The Jak inhibitor CP-690,550 preserves the function of CD4 +CD25brightFoxP3+ regulatory T cells and inhibits effector T cells

American Journal of Transplantation

Volumn 10, Issue 8, 2010, Pages 1785-1795

  Sewgobind, V D K D ^a   Quaedackers, M E ^a   Van Der Laan, L J W ^a   Kraaijeveld, R ^a   Korevaar, S S ^a   Chan, G ^b   Weimar, W ^a   Baan, C C ^a  

^a ERASMUS MEDICAL CENTER   (Netherlands)

^b PFIZER INC   (United States)

Author keywords

CP 690,550; kidney transplantation; patients; regulatory T cells

Indexed keywords

4 [N [1 (2 CYANO 1 OXOETHYL) 4 METHYL 3 PIPERIDINYL] N METHYLAMINO]PYRROLO[2,3 D]PYRIMIDINE; BASILIXIMAB; CYCLOSPORIN; CYCLOSPORIN A; INTERLEUKIN 2; MYCOPHENOLIC ACID 2 MORPHOLINOETHYL ESTER; PREDNISOLONE; STAT5 PROTEIN; TRANSCRIPTION FACTOR FOXP3;

ADULT; ALLOIMMUNITY; ARTICLE; CASE REPORT; CD4+ CD25+ T LYMPHOCYTE; CELL FUNCTION; CELL PROLIFERATION; CLINICAL TRIAL; CONTROLLED STUDY; DRUG EFFECT; EFFECTOR CELL; FEMALE; HUMAN; IC 50; KIDNEY GRAFT REJECTION; MALE; PHASE 1 CLINICAL TRIAL; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; REGULATORY T LYMPHOCYTE; T LYMPHOCYTE;

CD4-POSITIVE T-LYMPHOCYTES; FEMALE; HUMANS; INTERLEUKIN-2; INTERLEUKIN-2 RECEPTOR ALPHA SUBUNIT; KIDNEY TRANSPLANTATION; MALE; MIDDLE AGED; PYRIMIDINES; PYRROLES; STAT5 TRANSCRIPTION FACTOR; T-LYMPHOCYTES; T-LYMPHOCYTES, REGULATORY;

EID: 77954929352     PISSN: 16006135     EISSN: 16006143     Source Type: Journal    
DOI: 10.1111/j.1600-6143.2010.03200.x     Document Type: Article

References (31)

1. Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med 2004 351 : 2715 2729.
2. Pesu M, Laurence A, Kishore N, Zwillich SH, Chan G, O'Shea JJ. Therapeutic targeting of Janus kinases. Immunol Rev 2008 223 : 132 142.
3. O'Shea JJ, Park H, Pesu M, Borie D, Changelian P. New strategies for immunosuppression: Interfering with cytokines by targeting the Jak/Stat pathway. Curr Opin Rheumatol 2005 17 : 305 311.
4. Ghoreschi K, Laurence A, O'Shea JJ. Janus kinases in immune cell signaling. Immunol Rev 2009 228 : 273 287.
5. Passerini L, Allan SE, Battaglia M et al. STAT5-signaling cytokines regulate the expression of FOXP3 in CD4+CD25 +regulatory T cells and CD4+CD25- effector T cells. Int Immunol 2008 20 : 421 431.
6. Zorn E, Nelson EA, Mohseni M et al. IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T-cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 2006 108 : 1571 1579.
7. Yao Z, Kanno Y, Kerenyi M et al. Nonredundant roles for Stat5a/b in directly regulating Foxp3. Blood 2007 109 : 4368 4375.
8. Cohen AC, Nadeau KC, Tu W et al. Cutting edge: Decreased accumulation and regulatory function of CD4+ CD25(high) T-cells in human STAT5b deficiency. J Immunol 2006 177 : 2770 2774.
9. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function for interleukin 2 in Foxp3-expressing regulatory T-cells. Nat Immunol 2005 6 : 1142 1151.
10. Mayack SR, Berg LJ. Cutting edge: An alternative pathway of CD4+ T cell differentiation is induced following activation in the absence of gamma-chain-dependent cytokine signals. J Immunol 2006 176 : 2059 2063.
11. Changelian PS, Flanagan ME, Ball DJ et al. Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science 2003 302 : 875 878.
12. Conklyn M, Andresen C, Changelian P, Kudlacz E. The JAK3 inhibitor CP-690550 selectively reduces NK and CD8+ cell numbers in cynomolgus monkey blood following chronic oral dosing. J Leukoc Biol 2004 76 : 1248 1255.
13. Kudlacz E, Perry B, Sawyer P et al. The novel JAK-3 inhibitor CP-690550 is a potent immunosuppressive agent in various murine models. Am J Transplant 2004 4 : 51 57.
14. van Gurp EA, Schoordijk-Verschoor W, Klepper M et al. The effect of the JAK inhibitor CP-690,550 on peripheral immune parameters in stable kidney allograft patients. Transplantation 2009 87 : 79 86.
15. Quaedackers ME, Mol W, Korevaar SS et al. Monitoring of the immunomodulatory effect of CP-690,550 by analysis of the JAK/STAT pathway in kidney transplant patients. Transplantation 2009 88 : 1002 1009.
16. Abadja F, Alamartine E, Berthoux F, Mariat C, Genin C, Lambert C. Quantification of circulating regulatory T-cells by flow cytometry in kidney transplant patients after basiliximab induction therapy. Transplantation 2009 89 : 366 368.
17. Hendrikx TK, Klepper M, Ijzermans J, Weimar W, Baan CC. Clinical rejection and persistent immune regulation in kidney transplant patients. Transpl Immunol 2009 21 : 129 135.
18. Wang Z, Shi BY, Qian YY, Cai M, Wang Q. Short-term anti-CD25 monoclonal antibody administration down-regulated CD25 expression without eliminating the neogenetic functional regulatory T-cells in kidney transplantation. Clin Exp Immunol 2009 155 : 496.
19. Kreijveld E, Koenen HJ, Klasen IS, Hilbrands LB, Joosten I. Following anti-CD25 treatment, a functional CD4+C25+ regulatory T-cell pool is present in renal transplant recipients. Am J Transplant 2007 7 : 249 255.
20. Boulay JL, O'Shea JJ, Paul WE. Molecular phylogeny within type I cytokines and their cognate receptors. Immunity 2003 19 : 159 163.
21. Letourneau S, Krieg C, Pantaleo G, Boyman O. IL-2- and CD25-dependent immunoregulatory mechanisms in the homeostasis of T-cell subsets. J Allergy Clin Immunol 2009 123 : 758 762.
22. Yu A, Zhu L, Altman NH, Malek TR. A low interleukin-2 receptor signaling threshold supports the development and homeostasis of T regulatory cells. Immunity 2009 30 : 204 217.
23. Roessler E, Grant A, Ju G, Tsudo M, Sugamura K, Waldmann TA. Cooperative interactions between the interleukin 2 receptor alpha and beta chains alter the interleukin 2-binding affinity of the receptor subunits. Proc Natl Acad Sci USA 1994 91 : 3344 3347.
24. Varker KA, Kondadasula SV, Go MR et al. Multiparametric flow cytometric analysis of signal transducer and activator of transcription 5 phosphorylation in immune cell subsets in vitro and following interleukin-2 immunotherapy. Clin Cancer Res 2006 12 : 5850 5858.
25. Murray PJ. The JAK-STAT signaling pathway: Input and output integration. J Immunol 2007 178 : 2623 2629.
26. Changelian PS, Moshinsky D, Kuhn CF et al. The specificity of JAK3 kinase inhibitors. Blood 2008 111 : 2155 2157.
27. Bensinger SJ, Walsh PT, Zhang J et al. Distinct IL-2 receptor signaling pattern in CD4+CD25+ regulatory T-cells. J Immunol 2004 172 : 5287 5296.
28. Burchill MA, Yang J, Vogtenhuber C, Blazar BR, Farrar MA. IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T-cells. J Immunol 2007 178 : 280 290.
29. Nagahama K, Fehervari Z, Oida T, Yamaguchi T, Ogawa O, Sakaguchi S. Differential control of allo-antigen-specific regulatory T-cells and effector T-cells by anti-CD4 and other agents in establishing transplantation tolerance. Int Immunol 2009 21 : 379 391.
30. Strauss L, Czystowska M, Szajnik M, Mandapathil M, Whiteside TL. Differential responses of human regulatory T-cells (Treg) and effector T-cells to rapamycin. PLoS One 2009 4 : e5994.
31. Lopez M, Clarkson MR, Albin M, Sayegh MH, Najafian N. A novel mechanism of action for anti-thymocyte globulin: Induction of CD4+CD25+Foxp3+ Regulatory T-cells. J Am Soc Nephrol 2006 17 : 2844 2853.