RRC ID 65629
Author Kondo T, Ikegawa S, Fukumi T, Sumii Y, Sugiura H, Sando Y, Nakamura M, Meguri Y, Iwamoto M, Maeda Y, Matsuoka KI.
Title Pretransplant Short-Term Exposure of Donor Graft Cells to ITK Selective Inhibitor Ameliorates Acute Graft-versus-Host Disease by Inhibiting Effector T Cell Differentiation while Sparing Regulatory T Cells.
Journal Immunohorizons
Abstract Graft-versus-host disease (GVHD) remains to be a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). IL-2-inducible T cell kinase (ITK), a TEC cytoplasmic tyrosine kinase, has an essential role in T cell development and receptor signaling. The ITK/Bruton tyrosine kinase inhibitor ibrutinib has been shown to improve chronic GVHD symptoms; however, the effect of ITK selective inhibition on acute GVHD remains unclear. In this study, we evaluated the pharmacological effects of an ITK selective inhibitor (ITKsi) on acute GVHD using murine bone marrow transplantation models. First, we found that CD4+ T cell differentiation toward Th1, Th2, or Th17 was inhibited following ITKsi treatment in a dose-dependent manner while maintaining regulatory T cells in the presence of alloantigens both in vitro and in vivo. ITKsi preferentially inhibited inflammatory cytokine production and in vivo proliferation of alloreactive T cells. We then demonstrated that short-term exposure of donor graft cells to ITKsi significantly delayed the onset of GVHD-associated mortality without compromising the donor cell engraftment and the graft-versus-tumor effect, indicating the potential of ITK selective inhibition in the setting of clinical allogeneic HSCT. These findings suggest that ITK is a potential therapeutic target against GVHD, and the pharmacological ITK inhibitor may serve as a novel strategy for immune regulation after HSCT.
Volume 5(6)
Pages 424-437
Published 2021-6-10
DOI 10.4049/immunohorizons.2100042
PII immunohorizons.2100042
PMID 34112701
MeSH Animals Bone Marrow Transplantation / adverse effects* Cell Differentiation / drug effects Cell Differentiation / immunology Disease Models, Animal Drug Evaluation, Preclinical Female Graft vs Host Disease / immunology Graft vs Host Disease / prevention & control* Humans Mice Protein Kinase Inhibitors / pharmacology* Protein Kinase Inhibitors / therapeutic use Protein-Tyrosine Kinases / antagonists & inhibitors* Protein-Tyrosine Kinases / metabolism T-Lymphocytes, Cytotoxic / drug effects T-Lymphocytes, Cytotoxic / immunology T-Lymphocytes, Regulatory / drug effects T-Lymphocytes, Regulatory / immunology Transplantation Conditioning / methods*
Mice RBRC00144