JAK inhibition induces silencing of T Helper cytokine secretion and a profound reduction in T regulatory cells

British Journal of Haematology

Volumn 171, Issue 1, 2015, Pages 60-73

  Keohane, Clodagh ^a,b   Kordasti, Shahram ^b,c   Seidl, Thomas ^b   Perez Abellan, Pilar ^b   Thomas, Nicholas S B ^b   Harrison, Claire N ^a   Mclornan, Donal P ^a,c   Mufti, Ghulam J ^b,c  

^a GUY'S AND ST THOMAS' NHS FOUNDATION TRUST   (United Kingdom)

^b KING'S COLLEGE LONDON   (United Kingdom)

^c KING'S COLLEGE HOSPITAL NHS FOUNDATION TRUST   (United Kingdom)

Author keywords

Immunology; Myeloproliferative disorder; Therapy

Indexed keywords

CD27 ANTIGEN; CD4 ANTIGEN; CD45RA ANTIGEN; CXCL9 CHEMOKINE; FEDRATINIB; GAMMA INTERFERON; GAMMA INTERFERON INDUCIBLE PROTEIN 10; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; INTERLEUKIN 10; INTERLEUKIN 17; INTERLEUKIN 2 RECEPTOR; INTERLEUKIN 2 RECEPTOR ALPHA; INTERLEUKIN 4; JANUS KINASE; RUXOLITINIB; SCATTER FACTOR; STAT3 PROTEIN; TRANSCRIPTION FACTOR FOXP3; TUMOR NECROSIS FACTOR ALPHA; CYTOKINE; PROTEIN KINASE INHIBITOR; PYRAZOLE DERIVATIVE; PYRROLIDINE DERIVATIVE; SULFONAMIDE;

ADULT; AGED; ANTIGEN EXPRESSION; ARTICLE; CD3+ T LYMPHOCYTE; CD4+ T LYMPHOCYTE; CELL EXPANSION; CHRONIC OBSTRUCTIVE LUNG DISEASE; CLINICAL ARTICLE; CONTROLLED STUDY; CYTOKINE RELEASE; DRUG EFFICACY; DRUG SAFETY; ENZYME INHIBITION; FEMALE; HELPER CELL; HERPES SIMPLEX; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; LYMPHOCYTE COUNT; LYMPHOCYTE FUNCTION; LYMPHOCYTE PROLIFERATION; MALE; MIDDLE AGED; MYELOPROLIFERATIVE NEOPLASM; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; REGULATORY T LYMPHOCYTE; TOOTH ABSCESS; TREATMENT RESPONSE; TREATMENT WITHDRAWAL; TUMOR IMMUNITY; VERY ELDERLY; ANTAGONISTS AND INHIBITORS; COMPARATIVE STUDY; ENZYMOLOGY; IMMUNOLOGY; METABOLISM; MYELOPROLIFERATIVE DISORDERS; PATHOLOGY; TH17 CELL; TIME; TUMOR CELL CULTURE;

CYTOKINES; FEMALE; HUMANS; JANUS KINASES; MALE; MYELOPROLIFERATIVE DISORDERS; PROTEIN KINASE INHIBITORS; PYRAZOLES; PYRROLIDINES; SULFONAMIDES; T-LYMPHOCYTES, REGULATORY; TH17 CELLS; TIME FACTORS; TUMOR CELLS, CULTURED;

EID: 84941736772     PISSN: 00071048     EISSN: 13652141     Source Type: Journal    
DOI: 10.1111/bjh.13519     Document Type: Article

References (49)

1. + regulatory T cells in cancer patients. Blood, 107, 2409-2414.
2. Alizadeh, D., Katsanis, E. & Larmonier, N. (2013) The multifaceted role of Th17 lymphocytes and their associated cytokines in cancer. Clinical and Developmental Immunology, 2013, 957878 2013:11. doi: 10.1155/2013/957878.957878.
3. + T helper cells and hindered by naturally occurring T regulatory cells. Journal of Immunology, 174, 2591-2601.
4. Barosi, G., Mesa, R.A., Thiele, J., Cervantes, F., Campbell, P.J., Verstovsek, S., Dupriez, B., Levine, R.L., Passamonti, F., Gotlib, J., Reilly, J.T., Vannucchi, A.M., Hanson, C.A., Solberg, L.A., Orazi, A. & Tefferi, A.; International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). (2008) Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement from the International Working Group for Myelofibrosis Research and Treatment. Leukemia, 22, 437-438.
5. Barosi, G., Mesa, R., Finazzi, G., Harrison, C., Kiladjian, J.J., Lengfelder, E., McMullin, M.F., Passamonti, F., Vannucchi, A.M., Besses, C., Gisslinger, H., Samuelsson, J., Verstovsek, S., Hoffman, R., Pardanani, A., Cervantes, F., Tefferi, A. & Barbui, T. (2013) Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN and IWG-MRT consensus project. Blood, 121, 4778-4781.
6. Barron, L., Dooms, H., Hoyer, K.K., Kuswanto, W., Hofmann, J., O'Gorman, W.E. & Abbas, A.K. (2010) Cutting edge: mechanisms of IL-2-dependent maintenance of functional regulatory T cells. Journal of Immunology, 185, 6426-6430.
7. Bettelli, E., Carrier, Y., Gao, W., Korn, T., Strom, T.B., Oukka, M., Weiner, H.L. & Kuchroo, V.K. (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature, 441, 235-238.
8. Boniface, K., Blumenschein, W.M., Brovont-Porth, K., McGeachy, M.J., Basham, B., Desai, B., Pierce, R., McClanahan, T.K., Sadekova, S. & de Waal Malefyt, R. (2010) Human Th17 cells comprise heterogeneous subsets including IFN-gamma-producing cells with distinct properties from the Th1 lineage. Journal of Immunology, 185, 679-687.
9. Caocci, G., Murgia, F., Podda, L., Solinas, A., Atzeni, S. & La Nasa, G. (2014) Reactivation of hepatitis B virus infection following ruxolitinib treatment in a patient with myelofibrosis. Leukemia, 28, 225-227.
10. Cervantes, F., Vannucchi, A.M., Kiladjian, J.J., Al-Ali, H.K., Sirulnik, A., Stalbovskaya, V., McQuitty, M., Hunter, D.S., Levy, R.S., Passamonti, F., Barbui, T., Barosi, G., Harrison, C.N., Knoops, L. & Gisslinger, H. (2013) Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood, 122, 4047-4053.
11. Cowan, J., Pandey, S., Filion, L.G., Angel, J.B., Kumar, A. & Cameron, D.W. (2012) Comparison of interferon-γ-, interleukin (IL)-17- and IL-22-expressing CD4 T cells, IL-22-expressing granulocytes and proinflammatory cytokines during latent and active tuberculosis infection. Clinical and Experimental Immunology, 167, 317-329.
12. Epperson, D.E., Nakamura, R., Saunthararajah, Y., Melenhorst, J. & Barrett, A.J. (2001) Oligoclonal T cell expansion in myelodysplastic syndrome: evidence for an autoimmune process. Leukaemia Research, 25, 1075-1083.
13. Fleischman, A.G., Aichberger, K.J., Luty, S.B., Bumm, T.G., Petersen, C.L., Doratotaj, S., Vasudevan, K.B., LaTocha, D.H., Yang, F., Press, R.D., Loriaux, M.M., Pahl, H.L., Silver, R.T., Agarwal, A., O'Hare, T., Druker, B.J., Bagby, G.C. & Deininger, M.W. (2011) TNFalpha facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms. Blood, 118, 6392-6398.
14. Floess, S., Freyer, J., Siewert, C., Baron, U., Olek, S., Polansky, J., Schlawe, K., Chang, H.D., Bopp, T., Schmitt, E., Klein-Hessling, S., Serfling, E., Hamann, A. & Huehn, J. (2007) Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biology, 5, e38.
15. Ghoreschi, K., Laurence, A. & O'Shea, J.J. (2009) Janus kinases in immune cell signaling. Immunological Reviews, 228, 273-287.
16. Goldberg, R.A., Reichel, E. & Oshry, L.J. (2013) Bilateral toxoplasmosis retinitis associated with ruxolitinib. New England Journal of Medicine, 369, 681-683.
17. Harrison, C., Kiladjian, J.-J., Al-Ali, H.K., Gisslinger, H., Waltzman, R., Stalbovskaya, V., McQuitty, M., Hunter, D.S., Levy, R., Knoops, L., Cervantes, F., Vannucchi, A.M., Barbui, T. & Barosi, G. (2012) JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. New England Journal of Medicine, 366, 787-798.
18. Hasselbalch, H.C. (2012) Perspectives on chronic inflammation in essential thrombocythemia, polycythemia vera, and myelofibrosis: is chronic inflammation a trigger and driver of clonal evolution and development of accelerated atherosclerosis and second cancer? Blood, 119, 3219-3225.
19. Hasselbalch, H.C. (2013) Chronic inflammation as a promotor of mutagenesis in essential thrombocythemia, polycythemia vera and myelofibrosis. A human inflammation model for cancer development?. Leukaemia Research, 37, 214-220.
20. Heine, A., Held, S.A., Daecke, S.N., Wallner, S., Yajnanarayana, S.P., Kurts, C., Wolf, D. & Brossart, P. (2013) The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood, 122, 1192-1202.
21. Komrokji, R.S., Seymour, J.F., Roberts, A.W., Wadleigh, M., To, L.B., Scherber, R., Turba, E., Dorr, A., Zhu, J., Wang, L., Granston, T., Campbell, M.S. & Mesa, R.A. (2015) Results of a phase 2 study of pacritinib (SB1518), a JAK2/JAK2(V617F) inhibitor, in patients with myelofibrosis. Blood, 125, 2649-55.
22. + regulatory T cells in myelodysplastic syndrome (MDS). Blood, 110, 847-850.
23. Kordasti, S.Y., Afzali, B., Lim, Z., Ingram, W., Hayden, J., Barber, L., Matthews, K., Chelliah, R., Guinn, B., Lombardi, G., Farzaneh, F. & Mufti, G.J. (2009) IL-17-producing CD4(+) T cells, pro-inflammatory cytokines and apoptosis are increased in low risk myelodysplastic syndrome. British Journal of Haematology, 145, 64-72.
24. Leonard, W.J., Shores, E.W. & Love, P.E. (1995) Role of the common cytokine receptor gamma chain in cytokine signaling and lymphoid development. Immunological Reviews, 148, 97-114.
25. Long, K., Woodward, J., Procter, L., Ward, M., Meier, C., Williams, D. & Bernard, A. (2014) In vitro transfusion of red blood cells results in decreased cytokine production by human T cells. The Journal of Trauma and Acute Care Surgery, 77, 198-201.
26. Malek, T.R. (2003) The main function of IL-2 is to promote the development of T regulatory cells. Journal of Leukocyte Biology, 74, 961-965.
27. Massa, M., Rosti, V., Campanelli, R., Fois, G. & Barosi, G. (2014) Rapid and long-lasting decrease of T regulatory cells in patients with myelofibrosis treated with ruxolitinib. Leukemia, 28, 449-451.
28. McMullin, M.F., Bareford, D., Campbell, P., Green, A.R., Harrison, C., Hunt, B., Oscier, D., Polkey, M.I., Reilly, J.T., Rosenthal, E., Ryan, K., Pearson, T.C. & Wilkins, B.; General Haematology Task Force of the British Committee for Standards in Haematology. (2005) Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. British Journal of Haematology, 130, 174-195.
29. Mihara, M., Hashizume, M., Yoshida, H., Suzuki, M. & Shiina, M. (2012) IL-6/IL-6 receptor system and its role in physiological and pathological conditions. Clinical Science (Lond), 122, 143-159.
30. Pardanani, A., Gotlib, J.R., Jamieson, C., Cortes, J.E., Talpaz, M., Stone, R.M., Silverman, M.H., Gilliland, D.G., Shorr, J. & Tefferi, A. (2011) Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. Journal of Clinical Oncology, 29, 789-796.
31. Pardanani, A., Laborde, R.R., Lasho, T.L., Finke, C., Begna, K., Al-Kali, A., Hogan, W.J., Litzow, M.R., Leontovich, A., Kowalski, M. & Tefferi, A. (2013) Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. Leukemia, 27, 1322-1327.
32. Quintas-Cardama, A., Vaddi, K., Liu, P., Manshouri, T., Li, J., Scherle, P.A., Caulder, E., Wen, X., Li, Y., Waeltz, P., Rupar, M., Burn, T., Lo, Y., Kelley, J., Covington, M., Shepard, S., Rodgers, J.D., Haley, P., Kantarjian, H., Fridman, J.S. & Verstovsek, S. (2010) Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood, 115, 3109-3117.
33. Riley, C.H., Jensen, M.K., Brimnes, M.K., Cortes, J.E., Talpaz, M., Stone, R.M., Silverman, M.H., Gilliland, D.G., Shorr, J. & Tefferi, A. (2011) Increase in circulating CD4(+)CD25(+)Foxp3(+) T cells in patients with Philadelphia-negative chronic myeloproliferative neoplasms during treatment with IFN-alpha. Blood, 118, 2170-2173.
34. Rudolph, J., Cornez, I., Brossart, P. & Wolf, D. (2013) The JAK1/JAK2 inhibitor ruxolitinib substantially affects NK cell biology. Blood, 122, 16.
35. + regulatory T cells in the human immune system. Nature Review Immunology, 10, 490-500.
36. + T regulatory cell subpopulations. Haematologica, 98, 1291-1299.
37. Sharma, M.D., Hou, D.Y., Baban, B., Koni, P.A., He, Y., Chandler, P.R., Blazar, B.R., Mellor, A.L. & Munn, D.H. (2010) Reprogrammed foxp3(+) regulatory T cells provide essential help to support cross-presentation and CD8(+) T cell priming in naive mice. Immunity, 33, 942-954.
38. Silva, C.M., Lu, H., Weber, M.J. & Thorner, M.O. (1994) Differential tyrosine phosphorylation of JAK1, JAK2, and STAT1 by growth hormone and interferon-gamma in IM-9 cells. Journal of Biological Chemistry, 269, 27532-27539.
39. Swerdlow, S.H., Campo, E., Harris, N.L., Jaffe, E.S., Pileri, S.A., Stein, H., Thiele, J. & Vardiman, J.W. (2008) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edn. International Agency for Research on Cancer Press, Lyon, France.
40. Tefferi, A., Vaidya, R., Caramazza, D., Finke, C., Lasho, T. & Pardanani, A. (2011) Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study. Journal of Clinical Oncology, 29, 1356-1363.
41. Tefferi, A., Cervantes, F., Mesa, R., Birgegard, G., Cervantes, F., Finazzi, G., Gisslinger, H., Griesshammer, M., Harrison, C., Hehlmann, R., Hermouet, S., Kiladjian, J., Kröger, N., Mesa, R., Mc Mullin, M.F., Pardanani, A., Passamonti, F., Samuelsson, J., Vannucchi, A.M., Reiter, A., Silver, R.T., Verstovsek, S., Tognoni, G. & Barbui, T. (2013) Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. Blood, 122, 1395-1398.
42. Vaidya, R., Gangat, N., Jimma, T., Finke, C.M., Lasho, T.L., Pardanani, A. & Tefferi, A. (2012) Plasma cytokines in polycythemia vera: phenotypic correlates, prognostic relevance, and comparison with myelofibrosis. American Journal of Hematology, 87, 1003-1005.
43. Verstovsek, S., Kantarjian, H., Mesa, R.A., Pardanani, A.D., Cortes-Franco, J., Thomas, D.A., Estrov, Z., Fridman, J.S., Bradley, E.C., Erickson-Viitanen, S., Vaddi, K., Levy, R. & Tefferi, A. (2010) Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. New England Journal of Medicine, 363, 1117-1127.
44. Wang, X., Zheng, J., Liu, J., Yao, J., He, Y., Li, X., Yu, J., Yang, J., Liu, Z. & Huang, S. (2005) Increased population of CD4(+)CD25(high), regulatory T cells with their higher apoptotic and proliferating status in peripheral blood of acute myeloid leukemia patients. European Journal of Haematology, 75, 468-476.
45. Wathes, R., Moule, S. & Milojkovic, D. (2013) Progressive multifocal leukoencephalopathy associated with ruxolitinib. New England Journal of Medicine, 369, 197-198.
46. Wernig, G., Kharas, M.G., Okabe, R., Moore, S.A., Leeman, D.S., Cullen, D.E., Gozo, M., McDowell, E.P., Levine, R.L., Doukas, J., Mak, C.C., Noronha, G., Martin, M., Ko, Y.D., Lee, B.H., Soll, R.M., Tefferi, A., Hood, J.D. & Gilliland, D.G. (2008) Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Cancer Cell, 13, 311-320.
47. Wysham, N.G., Sullivan, D.R. & Allada, G. (2013) An opportunistic infection associated with ruxolitinib, a novel janus kinase 1, 2 inhibitor. Chest, 143, 1478-1479.
48. Zeiser, R. & Negrin, R.S. (2008) Interleukin-2 receptor downstream events in regulatory T cells: implications for the choice of immunosuppressive drug therapy. Cell Cycle, 7, 458-462.
49. Zhou, T., Georgeon, S., Moser, R., Moore, D.J., Caflisch, A. & Hantschel, O. (2014) Specificity and mechanism-of-action of the JAK2 tyrosine kinase inhibitors ruxolitinib and SAR302503 (TG101348). Leukemia, 28, 404-407.