no. 7090, pp. 235–238, 2006. View at Publisher · View at Google Scholar · View at Scopus
  34. P. R. Mangan, L. E. Harrington, D. B. O'Quinn et al., “Transforming growth factor-β induces development of the TH17 lineage,” Nature, vol. 441, no. 7090, pp. 231–234, 2006. View at Publisher · View at Google Scholar · View at Scopus
  35. R. Nurieva, X. O. Yang, G. Martinez et al., “Essential autocrine regulation by IL-21 in the generation of inflammatory T cells,” Nature, vol. 448, no. 7152, pp. 480–483, 2007. View at Publisher · View at Google Scholar · View at Scopus
  36. L. Zhou, I. I. Ivanov, R. Spolski et al., “IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways,” Nature Immunology, vol. 8, no. 9, pp. 967–974, 2007. View at Publisher · View at Google Scholar · View at Scopus
  37. T. Korn, E. Bettelli, W. Gao et al., “IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells,” Nature, vol. 448, no. 7152, pp. 484–487, 2007. View at Publisher · View at Google Scholar · View at Scopus
  38. J. M. Coquet, S. Chakravarti, M. J. Smyth, and D. I. Godfrey, “Cutting edge: IL-21 is not essential for Th17 differentiation or experimental autoimmune encephalomyelitis,” Journal of Immunology, vol. 180, no. 11, pp. 7097–7101, 2008. View at Publisher · View at Google Scholar · View at Scopus
  39. R. Liu, Y. Bai, T. L. Vollmer et al., “IL-21 Receptor expression determines the temporal phases of experimental autoimmune encephalomyelitis,” Experimental Neurology, vol. 211, no. 1, pp. 14–24, 2008. View at Publisher · View at Google Scholar · View at Scopus
  40. K. Hirota, B. Martin, and M. Veldhoen, “Development, regulation and functional capacities of Th17 cells,” Seminars in Immunopathology, vol. 32, no. 1, pp. 3–16, 2010. View at Publisher · View at Google Scholar · View at Scopus
  41. M. J. McGeachy, K. S. Bak-Jensen, Y. Chen et al., “TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology,” Nature Immunology, vol. 8, pp. 1390–1397, 2007. View at Google Scholar
  42. Y. Chen, C. L. Langrish, B. Mckenzie et al., “Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis,” The Journal of Clinical Investigation, vol. 116, no. 5, pp. 1317–1326, 2006. View at Publisher · View at Google Scholar · View at Scopus
  43. C. L. Leonardi, A. B. Kimball, K. A. Papp et al., “Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1),” The Lancet, vol. 371, no. 9625, pp. 1665–1674, 2008. View at Publisher · View at Google Scholar · View at Scopus
  44. W. J. Sandborn, C. Gasink, L.-L. Gao et al., “Ustekinumab induction and maintenance therapy in refractory Crohn's disease,” The New England Journal of Medicine, vol. 367, no. 16, pp. 1519–1528, 2012. View at Publisher · View at Google Scholar · View at Scopus
  45. E. V. Acosta-Rodriguez, G. Napolitani, A. Lanzavecchia, and F. Sallusto, “Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells,” Nature Immunology, vol. 8, no. 9, pp. 942–949, 2007. View at Publisher · View at Google Scholar · View at Scopus
  46. N. J. Wilson, K. Boniface, J. R. Chan et al., “Development, cytokine profile and function of human interleukin 17-producing helper T cells,” Nature Immunology, vol. 8, no. 9, pp. 950–957, 2007. View at Publisher · View at Google Scholar · View at Scopus
  47. K. Hirahara, K. Ghoreschi, A. Laurence, X.-P. Yang, Y. Kanno, and J. J. O'Shea, “Signal transduction pathways and transcriptional regulation in Th17 cell differentiation,” Cytokine and Growth Factor Reviews, vol. 21, no. 6, pp. 425–434, 2010. View at Publisher · View at Google Scholar · View at Scopus
  48. A. M. Jetten, “Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism,” Nuclear Receptor Signaling, vol. 7, article e003, 2009. View at Google Scholar · View at Scopus
  49. Y.-W. He, M. L. Deftos, E. W. Ojala, and M. J. Bevan, “RORγt, a novel isoform of an orphan receptor, negatively regulates Fas ligand expression and IL-2 production in T cells,” Immunity, vol. 9, no. 6, pp. 797–806, 1998. View at Publisher · View at Google Scholar · View at Scopus
  50. G. Eberl and D. R. Littman, “The role of the nuclear hormone receptor RORγt in the development of lymph nodes and Peyer's patches,” Immunological Reviews, vol. 195, pp. 81–90, 2003. View at Publisher · View at Google Scholar · View at Scopus
  51. G. Eberl, S. Marmon, M.-J. Sunshine, P. D. Rennert, Y. Choi, and D. R. Littmann, “An essential function for the nuclear receptor RORγt in the generation of fetal lymphoid tissue inducer cells,” Nature Immunology, vol. 5, no. 1, pp. 64–73, 2004. View at Publisher · View at Google Scholar · View at Scopus
  52. S. Kurebayashi, E. Ueda, M. Sakaue et al., “Retinoid-related orphan receptor γ (RORγ) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 18, pp. 10132–10137, 2000. View at Publisher · View at Google Scholar · View at Scopus
  53. Z. Sun, D. Unutmaz, Y.-R. Zou et al., “Requirement for RORγ in thymocyte survival and lymphoid organ development,” Science, vol. 288, no. 5475, pp. 2369–2373, 2000. View at Publisher · View at Google Scholar · View at Scopus
  54. N. Manel, D. Unutmaz, and D. R. Littman, “The differentiation of human TH-17 cells requires transforming growth factor-β and induction of the nuclear receptor RORγt,” Nature Immunology, vol. 9, no. 6, pp. 641–649, 2008. View at Publisher · View at Google Scholar · View at Scopus
  55. I. I. Ivanov, L. Zhou, and D. R. Littman, “Transcriptional regulation of Th17 cell differentiation,” Seminars in Immunology, vol. 19, no. 6, pp. 409–417, 2007. View at Publisher · View at Google Scholar · View at Scopus
  56. C. Q. Chu, A. Mello, P. Gulko, and K. B. Elkon, “RORγt overexpression predisposes to increased susceptibility and severity of experimental arthritis,” Arthritis & Rheumatism, vol. 58, p. S936, 2008. View at Google Scholar
  57. X. O. Yang, B. P. Pappu, R. Nurieva et al., “T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORα and RORγ,” Immunity, vol. 28, no. 1, pp. 29–39, 2008. View at Publisher · View at Google Scholar · View at Scopus
  58. X. O. Yang, A. D. Panopoulos, R. Nurieva et al., “STAT3 regulates cytokine-mediated generation of inflammatory helper T cells,” The Journal of Biological Chemistry, vol. 282, no. 13, pp. 9358–9363, 2007. View at Publisher · View at Google Scholar · View at Scopus
  59. A. N. Mathur, H.-C. Chang, D. G. Zisoulis et al., “Stat3 and Stat4 direct development of IL-17-secreting Th cells,” The Journal of Immunology, vol. 178, no. 8, pp. 4901–4907, 2007. View at Publisher · View at Google Scholar · View at Scopus
  60. T. J. Harris, J. F. Grosso, H.-R. Yen et al., “Cutting edge: an in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity,” Journal of Immunology, vol. 179, no. 7, pp. 4313–4317, 2007. View at Publisher · View at Google Scholar · View at Scopus
  61. L. Wei, A. Laurence, K. M. Elias, and J. J. O'Shea, “IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner,” The Journal of Biological Chemistry, vol. 282, no. 48, pp. 34605–34610, 2007. View at Publisher · View at Google Scholar · View at Scopus
  62. Z. Chen, A. Laurence, Y. Kanno et al., “Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 21, pp. 8137–8142, 2006. View at Publisher · View at Google Scholar · View at Scopus
  63. M. Lohoff, H.-W. Mittrücker, S. Prechtl et al., “Dysregulated T helper cell differentiation in the absence of interferon regulatory factor 4,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 18, pp. 11808–11812, 2002. View at Publisher · View at Google Scholar · View at Scopus
  64. P. S. Biswas, S. Gupta, E. Chang et al., “Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice,” The Journal of Clinical Investigation, vol. 120, no. 9, pp. 3280–3295, 2010. View at Publisher · View at Google Scholar · View at Scopus
  65. A. Brüstle, S. Heink, M. Huber et al., “The development of inflammatory TH-17 cells requires interferon-regulatory factor 4,” Nature Immunology, vol. 8, no. 9, pp. 958–966, 2007. View at Publisher · View at Google Scholar · View at Scopus
  66. B. U. Schraml, K. Hildner, W. Ise et al., “The AP-1 transcription factor Batf controls T H 17 differentiation,” Nature, vol. 460, no. 7253, pp. 405–409, 2009. View at Publisher · View at Google Scholar · View at Scopus
  67. F. Zhang, G. Meng, and W. Strober, “Interactions among the transcription factors Runx1, RORγt and Foxp3 regulate the differentiation of interleukin 17-producing T cells,” Nature Immunology, vol. 9, no. 11, pp. 1297–1306, 2008. View at Publisher · View at Google Scholar · View at Scopus
  68. J. R. Huh, M. W. L. Leung, P. Huang et al., “Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγt activity,” Nature, vol. 472, no. 7344, pp. 486–490, 2011. View at Publisher · View at Google Scholar
  69. S. Fujita-Sato, S. Ito, T. Isobe et al., “Structural basis of digoxin that antagonizes RORγt receptor activity and suppresses Th17 cell differentiation and interleukin (IL)-17 production,” The Journal of Biological Chemistry, vol. 286, no. 36, pp. 31409–31417, 2011. View at Publisher · View at Google Scholar · View at Scopus
  70. R. Cascão, B. Vidal, H. Raquel et al., “Effective treatment of rat adjuvant-induced arthritis by celastrol,” Autoimmunity Reviews, vol. 11, no. 12, pp. 856–862, 2012. View at Publisher · View at Google Scholar · View at Scopus
  71. J. R. Huh, E. E. Englund, H. Wang et al., “Identification of potent and selective diphenylpropanamide RORγ inhibitors,” ACS Medicinal Chemistry Letters, vol. 4, no. 1, pp. 79–84, 2013. View at Publisher · View at Google Scholar · View at Scopus
  72. N. Kumar, L. A. Solt, J. J. Conkright et al., “The benzenesulfoamide T0901317 [N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide] is a novel retinoic acid receptor-related orphan receptor-alpha/gamma inverse agonist,” Molecular Pharmacology, vol. 77, no. 2, pp. 228–236, 2010. View at Publisher · View at Google Scholar · View at Scopus
  73. L. A. Solt, N. Kumar, P. Nuhant et al., “Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand,” Nature, vol. 472, no. 7344, pp. 491–494, 2011. View at Publisher · View at Google Scholar · View at Scopus
  74. N. Kumar, B. Lyda, M. R. Chang et al., “Identification of SR2211: a potent synthetic RORγ-selective modulator,” ACS Chemical Biology, vol. 7, no. 4, pp. 672–677, 2012. View at Publisher · View at Google Scholar · View at Scopus
  75. M. R. Chang, B. Lyda, T. M. Kamenecka, and P. R. Griffin, “Pharmacologic repression of retinoic acid receptor-related orphan nuclear receptor gamma is therapeutic in the collagen-induced arthritis experimental model,” Arthritis and Rheumatology, vol. 66, no. 3, pp. 579–588, 2014. View at Publisher · View at Google Scholar · View at Scopus
  76. T. Xu, X. Wang, B. Zhong, R. I. Nurieva, S. Ding, and C. Dong, “Ursolic acid suppresses interleukin-17 (IL-17) production by selectively antagonizing the function of RORγt protein,” The Journal of Biological Chemistry, vol. 286, no. 26, pp. 22707–22710, 2011. View at Publisher · View at Google Scholar · View at Scopus
  77. S. Xiao, N. Yosef, J. Yang et al., “Small-molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms,” Immunity, vol. 40, no. 4, pp. 477–489, 2014. View at Publisher · View at Google Scholar · View at Scopus
  78. J. Skepner, R. Ramesh, M. Trocha et al., “Pharmacologic inhibition of RORγt regulates Th17 signature gene expression and suppresses cutaneous inflammation in vivo,” The Journal of Immunology, vol. 192, no. 6, pp. 2564–2575, 2014. View at Publisher · View at Google Scholar · View at Scopus
  79. J. R. Huh and D. R. Littman, “Small molecule inhibitors of RORγt: targeting Th17 cells and other applications,” European Journal of Immunology, vol. 42, no. 9, pp. 2232–2237, 2012. View at Publisher · View at Google Scholar · View at Scopus
  80. M. Freeley and A. Long, “Advances in siRNA delivery to T-cells: potential clinical applications for inflammatory disease, cancer and infection,” Biochemical Journal, vol. 455, no. 2, pp. 133–147, 2013. View at Publisher · View at Google Scholar · View at Scopus
  81. A. D. Ellington and J. W. Szostak, “In vitro selection of RNA molecules that bind specific ligands,” Nature, vol. 346, no. 6287, pp. 818–822, 1990. View at Publisher · View at Google Scholar · View at Scopus
  82. S. Shigdar, C. Qian, L. Lv et al., “The use of sensitive chemical antibodies for diagnosis: detection of low levels of EpCAM in breast cancer,” PLoS ONE, vol. 8, no. 2, Article ID e57613, 2013. View at Publisher · View at Google Scholar · View at Scopus
  83. L. Cerchia and V. de Franciscis, “Targeting cancer cells with nucleic acid aptamers,” Trends in Biotechnology, vol. 28, no. 10, pp. 517–525, 2010. View at Publisher · View at Google Scholar · View at Scopus
  84. A. D. Keefe and J. W. Szostak, “Functional proteins from a random-sequence library,” Nature, vol. 410, no. 6829, pp. 715–718, 2001. View at Publisher · View at Google Scholar · View at Scopus
  85. R. Stoltenburg, C. Reinemann, and B. Strehlitz, “SELEX—A (r)evolutionary method to generate high-affinity nucleic acid ligands,” Biomolecular Engineering, vol. 24, no. 4, pp. 381–403, 2007. View at Publisher · View at Google Scholar · View at Scopus
  86. S. M. Shamah, J. M. Healy, and S. T. Cload, “Complex target SELEX,” Accounts of Chemical Research, vol. 41, no. 1, pp. 130–138, 2008. View at Publisher · View at Google Scholar · View at Scopus
  87. K.-T. Guo, A. Paul, C. Schichor, G. Ziemer, and H. P. Wendel, “Cell-SELEX: novel perspectives of aptamer-based therapeutics,” International Journal of Molecular Sciences, vol. 9, no. 4, pp. 668–678, 2008. View at Publisher · View at Google Scholar · View at Scopus
  88. K. Sefah, Z. W. Tang, D. H. Shangguan et al., “Molecular recognition of acute myeloid leukemia using aptamers,” Leukemia, vol. 23, no. 2, pp. 235–244, 2009. View at Publisher · View at Google Scholar · View at Scopus
  89. D. Xiang, S. Shigdar, G. Qiao et al., “Nucleic acid aptamer-guided cancer therapeutics and diagnostics: the next generation of cancer medicine,” Theranostics, vol. 5, no. 1, pp. 23–42, 2015. View at Publisher · View at Google Scholar
  90. J. Zhou and J. J. Rossi, “Cell-type-specific, aptamer-functionalized agents for targeted disease therapy,” Molecular Therapy Nucleic Acids, vol. 3, article e169, 2014. View at Publisher · View at Google Scholar · View at Scopus
  91. S. Shigdar, J. Macdonald, M. O'Connor et al., “Aptamers as theranostic agents: modifications, serum stability and functionalisation,” Sensors, vol. 13, no. 10, pp. 13624–13637, 2013. View at Publisher · View at Google Scholar · View at Scopus
  92. A. D. Keefe, S. Pai, and A. Ellington, “Aptamers as therapeutics,” Nature Reviews Drug Discovery, vol. 9, no. 7, pp. 537–550, 2010. View at Publisher · View at Google Scholar · View at Scopus
  93. J. G. Bruno, “A review of therapeutic aptamer conjugates with emphasis on new approaches,” Pharmaceuticals, vol. 6, no. 3, pp. 340–357, 2013. View at Publisher · View at Google Scholar · View at Scopus
  94. L. Meng, L. Yang, X. Zhao et al., “Targeted delivery of chemotherapy agents using a liver cancer-specific aptamer,” PloS ONE, vol. 7, no. 4, Article ID e33434, 2012. View at Publisher · View at Google Scholar · View at Scopus
  95. P. R. Bouchard, R. M. Hutabarat, and K. M. Thompson, “Discovery and development of therapeutic aptamers,” Annual Review of Pharmacology and Toxicology, vol. 50, pp. 237–257, 2010. View at Publisher · View at Google Scholar · View at Scopus
  96. J. P. Dassie, X.-Y. Liu, G. S. Thomas et al., “Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMA-expressing tumors,” Nature Biotechnology, vol. 27, no. 9, pp. 839–846, 2009. View at Publisher · View at Google Scholar · View at Scopus
  97. F. A. Harding, M. M. Stickler, J. Razo, and R. B. DuBridge, “The immunogenicity of humanized and fully human antibodies: residual immunogenicity resides in the CDR regions,” mAbs, vol. 2, no. 3, pp. 256–265, 2010. View at Publisher · View at Google Scholar · View at Scopus
  98. L. Hedden, S. O'Reilly, C. Lohrisch et al., “Assessing the real-world cost-effectiveness of adjuvant trastuzumab in HER-2/neu positive breast cancer,” Oncologist, vol. 17, no. 2, pp. 164–171, 2012. View at Google Scholar · View at Scopus
  99. S. D. Jayasena, “Aptamers: an emerging class of molecules that rival antibodies in diagnostics,” Clinical Chemistry, vol. 45, no. 9, pp. 1628–1650, 1999. View at Google Scholar · View at Scopus
  100. E. W. M. Ng and A. P. Adamis, “Anti-VEGF aptamer (pegaptanib) therapy for ocular vascular diseases,” Annals of the New York Academy of Sciences, vol. 1082, pp. 151–171, 2006. View at Publisher · View at Google Scholar · View at Scopus
  101. J. C. Burnett and J. J. Rossi, “RNA-based therapeutics: current progress and future prospects,” Chemistry and Biology, vol. 19, no. 1, pp. 60–71, 2012. View at Publisher · View at Google Scholar · View at Scopus
  102. P. Sundaram, H. Kurniawan, M. E. Byrne, and J. Wower, “Therapeutic RNA aptamers in clinical trials,” European Journal of Pharmaceutical Sciences, vol. 48, no. 1-2, pp. 259–271, 2013. View at Publisher · View at Google Scholar · View at Scopus
  103. S. M. Nimjee, C. P. Rusconi, and B. A. Sullenger, “Aptamers: an emerging class of therapeutics,” Annual Review of Medicine, vol. 56, pp. 555–583, 2005. View at Publisher · View at Google Scholar · View at Scopus
  104. P. Song, Y. K. Chou, X. Zhang et al., “CD4 aptamer-RORγt shRNA chimera inhibits IL-17 synthesis by human CD4+ T cells,” Biochemical and Biophysical Research Communications, vol. 452, no. 4, pp. 1040–1045, 2014. View at Publisher · View at Google Scholar · View at Scopus
  105. A. Fire, S. Xu, M. K. Montgomery, S. A. Kostas, S. E. Driver, and C. C. Mello, “Potent and specific genetic interference by double-stranded RNA in caenorhabditis elegans,” Nature, vol. 391, no. 6669, pp. 806–811, 1998. View at Publisher · View at Google Scholar · View at Scopus
  106. S. M. Elbashir, J. Harborth, W. Lendeckel, A. Yalcin, K. Weber, and T. Tuschl, “Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells,” Nature, vol. 411, no. 6836, pp. 494–498, 2001. View at Publisher · View at Google Scholar · View at Scopus
  107. D. Bumcrot, M. Manoharan, V. Koteliansky, and D. W. Y. Sah, “RNAi therapeutics: a potential new class of pharmaceutical drugs,” Nature Chemical Biology, vol. 2, no. 12, pp. 711–719, 2006. View at Publisher · View at Google Scholar · View at Scopus
  108. J. Gehl, “Electroporation: theory and methods, perspectives for drug delivery, gene therapy and research,” Acta Physiologica Scandinavica, vol. 177, no. 4, pp. 437–447, 2003. View at Publisher · View at Google Scholar · View at Scopus
  109. W. Lai, C.-H. Chang, and D. L. Farber, “Gene transfection and expression in resting and activated murine CD4 T cell subsets,” Journal of Immunological Methods, vol. 282, no. 1-2, pp. 93–102, 2003. View at Publisher · View at Google Scholar · View at Scopus
  110. A. G. Gómez-Valadés, M. Llamas, S. Blanch et al., “Specific Jak3 downregulation in lymphocytes impairs γc cytokine signal transduction and alleviates antigen-driven inflammation in vivo,” Molecular Therapy—Nucleic Acids, vol. 1, article e42, 2012. View at Publisher · View at Google Scholar · View at Scopus
  111. M. Rangachari, C. Zhu, K. Sakuishi et al., “Bat3 promotes T cell responses and autoimmunity by repressing Tim-3-mediated cell death and exhaustion,” Nature Medicine, vol. 18, no. 9, pp. 1394–1400, 2012. View at Publisher · View at Google Scholar · View at Scopus
  112. H.-S. Jin, L. Liao, Y. Park, and Y.-C. Liu, “Neddylation pathway regulates T-cell function by targeting an adaptor protein Shc and a protein kinase Erk signaling,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 2, pp. 624–629, 2013. View at Publisher · View at Google Scholar · View at Scopus
  113. Z. Liu, M. Winters, M. Holodniy, and H. Dai, “siRNA delivery into human T cells and primary cells with carbon-nanotube transporters,” Angewandte Chemie—International Edition, vol. 46, no. 12, pp. 2023–2027, 2007. View at Publisher · View at Google Scholar · View at Scopus
  114. E. Song, P. Zhu, S.-K. Lee et al., “Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors,” Nature Biotechnology, vol. 23, no. 6, pp. 709–717, 2005. View at Publisher · View at Google Scholar · View at Scopus
  115. D. Peer, P. Zhu, C. V. Carman, J. Lieberman, and M. Shimaoka, “Selective gene silencing in activated leukocytes by targeting siRNAs to the integrin lymphocyte function-associated antigen-1,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 10, pp. 4095–4100, 2007. View at Publisher · View at Google Scholar · View at Scopus
  116. P. Kumar, H.-S. Ban, S.-S. Kim et al., “T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice,” Cell, vol. 134, no. 4, pp. 577–586, 2008. View at Publisher · View at Google Scholar · View at Scopus
  117. S. Shigdar, A. C. Ward, A. De, C. J. Yang, M. Wei, and W. Duan, “Clinical applications of aptamers and nucleic acid therapeutics in haematological malignancies,” British Journal of Haematology, vol. 155, no. 1, pp. 3–13, 2011. View at Publisher · View at Google Scholar · View at Scopus
  118. J. O. McNamara II, E. R. Andrechek, Y. Wang et al., “Cell type-specific delivery of siRNAs with aptamer-siRNA chimeras,” Nature Biotechnology, vol. 24, no. 8, pp. 1005–1015, 2006. View at Publisher · View at Google Scholar · View at Scopus
  119. J. Zhou, H. Li, S. Li, J. Zaia, and J. J. Rossi, “Novel dual inhibitory function aptamer-siRNA delivery system for HIV-1 therapy,” Molecular Therapy, vol. 16, no. 8, pp. 1481–1489, 2008. View at Publisher · View at Google Scholar · View at Scopus
  120. J. Zhou, P. Swiderski, H. Li et al., “Selection, characterization and application of new RNA HIV gp 120 aptamers for facile delivery of Dicer substrate siRNAs into HIV infected cells,” Nucleic Acids Research, vol. 37, no. 9, pp. 3094–3109, 2009. View at Publisher · View at Google Scholar · View at Scopus
  121. C. P. Neff, J. Zhou, L. Remling et al., “An aptamer-siRNA chimera suppresses HIV-1 viral loads and protects from helper CD4+ T cell decline in humanized mice,” Science Translational Medicine, vol. 3, no. 66, Article ID 66ra6, 2011. View at Publisher · View at Google Scholar · View at Scopus
  122. L. A. Wheeler, R. Trifonova, V. Vrbanac et al., “Inhibition of HIV transmission in human cervicovaginal explants and humanized mice using CD4 aptamer-siRNA chimeras,” The Journal of Clinical Investigation, vol. 121, no. 6, pp. 2401–2412, 2011. View at Publisher · View at Google Scholar · View at Scopus
  123. M. Takahashi, J. C. Burnett, and J. J. Rossi, “Aptamer-siRNA chimeras for HIV,” Advances in Experimental Medicine & Biology, vol. 848, pp. 211–234, 2015. View at Publisher · View at Google Scholar
  124. P. Zhang, N. Zhao, Z. Zeng, C.-C. Chang, and Y. Zu, “Combination of an aptamer probe to CD4 and antibodies for multicolored cell phenotyping,” American Journal of Clinical Pathology, vol. 134, no. 4, pp. 586–593, 2010. View at Publisher · View at Google Scholar · View at Scopus