Only therapeutic ICOS:ICOSL blockade alleviates acute graft versus host disease

Klin Padiatr. 2009 Nov-Dec;221(6):344-50. doi: 10.1055/s-0029-1239532. Epub 2009 Nov 4.

Abstract

Inducible co-stimulator (ICOS) interaction with its ligand (ICOSL) is involved in several T cell effector functions. While blockade of ICOS:ICOSL interaction in chronic graft versus host disease (GVHD) seems beneficial, results for acute GVHD remain controversial. To further elucidate its role in acute GVHD, C57BL/6 mice were reconstituted with allogeneic spleen cells in the absence or presence of ICOSL-blocking mAb. Mice reconstituted with allogeneic spleen cells experienced severe GVHD and died untreated within 6-9 days after transplantation. Mice treated with an anti-ICOSL mAb starting from day 3 after transplantation gained weight again and survived for at least additional 12 days, although the treatment was already stopped at day 11 after transplantation. In contrast, the anti-ICOSL treatment starting from day 0 did not prevent GVHD. The difference between therapeutic (day 3) and prophylactic (day 0) anti-ICOSL treatment was independent of CD25+CD4+ regulatory T cells since their depletion did not abrogate the therapeutic effect of ICOSL blockade. Microarray analysis revealed IFN-gamma and chemokine up-regulation in spleen cells of prophylactically treated mice, emphasizing kinetic dependence of acute GVHD modulation via blockade of ICOS:ICOSL interaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Antigens, Differentiation, T-Lymphocyte / drug effects*
  • Bone Marrow Transplantation
  • Chemokines / metabolism
  • Drug Administration Schedule
  • Female
  • Graft vs Host Disease / immunology*
  • Inducible T-Cell Co-Stimulator Ligand
  • Inducible T-Cell Co-Stimulator Protein
  • Interferon-gamma / metabolism
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Oligonucleotide Array Sequence Analysis
  • Proteins / antagonists & inhibitors*
  • Spleen / immunology
  • Spleen / transplantation
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • Up-Regulation

Substances

  • Antibodies, Monoclonal
  • Antigens, Differentiation, T-Lymphocyte
  • Chemokines
  • Icos protein, mouse
  • Icosl protein, mouse
  • Inducible T-Cell Co-Stimulator Ligand
  • Inducible T-Cell Co-Stimulator Protein
  • Proteins
  • Interferon-gamma