Blood Journal
Leading the way in experimental and clinical research in hematology

Brief report
STAT-3 and ERK 1/2 phosphorylation are critical for T-cell alloactivation and graft-versus-host disease

  1. Sydney X. Lu1,
  2. Onder Alpdogan1,*,
  3. Janine Lin1,*,
  4. Robert Balderas2,
  5. Roberto Campos-Gonzalez2,
  6. Xiao Wang2,
  7. Guo-Jian Gao2,
  8. David Suh1,
  9. Christopher King1,
  10. Melanie Chow1,
  11. Odette M. Smith1,
  12. Vanessa M. Hubbard1,3,
  13. Johanne L. Bautista1,
  14. Javier Cabrera-Perez1,
  15. Johannes L. Zakrzewski1,
  16. Adam A. Kochman1,
  17. Andrew Chow1,
  18. Gregoire Altan-Bonnet1,4, and
  19. Marcel R. M. van den Brink1
  1. 1Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY;
  2. 2BD Biosciences, San Diego, CA;
  3. 3Department of Pathology, Albert Einstein College of Medicine, New York, NY; and
  4. 4Department of Computational Biology, Memorial Sloan-Kettering Cancer Center, New York, NY

Abstract

Graft-versus-host disease (GVHD) is a serious complication of allogeneic bone marrow transplantation, and donor T cells are indispensable for GVHD. Current therapies have limited efficacy, selectivity, and high toxicities. We used a novel flow cytometry technique for the analysis of intracellular phosphorylation events in single cells in murine BMT models to identify and validate novel GVHD drug targets.17 This method circumvents the requirement for large numbers of purified cells, unlike western blots. We defined a signaling profile for alloactivated T cells in vivo and identified the phosphorylation of ERK1/2 and STAT-3 as important events during T-cell (allo)activation in GVHD. We establish that interference with STAT-3 phosphorylation can inhibit T-cell activation and proliferation in vitro and GVHD in vivo. This suggests that phospho-specific flow cytometry is useful for the identification of promising drug targets, and ERK1/2 and STAT-3 phosphorylation in alloactivated T cells may be important for GVHD.

  • Submitted March 25, 2008.
  • Accepted August 25, 2008.
View Full Text