Unraveling the Challenges in the Retinoid-related Orphan Receptor (ROR)-y(t) Therapeutic Landscape for Autoimmune Diseases
Main Article Content
Abstract
RORyt/y driven type-17 “pro-inflammatory “gene expression profile has been implicated in the pathogenesis of several human immune-mediated diseases and remains a compelling target for therapeutic intervention. However, several challenges, from both drug discovery and biology standpoint, have made it intractable. While biologics targeting IL-23, IL-17, IL-17R, and other cytokines in the ROR pathway have demonstrated clinical efficacy in psoriasis, ankylosing spondylitis, etc., it has been challenging to extend the utility of these therapeutics beyond a handful of autoimmune diseases, especially in atopic or rheumatic diseases. This review summarizes the complexities in defining the pathogenicity of the human type-17 pathway and underscores the need for targeting a phenotypically heterogeneous and therapeutically relevant pathogenic cell subset marked by CD161.
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How to Cite
BANERJEE, Daliya.
Unraveling the Challenges in the Retinoid-related Orphan Receptor (ROR)-y(t) Therapeutic Landscape for Autoimmune Diseases.
Medical Research Archives, [S.l.], v. 12, n. 4, apr. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5306>. Date accessed: 09 may 2024.
doi: https://doi.org/10.18103/mra.v12i4.5306.
Section
Research 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
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19. Korn, T., Bettelli, E., Oukka, M., & Kuchroo, V. K. (2009). IL-17 and Th17 Cells. Annu Rev Immunol, 27, 485-517. Doi:10.1146/annurev.immunol.021908.132710
20. Kotake, S., Nanke, Y., Yago, T., Kawamoto, M., Kobashigawa, T., & Yamanaka, H. (2016). Elevated Ratio of Th17 Cell-Derived Th1 Cells (CD161(+)Th1 Cells) to CD161(+)Th17 Cells in Peripheral Blood of Early-Onset Rheumatoid Arthritis Patients. Biomed Res Int, 2016, 4186027. Doi:10.1155/2016/4186027
21. Kragstrup, T. W., Glintborg, B., Svensson, A. L., McMaster, C., Robinson, P. C., Deleuran, B., & Liew, D. F. (2022). Waiting for JAK inhibitor safety data. RMD Open, 8(1). Doi:10.1136/rmdopen-2022-002236
22. Kunwar, S., Dahal, K., & Sharma, S. (2016). Anti-IL-17 therapy in treatment of rheumatoid arthritis: a systematic literature review and meta-analysis of randomized controlled trials. Rheumatol Int, 36(8), 1065-1075. Doi:10.1007/s00296-016-3480-9
23. Leonardi, C. L., Kimball, A. B., Papp, K. A., Yeilding, N., Guzzo, C., Wang, Y., . . . investigators, P. s. (2008). 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). Lancet, 371(9625), 1665-1674. Doi:10.1016/S0140-6736(08)60725-4
24. Maggi, L., Santarlasci, V., Capone, M., Peired, A., Frosali, F., Crome, S. Q., . . . Annunziato, F. (2010). CD161 is a marker of all human IL-17-producing T-cell subsets and is induced by RORC. Eur J Immunol, 40(8), 2174-2181. Doi:10.1002/eji.200940257
25. Nair, R. P., Duffin, K. C., Helms, C., Ding, J., Stuart, P. E., Goldgar, D., . . . Collaborative Association Study of, P. (2009). Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet, 41(2), 199-204. Doi:10.1038/ng.311
26. Nistala, K., Adams, S., Cambrook, H., Ursu, S., Olivito, B., de Jager, W., . . . Wedderburn, L. R. (2010). Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proc Natl Acad Sci U S A, 107(33), 14751-14756. Doi:10.1073/pnas.1003852107
27. Schinocca, C., Rizzo, C., Fasano, S., Grasso, G., La Barbera, L., Ciccia, F., & Guggino, G. (2021). Role of the IL-23/IL-17 Pathway in Rheumatic Diseases: An Overview. Front Immunol, 12, 637829. Doi:10.3389/fimmu.2021.637829
28. Smolen, J. S., Agarwal, S. K., Ilivanova, E., Xu, X. L., Miao, Y., Zhuang, Y., . . . Baker, D. (2017). A randomised phase II study evaluating the efficacy and safety of subcutaneously administered ustekinumab and guselkumab in patients with active rheumatoid arthritis despite treatment with methotrexate. Ann Rheum Dis, 76(5), 831-839. Doi:10.1136/annrheumdis-2016-209831
29. Stahl, E. A., Raychaudhuri, S., Remmers, E. F., Xie, G., Eyre, S., Thomson, B. P., . . . Plenge, R. M. (2010). Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet, 42(6), 508-514. Doi:10.1038/ng.582
30. Wambre, E., Bajzik, V., DeLong, J. H., O'Brien, K., Nguyen, Q. A., Speake, C., . . . Kwok, W. W. (2017). A phenotypically and functionally distinct human T(H)2 cell subpopulation is associated with allergic disorders. Sci Transl Med, 9(401). Doi:10.1126/scitranslmed.aam9171
31. Yokoi, T., Murakami, M., Kihara, T., Seno, S., Arase, M., Wing, J. B., . . . Takeda, K. (2023). Identification of a unique subset of tissue-resident memory CD4(+) T cells in Crohn's disease. Proc Natl Acad Sci U S A, 120(1), e2204269120. Doi:10.1073/pnas.2204269120
32. Zeng, J., Li, M., Zhao, Q., Chen, M., Zhao, L., Wei, S., . . . Wu, X. (2023). Small molecule inhibitors of RORgammat for Th17 regulation in inflammatory and autoimmune diseases. J Pharm Anal, 13(6), 545-562. Doi:10.1016/j.jpha.2023.05.009
33. Zhao, J., Chen, Y., Zhao, Q., Shi, J., Yang, W., Zhu, Z., . . . Liu, J. (2018). Increased circulating Tfh17 and PD-1(+)Tfh cells are associated with autoantibodies in Hashimoto's thyroiditis. Autoimmunity, 51(7), 352-359. Doi:10.1080/08916934.2018.1516761
34. Zhao, L., Nocturne, G., Haskett, S., Boudaoud, S., Lazure, T., Le Pajolec, C., . . . Banerjee, D. (2017). Clinical relevance of RORgamma positive and negative subsets of CD161+CD4+ T cells in primary Sjogren's syndrome. Rheumatology (Oxford), 56(2), 303-312. Doi:10.1093/rheumatology/kew360
2. Annunziato, F., Cosmi, L., Liotta, F., Maggi, E., & Romagnani, S. (2012). Defining the human T helper 17 cell phenotype. Trends Immunol, 33(10), 505-512. Doi:10.1016/j.it.2012.05.004
3. Annunziato, F., & Romagnani, S. (2009). Do studies in humans better depict Th17 cells? Blood, 114(11), 2213-2219. Doi:10.1182/blood-2009-03-209189
4. Banerjee, D., Zhao, L., Wu, L., Palanichamy, A., Ergun, A., Peng, L., . . . Fontenot, J. D. (2016). Small molecule mediated inhibition of RORgamma-dependent gene expression and autoimmune disease pathology in vivo. Immunology, 147(4), 399-413. Doi:10.1111/imm.12570
5. Basdeo, S. A., Moran, B., Cluxton, D., Canavan, M., McCormick, J., Connolly, M., . . . Fletcher, J. M. (2015). Polyfunctional, Pathogenic CD161+ Th17 Lineage Cells Are Resistant to Regulatory T Cell-Mediated Suppression in the Context of Autoimmunity. J Immunol, 195(2), 528-540. Doi:10.4049/jimmunol.1402990
6. Blom, L. H., Martel, B. C., Larsen, L. F., Hansen, C. V., Christensen, M. P., Juel-Berg, N., . . . Poulsen, L. K. (2017). The immunoglobulin superfamily member CD200R identifies cells involved in type 2 immune responses. Allergy, 72(7), 1081-1090. Doi:10.1111/all.13129
7. Cenit, M. C., Alcina, A., Marquez, A., Mendoza, J. L., Diaz-Rubio, M., de las Heras, V., . . . Urcelay, E. (2010). STAT3 locus in inflammatory bowel disease and multiple sclerosis susceptibility. Genes Immun, 11(3), 264-268. Doi:10.1038/gene.2010.10
8. Ciofani, M., Madar, A., Galan, C., Sellars, M., Mace, K., Pauli, F., . . . Littman, D. R. (2012). A validated regulatory network for Th17 cell specification. Cell, 151(2), 289-303. Doi:10.1016/j.cell.2012.09.016
9. Cornelissen, F., Asmawidjaja, P. S., Mus, A. M., Corneth, O., Kikly, K., & Lubberts, E. (2013). IL-23 dependent and independent stages of experimental arthritis: no clinical effect of therapeutic IL-23p19 inhibition in collagen-induced arthritis. PLoS One, 8(2), e57553. Doi:10.1371/journal.pone.0057553
10. Cosmi, L., De Palma, R., Santarlasci, V., Maggi, L., Capone, M., Frosali, F., . . . Annunziato, F. (2008). Human interleukin 17-producing cells originate from a CD161+CD4+ T cell precursor. J Exp Med, 205(8), 1903-1916. Doi:10.1084/jem.20080397
11. Cosmi, L., Maggi, L., Santarlasci, V., Capone, M., Cardilicchia, E., Frosali, F., . . . Annunziato, F. (2010). Identification of a novel subset of human circulating memory CD4(+) T cells that produce both IL-17A and IL-4. J Allergy Clin Immunol, 125(1), 222-230 e221-224. Doi:10.1016/j.jaci.2009.10.012
12. Cua, D. J., & Tato, C. M. (2010). Innate IL-17-producing cells: the sentinels of the immune system. Nat Rev Immunol, 10(7), 479-489. Doi:10.1038/nri2800
13. Duerr, R. H., Taylor, K. D., Brant, S. R., Rioux, J. D., Silverberg, M. S., Daly, M. J., . . . Cho, J. H. (2006). A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science, 314(5804), 1461-1463. Doi:10.1126/science.1135245
14. Fergusson, J. R., Smith, K. E., Fleming, V. M., Rajoriya, N., Newell, E. W., Simmons, R., . . . Klenerman, P. (2014). CD161 defines a transcriptional and functional phenotype across distinct human T cell lineages. Cell Rep, 9(3), 1075-1088. Doi:10.1016/j.celrep.2014.09.045
15. Gara, S. K., Guntipalli, P., Marzban, S., Taqi, M., Aryal, V., Khan, Q. U. A., . . . Diaz-Miret, M. (2023). Clinical Outcomes of Ustekinumab in Inflammatory Bowel Disease. Cureus, 15(10), e46833. Doi:10.7759/cureus.46833
16. Haggerty, H. G., Sathish, J. G., Gleason, C. R., Al-Haddawi, M., Brodie, T. A., Bonnette, K. L., . . . Graziano, M. J. (2021). Thymic Lymphomas in a 6-Month rasH2-Tg Mouse Carcinogenicity Study With the RORgammat Inverse Agonist, BMS-986251. Toxicol Sci, 183(1), 93-104. Doi:10.1093/toxsci/kfab086
17. Hueber, W., Patel, D. D., Dryja, T., Wright, A. M., Koroleva, I., Bruin, G., Di Padova, F. (2010). Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med, 2(52), 52ra72. Doi:10.1126/scitranslmed.3001107
18. Jaeger, N., Gamini, R., Cella, M., Schettini, J. L., Bugatti, M., Zhao, S., . . . Colonna, M. (2021). Single-cell analyses of Crohn's disease tissues reveal intestinal intraepithelial T cells heterogeneity and altered subset distributions. Nat Commun, 12(1), 1921. Doi:10.1038/s41467-021-22164-6
19. Korn, T., Bettelli, E., Oukka, M., & Kuchroo, V. K. (2009). IL-17 and Th17 Cells. Annu Rev Immunol, 27, 485-517. Doi:10.1146/annurev.immunol.021908.132710
20. Kotake, S., Nanke, Y., Yago, T., Kawamoto, M., Kobashigawa, T., & Yamanaka, H. (2016). Elevated Ratio of Th17 Cell-Derived Th1 Cells (CD161(+)Th1 Cells) to CD161(+)Th17 Cells in Peripheral Blood of Early-Onset Rheumatoid Arthritis Patients. Biomed Res Int, 2016, 4186027. Doi:10.1155/2016/4186027
21. Kragstrup, T. W., Glintborg, B., Svensson, A. L., McMaster, C., Robinson, P. C., Deleuran, B., & Liew, D. F. (2022). Waiting for JAK inhibitor safety data. RMD Open, 8(1). Doi:10.1136/rmdopen-2022-002236
22. Kunwar, S., Dahal, K., & Sharma, S. (2016). Anti-IL-17 therapy in treatment of rheumatoid arthritis: a systematic literature review and meta-analysis of randomized controlled trials. Rheumatol Int, 36(8), 1065-1075. Doi:10.1007/s00296-016-3480-9
23. Leonardi, C. L., Kimball, A. B., Papp, K. A., Yeilding, N., Guzzo, C., Wang, Y., . . . investigators, P. s. (2008). 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). Lancet, 371(9625), 1665-1674. Doi:10.1016/S0140-6736(08)60725-4
24. Maggi, L., Santarlasci, V., Capone, M., Peired, A., Frosali, F., Crome, S. Q., . . . Annunziato, F. (2010). CD161 is a marker of all human IL-17-producing T-cell subsets and is induced by RORC. Eur J Immunol, 40(8), 2174-2181. Doi:10.1002/eji.200940257
25. Nair, R. P., Duffin, K. C., Helms, C., Ding, J., Stuart, P. E., Goldgar, D., . . . Collaborative Association Study of, P. (2009). Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet, 41(2), 199-204. Doi:10.1038/ng.311
26. Nistala, K., Adams, S., Cambrook, H., Ursu, S., Olivito, B., de Jager, W., . . . Wedderburn, L. R. (2010). Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proc Natl Acad Sci U S A, 107(33), 14751-14756. Doi:10.1073/pnas.1003852107
27. Schinocca, C., Rizzo, C., Fasano, S., Grasso, G., La Barbera, L., Ciccia, F., & Guggino, G. (2021). Role of the IL-23/IL-17 Pathway in Rheumatic Diseases: An Overview. Front Immunol, 12, 637829. Doi:10.3389/fimmu.2021.637829
28. Smolen, J. S., Agarwal, S. K., Ilivanova, E., Xu, X. L., Miao, Y., Zhuang, Y., . . . Baker, D. (2017). A randomised phase II study evaluating the efficacy and safety of subcutaneously administered ustekinumab and guselkumab in patients with active rheumatoid arthritis despite treatment with methotrexate. Ann Rheum Dis, 76(5), 831-839. Doi:10.1136/annrheumdis-2016-209831
29. Stahl, E. A., Raychaudhuri, S., Remmers, E. F., Xie, G., Eyre, S., Thomson, B. P., . . . Plenge, R. M. (2010). Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet, 42(6), 508-514. Doi:10.1038/ng.582
30. Wambre, E., Bajzik, V., DeLong, J. H., O'Brien, K., Nguyen, Q. A., Speake, C., . . . Kwok, W. W. (2017). A phenotypically and functionally distinct human T(H)2 cell subpopulation is associated with allergic disorders. Sci Transl Med, 9(401). Doi:10.1126/scitranslmed.aam9171
31. Yokoi, T., Murakami, M., Kihara, T., Seno, S., Arase, M., Wing, J. B., . . . Takeda, K. (2023). Identification of a unique subset of tissue-resident memory CD4(+) T cells in Crohn's disease. Proc Natl Acad Sci U S A, 120(1), e2204269120. Doi:10.1073/pnas.2204269120
32. Zeng, J., Li, M., Zhao, Q., Chen, M., Zhao, L., Wei, S., . . . Wu, X. (2023). Small molecule inhibitors of RORgammat for Th17 regulation in inflammatory and autoimmune diseases. J Pharm Anal, 13(6), 545-562. Doi:10.1016/j.jpha.2023.05.009
33. Zhao, J., Chen, Y., Zhao, Q., Shi, J., Yang, W., Zhu, Z., . . . Liu, J. (2018). Increased circulating Tfh17 and PD-1(+)Tfh cells are associated with autoantibodies in Hashimoto's thyroiditis. Autoimmunity, 51(7), 352-359. Doi:10.1080/08916934.2018.1516761
34. Zhao, L., Nocturne, G., Haskett, S., Boudaoud, S., Lazure, T., Le Pajolec, C., . . . Banerjee, D. (2017). Clinical relevance of RORgamma positive and negative subsets of CD161+CD4+ T cells in primary Sjogren's syndrome. Rheumatology (Oxford), 56(2), 303-312. Doi:10.1093/rheumatology/kew360