CP-690550, a Janus Kinase Inhibitor, Suppresses CD4+ T-Cell–Mediated Acute Graft-Versus-Host Disease by Inhibiting the Interferon-γ Pathway

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Abstract

Background.

Acute graft-versus-host disease (GVHD) is a critical obstacle to bone marrow transplantation. Although numerous studies have described immunosuppression protocols to mitigate acute GVHD, the need still exists for a more efficient immunosuppressant with fewer side effects. Here, we evaluated the protective effect of CP-690550, a newly developed Janus kinase inhibitor, in an acute GVHD model.

Methods.

CP-690550 was chemically synthesized. Acute GVHD was induced through the transfer of parent B6 (H-2b) bone marrow and CD4+ T cells into lethally irradiated (B6×bm12)F1 (H-2b×bm12) mice.

Results.

CP-690550 treatments confined to days −3 to 11 of GVHD induction provided full protection against allogeneic, acute GVHD-related lethality and histopathology. An analysis of the initial donor-derived CD4+ T-cell responses revealed that the inhibitory effects of CP-690550 were largely related to the suppression of donor CD4+ T-cell–mediated interferon (IFN)-γ production. Enhanced inhibition of T helper 1 cell differentiation, rather than the inhibition of allogeneic CD4+ T-cell proliferation or T helper 17 cell differentiation, was also confirmed in allogeneic mixed lymphocyte reactions. Because lethality was considerably delayed by the systemic blockade of IFN-γ, the principal protective effect of CP-690550 occurred through the modulation of IFN-γ production.

Conclusion.

The targeting of Janus kinase with a sensitive and specific inhibitor, CP-690550, conferred effective protection from acute GVHD induced by a semiallogeneic major histocompatibility complex class II-disparate combination. Protection from acute GVHD was largely mediated by the inhibition of IFN-γ production.

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