Ror-gamma T inhibition as a Pharmacological Approach for Inflammatory Bowel Disease
Main Article Content
Abstract
Retinoic Acid Related Orphan Nuclear Receptor gamma T (ROR-γT) is the lineage specifying transcription factor for IL-17 expressing cells. ROR-γT expression is up-regulated in various animal models of colitis, as well as in certain patients with Inflammatory Bowel Disease (IBD). Transfer of ROR-gamma null T cells to RAG1 deficient mice did not induce colitis in these animals. Recently, data with a specific small molecule inhibitor (VPR-7) of ROR-γT showed efficacy in a murine model of IBD. In principle, ROR-γT inhibitors would specifically inhibit Th17 cell differentiation and expansion. ROR-γT, which is functioning in innate intestinal lymphoid cells, may also be a target for ROR-γT inhibitors. These drugs would block the transcription of possible pro-inflammatory receptors (IL-23R) cytokines (IL-17, IL-21) and chemokines (CCL20) putatively involved in the pathogenesis of IBD. Off-target effects of ROR-γT inhibitors have been reported, including the inhibition of colonic IL-23 in a mouse model of colitis. Several pharmaceutical companies are actively involved in the development of specific inhibitors targeting ROR-γT. It is possible that ROR-γT inhibitors will enter clinical trials for the treatment of IBD in the near future.
Article Details
How to Cite
FITZPATRICK, Leo Robert.
Ror-gamma T inhibition as a Pharmacological Approach for Inflammatory Bowel Disease.
Medical Research Archives, [S.l.], v. 2, n. 2, aug. 2015.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/334>. Date accessed: 18 dec. 2024.
Keywords
Ror-Gama T, Colitis, Mice, Inflammatory Bowel Disease
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
Almeida, Cde.S.., V.A. Oliveira, N.O.S. Cavera, J.F. Jacysyn and E.L. Faquim-Mauro. “Crotoxin from Crotalus durrisus terrificus is able to down-modulate the acute intestinal inflammation in mice.” 2015. PLoS One 10 (4): 1-19. doi: 10.1371/journal.pone.0121427.
Arakai, A., H. Nara, M. Rahman, T. Onoda, J. Li, F.M. Juliana, L. Jim, K. Murata, Y. Takeda and H. Asao. 2013. “Role of interleukin-21 isoform in dextran sodium (DSS)-induced colitis.” Cytokine 62: 262-71. doi: 10.1016/j.cyto.2013.03.006.
Annunziato, F., L. Cosmi, V. Santarlasci, L. Maggi, F. Liotta, B. Mazzinghi, E. Parente, L. Fili, S. Ferri, F. Frosali, F. Giudici, P. Romagnani, F. Tonelli, E. Maggi and S. Romagnani. 2007. “Phenotypic and functional features of human Th17 cells.” JEM 24 (8): 1849-61.
Buonocore, S., P.P. Ahern, H.H. Uhlig, I.I. Ivanov, D.R. Littman, K.J. Maloy and F.P. Powrie. 2010. “Innate lymphoid cells drive IL-23 dependent innate intestinal pathology.” Nature 464 (7293): 1371-75. doi: 10.1038/nature08949.
Chen, Q.Q.., L. Yan, C.Z. Wang, W.H. Wang, H. Shi, B.B. Su, Q.H. Zeng, H.T. Du and J. Wan. 2013. “Mesenchymal stem cells alleviate TNBS-induced colitis by modulating inflammatory and autoimmune responses.” WJG 19 (29): 4702-17. doi: 10.3748/wjg.v19.i29.4702.
Cox, J.H., N.M. Kljavin, N. Ota, J. Leonard, M. Roose-Garma, l. Diehl, W. Ouyang and N. Ghilardi. 2012. “Opposing consequences of IL-23 signaling mediated by innate and adaptive cells in chemically induced colitis in mice.” Mucosal Immunol 5 (1): 99-109. doi: 10.1038/mi.2011.54.
Cravo, M.L., P.A. Ferreria, P. Sousa, P. Moura-Santos, S. Vello, L. Tavares, J.R. de Deus, P. Ministro, P. Peixe, L.A. Correia, J.E. Velosa, R.F. Maio and M. Brito. 2014. “IL23R polymorphisms influence phenotype and response to therapy in patients with ulcerative colitis. Eur J Gastroenterol Hepatol 26 (1): 26-32. doi: 10.1097/MEG.0000000000000004.
Dambacher, J., F. Beigel, K. Zitzmann, E.N. De Toni, B. Goke, H.M. Diepolder, C.J. Auernhammer and S. Brand. 2009. “The role of the novel Th17 cytokine IL-26 in intestinal inflammation.” Gut 58 (9): 1207-17. doi: 10.1136/gut.2007.130112.
Dong, Z., L. Du, X. Xu, Y. Yang, H. Wang, A. Qu, X. Qu and C. Wang. 2013. “Aberrant expression of circulating Th17, Th1 and Tc1 cells in patients with active and inactive ulcerative colitis.” 2013. International Journal of Molecular Medicine 31: 989-97. doi: 10.3892/ijmm.2013.1287.
Eken, A., A.K. Singh, P.M. Treuting and M. Oukka. 2014. “IL-23R+ innate lymphoid cells induce colitis via interleukin-22-dependent mechanism.” Mucosal Immunology 7 (1): 143-54. doi: 10.1038/mi.2013.33.
Fantini M.C., A. Rizzo, D. Fina, R. Caruso, C. Becker, M.F. Neurath, T.T. MacDonald, F. Pallone and G. Monteleone. 2007. “IL-21 regulates experimental colitis by modulating the balance between Treg and Th17 cells.” Eur J Immunol 37 (11): 3155-63.
Fitzpatrick, L.R. 2012. “Novel pharmacological approaches for inflammatory bowel disease: targeting key intracellular pathways and the IL-23/IL-17 axis.” Int J Inflam 2012:384904. doi: 10.1155/2012/389404.
Fitzpatrick L.R. 2013. “Inhibition of IL-17 as a pharmacological approach for IBD.” Int Rev Immunol 32 (5-6): 544-55. doi: 10.3109/08830185.2013.821118.
Fitzpatrick, L.R., J. Zapf, E. M. Flood, S. B. Ravula, L.K. Lingardo, J. Small, F. Tucci, C.A. Buhr and G. Alton. 2015. “Efficacy of a novel small molecule Rorγt inverse agonist in mouse DSS and TNBS models of inflammatory bowel disease.” Gastroenterology 148 (4) Supplement 1, S-26.
Galvez, J. 2014. “Role of the Th17 cells in the pathogenesis of human IBD.” ISRN Inflammation 2014: 1-14. doi: 10.1155/2014/928461.
Kamanaka, M., S. Huber, L.A. Zenewicz, N. Gagliani, C. Rathinam, W. O’connor, Y.Y. Wan, S. Nakae, Y. Iwakura, L. Hao and R.A. Flavell. 2011. “Memory/effector (CD45RB (lo)/ CD4 t cells are controlled directly by IL-10 and cause IL-22 dependent intestinal pathology.” J Exp Med 208 (5): 1027-40. doi: 10.1084/jem.20102149.
Kanai, T., Y. Mikami, T. Sujno, T. Hisamatsu and T. Hibi. 2012. “Rorγt-dependent IL-17A-producing cells in the pathogenesis of intestinal inflammation.” Mucosal Immunology 5 (3): 240-7. doi: 10.1038/mi.2012.6.
Katchar, K., C.P. Kelly, S. Keates, M.J. O’brien and A.C. Keates. 2007. “MIP-3 alpha neutralizing monoclonal antibody protects against TNBS-induced colonic injury and inflammation in mice.” Am J Physiol Gastrointest Liver Physiol 292 (5): G1263-71.
Lee, S.Y., T.H. Lee, J.J. Jeong, S.H. Eun, M.D. Nyugen, J.H. Park and D.H. Kim. 2015. “Ocotillol, a majonoside R2 metabolite, ameliorated 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice by restoring the imbalance of Th17/Treg cells.” J Agric Food Chem. Publshed online.
Leppkes, M., C. Becker, I.I. Ivanov, S. Hirth, S. Wirtz, C. Neufert, S. Pouly, A. J. Murphy, D.M. Valenzuela, G.M. Yancopoulos, B. Becher, D.R. Littman and M.F. Neurath. 2009. “Rorγ-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F.” Gastroenterology 136 (1): 257-67. doi: 10.1053/j.gastro.2008.10.018.
Liu, Z., L. Yang, Y. Cui, X. Wang, C. Guo, Z. Huang, Q. Kan, Z. Liu and Y. Liu. 2009. “IL-21 enhances NK cell activation and cytolytic activity and induces Th17 cell differentiation in inflammatory bowel disease.” Inflamm Bowel Dis 15 (8): 1133-44. doi: 10.1002/ibd.20923.
Lochner, M., C. Ohnmacher, L. Presley, P. Bruhns, M. Si-Tahar, S. Sawa and G. Eberl. 2011. “Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of Rorγt and LTi cells.” J Exp Med 208 (1): 125-34. doi: 10.1084/jem.20100052.
Martin, M., R.K. Kesserling, S. Balam, S.M. Brunner, G. Schiechl, V.F. Mouris, A.K. Wege, P. Rummele, H.J. Schlitt, E.K. Geissler and S. Fichtner-Feigl. 2015. “Rorγt+ hematopoietic cells are necessary for tumor cell proliferation during colitis-associated tumorigenesis in mice.” Eur J Immunol 45 (6): 1667-79. doi: 10.1002/eji.201444915.
McGovern, D. and F. Powrie. 2007. “The IL23 axis plays a key role in the pathogenesis of IBD.” Gut 56 (10): 1333-36.
Mori, K. H. Yamanishi, Y. Ikeda, T. Kumagi, Y. Hiasa, B. Matsuura, M. Abe and M. Oniji. 2013. “Oral administration of carbonic anhydrase I ameliorates murine experimental colitis induced by Foxp3-CD4+CD25-T cells.” J Leukoc Biol 93 (6):963-72. doi: 10.1189/jlb.1212612.
Ohnmacht, C., R. Marques, L. Presley, S. Sawa, M. Lochner and G. Eberl. 2011. “Intestinal microbiota, evolution of the immune system and the bad reputation of pro-inflammatory immunity.” Cellular Microbiology 13 (5): 653-59. doi: 10.1111/j.1462-5822.2011.01577.x.
Punkenberg E., T. Vogler, M. Buttner, K. Armann, M. Waldner, R. Atreya, B. Abendroth, J. Mudter, S. Merkel, E. Gallmeier, S. Rose-John, M.F. Neurath and K. Hildner. 2015. “Batf-dependent TH17 cells critically regulate IL-23 driven colitis-associated cancer.” Gut: published online. doi: 10.1136/gutjnl-2014-308227.
Sawa, S., M. Lochner, N.S. Takayama, S. Dulauroy, M. Berard, M. Kleinshek, D. Cua, J.P. Di Santo and G. Eberl. 2011. “Rorγt innate intestinal lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota.” Nature Immunology 12 (4): 320-326. doi: 10.1038/ni.2002.
Sheikh, S., J. Uno, K. Matsuoka and S. Plevy. 2008. “Abnormal mucosal immune response to altered bacterial flora following restorative proctolectomy in patients with ulcerative colitis: serologic measures, immunogenetics, and clinical correlations. Clin Immunol 127 (3): 270-9. doi: 10.1016/j.clim.2008.03.511.
Shen, Y.M., Y. Zhao, Y. Zeng, L. Yan, B.L. Chen, A.M. Lin, Y.B. Mu and G.Y. Zhang. 2012. “Inhibition of pim-1kinase ameliorates dextran sodium sulfate-induced colitis in mice.” Dig Dis Sci 57 (7): 1822-31. doi: 10.1007/s10620-012-2106-7.
Skepner, J., R. Ramesh, M. Trocha, D. Schmidt, E. Baloglu, M. Lobera, T. Carlson, J. Hill, L.A. Orband-Miller, A. Barnes, M. Boudjehal, M. Sundrud, S. Ghosh and J. Yang. 2014. Pharmacological inhibition of Rorγt regulates Th17 signature gene expression and suppresses cutaneous inflammation in vivo.” J Immunol 192 (6) :2564-75. doi: 10.4049/jimmunol.1302190.
Skepner, J., M. Trocha, R. Ramesh, X.A. Qu, D. Schmidt, E. Bagolu, M. Lobera, S. Davis, M.A. Nolan, T.J. Carlson, J. Hill, S. Ghosh, M.S. Schmidt and J. Yang. 2015. “In vivo regulation of gene expression and T helper type 17 differentiation by Rorγt inverse agonists.” Immunology 145: 347-56. doi: 10.1111/imm.12444.
Teramoto, K., S. Mura, Y. Tzuzuki, R. Hokari, C. Watanabe, T. Inamura, T. Ogawa, N. Hosoe, H. Nagata, H. Ishi and T. Hibi. 2005. “Increased lymphyocyte trafficking to colonic microvessels is dependent on MADCAM-1 and C-C chemokine mLARC/CCL20 in DSS-induced mice colitis.” Clin Exp Immunol 139 (3): 421-8.
Wang, Y., W. Cai, G. Zhang, T. Yang, Q. Liu, Y. Cheng, L. Zhou, Y. Ma, Z. Cheng, S. Liu, Y.G. Zhao, W. Zhang, Z Xiang, S. Wang, L. Yang, Q. Wu, L.A. Orband-Miller, Y. Xu, J. Zhang, R, Gao, M. Huxdorf, J.N. Xiang, Z. Zhong, J.D. Elliott, S. Leung and X. Lien. 2014. “Discovery of novel N-(5(arylcarbonyl)thiazol-2-yl) amides and N-(5-(arylcarbonyl)thiopen-2yl) amides as potent Rorγt inhibitors.” Bioorganic & Medicinal Chemistry 22: 692-702. doi: 10.1016/j.bmc.2013.12.021.
Wedebye Schmidt, E.G.., H.L. Larsen, N.N. Kristensen, S.S. Poulsen, A.M.L. Pedersen, M.H. Claesson and A.E. Pedersen. 2013. “TH17 cell induction and effects of IL-17A and IL-17F blockade in experimental colitis.” Inflamm Bowel Dis 19 (8): 1567-76. doi: 10.1097/MIB.0b013e318286fa1c.
Xiao, S., N. Yosef, J. Yiang, Y. Wang, L. Zhou, C. Zhu, C. Wu, E. Balogfu, D. Schmidt, R. Ramesh, M. Lobera, M.S. Sundrud, P.Y. Tsai, Z. Xiang, J. Wang, Y. Xu, X. Lin, K. Kretshmer, P.B. Rahl, R.A. Young, Z. Zhong, D.A. Hafler, A. Regev, S. Ghosh, A. Marson and V.K. Kuchroo. 2014. “Small molecule Rorγt antagonists inhibit t helper 17 cell transcriptional network by divergent mechanisms.” Immunity 40: 477-89. doi: 10.1016/j.immuni.2014.04.004.
Zenewicz, L.A., G.D. Yancopolous, D. M. Valenzuela, A.J. Murphy, S. Stevens and R.A. Flavell. 2008. “Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease.” Immunity 29 (6): 947-57. doi: 10.1016/j.immuni.2008.11.003.
Zhang, H., W. Zhong, G. Zhou, X. Ding and H. Chen. 2012. “Expression of chemokine CCL20 in ulcerative colitis.” Molecular Medicine Reports 6: 1255-60. doi: 10.3892/mmr.2012.1088.
Zhang, Z., M. Zheng, J. Bindas, P. Schwarzenberger and J.K. Kolls. 2006. “Critical role of IL-17 receptor signaling in acute TNBS-induced colitis.” Inflamm Bowel Dis 12 (5): 382-88.
Zhou, L. and D.R. Littman. 2009. “Transcriptional regulatory networks in Th17 cell differentiation.” Curr Opin Immunol 21 (2): 146-52. doi: 0.1016/j.coi.2009.03.001.
Arakai, A., H. Nara, M. Rahman, T. Onoda, J. Li, F.M. Juliana, L. Jim, K. Murata, Y. Takeda and H. Asao. 2013. “Role of interleukin-21 isoform in dextran sodium (DSS)-induced colitis.” Cytokine 62: 262-71. doi: 10.1016/j.cyto.2013.03.006.
Annunziato, F., L. Cosmi, V. Santarlasci, L. Maggi, F. Liotta, B. Mazzinghi, E. Parente, L. Fili, S. Ferri, F. Frosali, F. Giudici, P. Romagnani, F. Tonelli, E. Maggi and S. Romagnani. 2007. “Phenotypic and functional features of human Th17 cells.” JEM 24 (8): 1849-61.
Buonocore, S., P.P. Ahern, H.H. Uhlig, I.I. Ivanov, D.R. Littman, K.J. Maloy and F.P. Powrie. 2010. “Innate lymphoid cells drive IL-23 dependent innate intestinal pathology.” Nature 464 (7293): 1371-75. doi: 10.1038/nature08949.
Chen, Q.Q.., L. Yan, C.Z. Wang, W.H. Wang, H. Shi, B.B. Su, Q.H. Zeng, H.T. Du and J. Wan. 2013. “Mesenchymal stem cells alleviate TNBS-induced colitis by modulating inflammatory and autoimmune responses.” WJG 19 (29): 4702-17. doi: 10.3748/wjg.v19.i29.4702.
Cox, J.H., N.M. Kljavin, N. Ota, J. Leonard, M. Roose-Garma, l. Diehl, W. Ouyang and N. Ghilardi. 2012. “Opposing consequences of IL-23 signaling mediated by innate and adaptive cells in chemically induced colitis in mice.” Mucosal Immunol 5 (1): 99-109. doi: 10.1038/mi.2011.54.
Cravo, M.L., P.A. Ferreria, P. Sousa, P. Moura-Santos, S. Vello, L. Tavares, J.R. de Deus, P. Ministro, P. Peixe, L.A. Correia, J.E. Velosa, R.F. Maio and M. Brito. 2014. “IL23R polymorphisms influence phenotype and response to therapy in patients with ulcerative colitis. Eur J Gastroenterol Hepatol 26 (1): 26-32. doi: 10.1097/MEG.0000000000000004.
Dambacher, J., F. Beigel, K. Zitzmann, E.N. De Toni, B. Goke, H.M. Diepolder, C.J. Auernhammer and S. Brand. 2009. “The role of the novel Th17 cytokine IL-26 in intestinal inflammation.” Gut 58 (9): 1207-17. doi: 10.1136/gut.2007.130112.
Dong, Z., L. Du, X. Xu, Y. Yang, H. Wang, A. Qu, X. Qu and C. Wang. 2013. “Aberrant expression of circulating Th17, Th1 and Tc1 cells in patients with active and inactive ulcerative colitis.” 2013. International Journal of Molecular Medicine 31: 989-97. doi: 10.3892/ijmm.2013.1287.
Eken, A., A.K. Singh, P.M. Treuting and M. Oukka. 2014. “IL-23R+ innate lymphoid cells induce colitis via interleukin-22-dependent mechanism.” Mucosal Immunology 7 (1): 143-54. doi: 10.1038/mi.2013.33.
Fantini M.C., A. Rizzo, D. Fina, R. Caruso, C. Becker, M.F. Neurath, T.T. MacDonald, F. Pallone and G. Monteleone. 2007. “IL-21 regulates experimental colitis by modulating the balance between Treg and Th17 cells.” Eur J Immunol 37 (11): 3155-63.
Fitzpatrick, L.R. 2012. “Novel pharmacological approaches for inflammatory bowel disease: targeting key intracellular pathways and the IL-23/IL-17 axis.” Int J Inflam 2012:384904. doi: 10.1155/2012/389404.
Fitzpatrick L.R. 2013. “Inhibition of IL-17 as a pharmacological approach for IBD.” Int Rev Immunol 32 (5-6): 544-55. doi: 10.3109/08830185.2013.821118.
Fitzpatrick, L.R., J. Zapf, E. M. Flood, S. B. Ravula, L.K. Lingardo, J. Small, F. Tucci, C.A. Buhr and G. Alton. 2015. “Efficacy of a novel small molecule Rorγt inverse agonist in mouse DSS and TNBS models of inflammatory bowel disease.” Gastroenterology 148 (4) Supplement 1, S-26.
Galvez, J. 2014. “Role of the Th17 cells in the pathogenesis of human IBD.” ISRN Inflammation 2014: 1-14. doi: 10.1155/2014/928461.
Kamanaka, M., S. Huber, L.A. Zenewicz, N. Gagliani, C. Rathinam, W. O’connor, Y.Y. Wan, S. Nakae, Y. Iwakura, L. Hao and R.A. Flavell. 2011. “Memory/effector (CD45RB (lo)/ CD4 t cells are controlled directly by IL-10 and cause IL-22 dependent intestinal pathology.” J Exp Med 208 (5): 1027-40. doi: 10.1084/jem.20102149.
Kanai, T., Y. Mikami, T. Sujno, T. Hisamatsu and T. Hibi. 2012. “Rorγt-dependent IL-17A-producing cells in the pathogenesis of intestinal inflammation.” Mucosal Immunology 5 (3): 240-7. doi: 10.1038/mi.2012.6.
Katchar, K., C.P. Kelly, S. Keates, M.J. O’brien and A.C. Keates. 2007. “MIP-3 alpha neutralizing monoclonal antibody protects against TNBS-induced colonic injury and inflammation in mice.” Am J Physiol Gastrointest Liver Physiol 292 (5): G1263-71.
Lee, S.Y., T.H. Lee, J.J. Jeong, S.H. Eun, M.D. Nyugen, J.H. Park and D.H. Kim. 2015. “Ocotillol, a majonoside R2 metabolite, ameliorated 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice by restoring the imbalance of Th17/Treg cells.” J Agric Food Chem. Publshed online.
Leppkes, M., C. Becker, I.I. Ivanov, S. Hirth, S. Wirtz, C. Neufert, S. Pouly, A. J. Murphy, D.M. Valenzuela, G.M. Yancopoulos, B. Becher, D.R. Littman and M.F. Neurath. 2009. “Rorγ-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F.” Gastroenterology 136 (1): 257-67. doi: 10.1053/j.gastro.2008.10.018.
Liu, Z., L. Yang, Y. Cui, X. Wang, C. Guo, Z. Huang, Q. Kan, Z. Liu and Y. Liu. 2009. “IL-21 enhances NK cell activation and cytolytic activity and induces Th17 cell differentiation in inflammatory bowel disease.” Inflamm Bowel Dis 15 (8): 1133-44. doi: 10.1002/ibd.20923.
Lochner, M., C. Ohnmacher, L. Presley, P. Bruhns, M. Si-Tahar, S. Sawa and G. Eberl. 2011. “Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of Rorγt and LTi cells.” J Exp Med 208 (1): 125-34. doi: 10.1084/jem.20100052.
Martin, M., R.K. Kesserling, S. Balam, S.M. Brunner, G. Schiechl, V.F. Mouris, A.K. Wege, P. Rummele, H.J. Schlitt, E.K. Geissler and S. Fichtner-Feigl. 2015. “Rorγt+ hematopoietic cells are necessary for tumor cell proliferation during colitis-associated tumorigenesis in mice.” Eur J Immunol 45 (6): 1667-79. doi: 10.1002/eji.201444915.
McGovern, D. and F. Powrie. 2007. “The IL23 axis plays a key role in the pathogenesis of IBD.” Gut 56 (10): 1333-36.
Mori, K. H. Yamanishi, Y. Ikeda, T. Kumagi, Y. Hiasa, B. Matsuura, M. Abe and M. Oniji. 2013. “Oral administration of carbonic anhydrase I ameliorates murine experimental colitis induced by Foxp3-CD4+CD25-T cells.” J Leukoc Biol 93 (6):963-72. doi: 10.1189/jlb.1212612.
Ohnmacht, C., R. Marques, L. Presley, S. Sawa, M. Lochner and G. Eberl. 2011. “Intestinal microbiota, evolution of the immune system and the bad reputation of pro-inflammatory immunity.” Cellular Microbiology 13 (5): 653-59. doi: 10.1111/j.1462-5822.2011.01577.x.
Punkenberg E., T. Vogler, M. Buttner, K. Armann, M. Waldner, R. Atreya, B. Abendroth, J. Mudter, S. Merkel, E. Gallmeier, S. Rose-John, M.F. Neurath and K. Hildner. 2015. “Batf-dependent TH17 cells critically regulate IL-23 driven colitis-associated cancer.” Gut: published online. doi: 10.1136/gutjnl-2014-308227.
Sawa, S., M. Lochner, N.S. Takayama, S. Dulauroy, M. Berard, M. Kleinshek, D. Cua, J.P. Di Santo and G. Eberl. 2011. “Rorγt innate intestinal lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota.” Nature Immunology 12 (4): 320-326. doi: 10.1038/ni.2002.
Sheikh, S., J. Uno, K. Matsuoka and S. Plevy. 2008. “Abnormal mucosal immune response to altered bacterial flora following restorative proctolectomy in patients with ulcerative colitis: serologic measures, immunogenetics, and clinical correlations. Clin Immunol 127 (3): 270-9. doi: 10.1016/j.clim.2008.03.511.
Shen, Y.M., Y. Zhao, Y. Zeng, L. Yan, B.L. Chen, A.M. Lin, Y.B. Mu and G.Y. Zhang. 2012. “Inhibition of pim-1kinase ameliorates dextran sodium sulfate-induced colitis in mice.” Dig Dis Sci 57 (7): 1822-31. doi: 10.1007/s10620-012-2106-7.
Skepner, J., R. Ramesh, M. Trocha, D. Schmidt, E. Baloglu, M. Lobera, T. Carlson, J. Hill, L.A. Orband-Miller, A. Barnes, M. Boudjehal, M. Sundrud, S. Ghosh and J. Yang. 2014. Pharmacological inhibition of Rorγt regulates Th17 signature gene expression and suppresses cutaneous inflammation in vivo.” J Immunol 192 (6) :2564-75. doi: 10.4049/jimmunol.1302190.
Skepner, J., M. Trocha, R. Ramesh, X.A. Qu, D. Schmidt, E. Bagolu, M. Lobera, S. Davis, M.A. Nolan, T.J. Carlson, J. Hill, S. Ghosh, M.S. Schmidt and J. Yang. 2015. “In vivo regulation of gene expression and T helper type 17 differentiation by Rorγt inverse agonists.” Immunology 145: 347-56. doi: 10.1111/imm.12444.
Teramoto, K., S. Mura, Y. Tzuzuki, R. Hokari, C. Watanabe, T. Inamura, T. Ogawa, N. Hosoe, H. Nagata, H. Ishi and T. Hibi. 2005. “Increased lymphyocyte trafficking to colonic microvessels is dependent on MADCAM-1 and C-C chemokine mLARC/CCL20 in DSS-induced mice colitis.” Clin Exp Immunol 139 (3): 421-8.
Wang, Y., W. Cai, G. Zhang, T. Yang, Q. Liu, Y. Cheng, L. Zhou, Y. Ma, Z. Cheng, S. Liu, Y.G. Zhao, W. Zhang, Z Xiang, S. Wang, L. Yang, Q. Wu, L.A. Orband-Miller, Y. Xu, J. Zhang, R, Gao, M. Huxdorf, J.N. Xiang, Z. Zhong, J.D. Elliott, S. Leung and X. Lien. 2014. “Discovery of novel N-(5(arylcarbonyl)thiazol-2-yl) amides and N-(5-(arylcarbonyl)thiopen-2yl) amides as potent Rorγt inhibitors.” Bioorganic & Medicinal Chemistry 22: 692-702. doi: 10.1016/j.bmc.2013.12.021.
Wedebye Schmidt, E.G.., H.L. Larsen, N.N. Kristensen, S.S. Poulsen, A.M.L. Pedersen, M.H. Claesson and A.E. Pedersen. 2013. “TH17 cell induction and effects of IL-17A and IL-17F blockade in experimental colitis.” Inflamm Bowel Dis 19 (8): 1567-76. doi: 10.1097/MIB.0b013e318286fa1c.
Xiao, S., N. Yosef, J. Yiang, Y. Wang, L. Zhou, C. Zhu, C. Wu, E. Balogfu, D. Schmidt, R. Ramesh, M. Lobera, M.S. Sundrud, P.Y. Tsai, Z. Xiang, J. Wang, Y. Xu, X. Lin, K. Kretshmer, P.B. Rahl, R.A. Young, Z. Zhong, D.A. Hafler, A. Regev, S. Ghosh, A. Marson and V.K. Kuchroo. 2014. “Small molecule Rorγt antagonists inhibit t helper 17 cell transcriptional network by divergent mechanisms.” Immunity 40: 477-89. doi: 10.1016/j.immuni.2014.04.004.
Zenewicz, L.A., G.D. Yancopolous, D. M. Valenzuela, A.J. Murphy, S. Stevens and R.A. Flavell. 2008. “Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease.” Immunity 29 (6): 947-57. doi: 10.1016/j.immuni.2008.11.003.
Zhang, H., W. Zhong, G. Zhou, X. Ding and H. Chen. 2012. “Expression of chemokine CCL20 in ulcerative colitis.” Molecular Medicine Reports 6: 1255-60. doi: 10.3892/mmr.2012.1088.
Zhang, Z., M. Zheng, J. Bindas, P. Schwarzenberger and J.K. Kolls. 2006. “Critical role of IL-17 receptor signaling in acute TNBS-induced colitis.” Inflamm Bowel Dis 12 (5): 382-88.
Zhou, L. and D.R. Littman. 2009. “Transcriptional regulatory networks in Th17 cell differentiation.” Curr Opin Immunol 21 (2): 146-52. doi: 0.1016/j.coi.2009.03.001.