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 Blood, 15 December 2008, Vol. 112, No. 13, pp. 5254-5258.
Prepublished online as a Blood First Edition Paper on October 6, 2008; DOI 10.1182/blood-2008-03-147322.

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TRANSPLANTATION

Brief report

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

Sydney X. Lu1, Onder Alpdogan1,*, Janine Lin1,*, Robert Balderas2, Roberto Campos-Gonzalez2, Xiao Wang2, Guo-Jian Gao2, David Suh1, Christopher King1, Melanie Chow1, Odette M. Smith1, Vanessa M. Hubbard1,3, Johanne L. Bautista1, Javier Cabrera-Perez1, Johannes L. Zakrzewski1, Adam A. Kochman1, Andrew Chow1, Gregoire Altan-Bonnet1,4, and Marcel R. M. van den Brink1

1 Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY; 2 BD Biosciences, San Diego, CA; 3 Department of Pathology, Albert Einstein College of Medicine, New York, NY; and 4 Department of Computational Biology, Memorial Sloan-Kettering Cancer Center, New York, NY

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.1–7 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.


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