Inhibition of BTK and ITK with Ibrutinib Is Effective in the Prevention of Chronic Graft-versus-Host Disease in Mice.
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.
Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, South Carolina, United States of America.
Steven D
SD
Schutt
Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, South Carolina, United States of America; Cancer Biology PhD Program, University of South Florida and H. Lee Moffitt Cancer Center, Tampa, Florida, United States of America.
Jianing
J
Fu
Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, South Carolina, United States of America.
Hung
H
Nguyen
Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, South Carolina, United States of America.
David
D
Bastian
Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, South Carolina, United States of America.
Jessica
J
Heinrichs
Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, South Carolina, United States of America.
Yongxia
Y
Wu
Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida, United States of America.
Chen
C
Liu
Department of Radiation Oncology, Medical University of South Carolina, Charleston, South Carolina, United States of America.
Daniel G
DG
McDonald
Blood and Bone Marrow Transplant Department, Moffitt Cancer Center, Tampa, Florida, United States of America.
Joseph
J
Pidala
Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, South Carolina, United States of America; Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America.
Xue-Zhong
XZ
Yu
D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D015398:Signal Transduction / Q000187:drug effects
D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; C080813:emt protein-tyrosine kinase; D000225:Adenine