CP-690550, a Janus kinase inhibitor, suppresses CD4+ T-cell-mediated acute graft-versus-host disease by inhibiting the interferon-γ pathway.
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-2) bone marrow and CD4 T cells into lethally irradiated (B6×bm12)F1 (H-2) 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.


CONCLUSIONS
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.
Park
Hyung-Bae
HB
Department of Anatomy, Seoul National University College of Medicine, Seoul, South Korea.
Oh
Keunhee
K
Garmaa
Nandin
N
Seo
Myung Won
MW
Byoun
Ok-Jin
OJ
Lee
Hee-Yoon
HY
Lee
Dong-Sup
DS
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects; D016207:Cytokines / Q000032:analysis; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors*; D007376:Interleukin-2 / Q000276:immunology; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D008213:Lymphocyte Activation / Q000187:drug effects; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D010766:Phosphorylation; D010880:Piperidines; D011743:Pyrimidines / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism
D016207:Cytokines; D007376:Interleukin-2; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D007371:Interferon-gamma; C479163:tofacitinib; D053616:Janus Kinase 3