IMMUNE REGULATION AND TOLERANCE I

C. Baan¹, V. Sewgobind¹, M. Quaedackers¹, L.V.D. Laan², G. Chan³, W. Weimar^4
1Internal Medicine, Erasmus MC, Rotterdam/NETHERLANDS, ²Surgery, Erasmus MC, Rotterdam/NETHERLANDS, ³, Pfizer, New London/CT/UNITED STATES OF AMERICA, ⁴Internal Medicine, Erasmus Medical Center, Rotterdam/NETHERLANDS

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Background: The Jak inhibitor CP-690,550 inhibits alloreactivity and is currently being investigated for prevention of allograft rejection after transplantation. The Jak/STAT pathway regulates multiple aspects of T cell function. In this study, we examined the effect of CP-690,550 on IL-2-mediated Jak/STAT5 phosphorylation by CD4⁺CD25^brightFoxP3⁺CD127^-/low T-cells (Treg) and CD4⁺CD25^neg effector T cells (Teff) in kidney transplant patients. Methods: The effect of CP-690,550 on IL-2-induced intracellular STAT5-phosphorylation in Teff and Treg was investigated in peripheral blood samples collected from healthy controls and kidney transplant patients by phospho-specific flow cytometry. The function of Teff and Treg was examined by MLRs and suppression assays in the presence and absence of CP-690,550. Results: 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, the IL-2 induced P-STAT5 was partially inhibited in CD4⁺CD25^bright Treg (% inhibition; 51%, mean), while almost completely blocked in the Teff (% inhibition; 84%, p=0.03). The IC₅₀ 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 (% inhibition; 56%, mean). In addition, CD4⁺CD25^bright Treg from kidney transplant patients receiving CP-690,550 vigorously suppressed the proliferation of Teff (% inhibition; 87%). Conclusion: Our findings show that the Jak inhibitor CP-690,550 effectively inhibits Teff function but preserves the suppressive activity of CD4⁺CD25^bright regulatory T-cells.

Disclosure: All authors have declared no conflicts of interest.