Bruton's Tyrosine Kinase (BTK) and
IL-2 Inducible T-cell Kinase (ITK) are
enzymes responsible for the phosphorylation and activation of downstream effectors in the B-cell receptor (BCR) signaling and
T cell receptor (TCR) signaling pathways, respectively.
Ibrutinib is an FDA-approved potent inhibitor of both BTK and ITK that impairs B-cell and T-cell function. CD4 T cells and B cells are essential for the induction of
chronic graft-versus-host disease (cGVHD). We evaluated these targets by testing the ability of
Ibrutinib to prevent or ameliorate cGVHD, which is one of the major complications for patients undergoing allogeneic
hematopoietic stem cell transplantation (allo-HSCT). We found that
Ibrutinib significantly alleviated cGVHD across four different mouse models, accompanied by increased long-term survival and reduced clinical score. The clinical improvements in
Ibrutinib-treated recipients were associated with decreased serum-
autoantibodies, costimulatory molecule activation, B-cell proliferation, and
glomerulonephritis compared to vehicle controls.
Ibrutinib was also able to alleviate the clinical manifestations in acute GVHD (aGVHD), where the recipients were given grafts with or without B cells, suggesting that an inhibitory effect of
Ibrutinib on T cells contributes to a reduction in both aGVHD and cGVHD pathogenesis. An effective prophylactic regimen is still lacking to both reduce the incidence and severity of human cGVHD following allo-HSCT. Our study shows that
Ibrutinib is an effective prophylaxis against several mouse models of cGVHD with minimal toxicity and could be a promising strategy to combat human cGVHD clinically.