title: The Jak inhibitor CP-690,550 preserves the function of CD4CD25FoxP3 regulatory T cells and inhibits effector T cells.
abstract: The Jak inhibitor CP-690,550 inhibits alloreactivity and is currently being investigated for prevention of allograft rejection after transplantation. In this study, we examined the effect of CP-690,550 on IL-2-mediated Jak/STAT5 phosphorylation by CD4(+)CD25(bright)FoxP3(+)CD127(-/low) T cells (Treg) and CD4(+)CD25(neg) effector T cells (Teff) in kidney transplant (KTx) patients. Phosphospecific flow cytometry was used to study the effect of CP-690,550 on IL-2-induced intracellular STAT5-phosphorylation. IL-2-induced phosphorylation of STAT5 (P-STAT5) in both Treg and Teff, which was significantly higher for CD4(+)CD25(bright) Treg (increased by 71%, mean) than for CD4(+)CD25(neg) Teff (increased by 42%). In the presence of 100 ng/mL CP-690,550, a clinically relevant exposure, IL-2-induced P-STAT5 was partially inhibited in CD4(+)CD25(bright)Treg (% inhibition; 51%), while almost completely blocked in Teff (%inhibition; 84%, p = 0.03). The IC(50) was 2-3 times higher for Treg (104 ng/mL) than for Teff (40 ng/mL, p = 0.02). In the presence of CP-690,550, Treg exhibited additional suppressive activities on the alloactivated proliferation of Teff (56%, mean). In addition, CD4(+)CD25(bright) Treg from KTx-patients receiving CP-690,550 vigorously suppressed the proliferation of Teff (87%, mean). Our findings show that CP-690,550 effectively inhibits Teff function but preserves the suppressive activity of CD4(+)CD25(bright) regulatory T cells.
authors.affiliation: Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: V D K D
authors.initials: VD
authors.lastname: Sewgobind
authors.forename: M E
authors.initials: ME
authors.lastname: Quaedackers
authors.forename: L J W
authors.initials: LJ
authors.lastname: van der Laan
authors.forename: R
authors.initials: R
authors.lastname: Kraaijeveld
authors.forename: S S
authors.initials: SS
authors.lastname: Korevaar
authors.forename: G
authors.initials: G
authors.lastname: Chan
authors.forename: W
authors.initials: W
authors.lastname: Weimar
authors.forename: C C
authors.initials: CC
authors.lastname: Baan
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D016030:Kidney Transplantation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology*
chemical_list: C508017:IL2RA protein, human; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D050799:STAT5 Transcription Factor; C479163:tofacitinib