SYK inhibitor entospletinib prevents ocular and skin GVHD in mice

JCI Insight. 2018 Oct 4;3(19):e122430. doi: 10.1172/jci.insight.122430.

Abstract

Graft-versus-host disease (GVHD) is a major complication of hematopoietic stem cell transplantation (HCT). The tyrosine kinase SYK contributes to both acute and chronic GVHD development, making it an attractive target for GVHD prevention. Entospletinib (ENTO) is a second-generation highly selective SYK inhibitor with a high safety profile. Potential utility of ENTO as GVHD prophylaxis in patients was examined using a preclinical mouse model of eye and skin GVHD and ENTO-compounded chow. We found that early SYK inhibition improved blood immune cell reconstitution in GVHD mice and prolonged survival, with 60% of mice surviving to day +120 compared with 10% of mice treated with placebo. Compared with mice receiving placebo, mice receiving ENTO had dramatic improvements in clinical eye scores, alopecia scores, and skin scores. Infiltrating SYK+ cells expressing B220 or F4/80, resembling SYK+ cells found in lichenoid skin lesions of chronic GVHD patients, were abundant in the skin of placebo mice but were rare in ENTO-treated mice. Thus, ENTO given early after HCT safely prevented GVHD.

Keywords: B cells; Immunology; Protein kinases; Stem cell transplantation; Transplantation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Eye / drug effects
  • Eye / immunology
  • Eye / pathology
  • Female
  • Graft vs Host Disease / immunology
  • Graft vs Host Disease / mortality
  • Graft vs Host Disease / prevention & control*
  • Hematopoietic Stem Cell Transplantation / adverse effects*
  • Humans
  • Indazoles / administration & dosage*
  • Mice
  • Protein Kinase Inhibitors / administration & dosage*
  • Pyrazines / administration & dosage*
  • Skin / drug effects
  • Skin / immunology
  • Skin / pathology
  • Survival Analysis
  • Syk Kinase / antagonists & inhibitors*
  • Syk Kinase / immunology
  • Syk Kinase / metabolism
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Treatment Outcome

Substances

  • 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo(1,2-a)pyrazin-8-amine
  • Indazoles
  • Protein Kinase Inhibitors
  • Pyrazines
  • Syk Kinase
  • Syk protein, mouse