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

2008; Elsevier BV; Volume: 112; Issue: 13 Linguagem: Inglês

10.1182/blood-2008-03-147322

1528-0020

Sydney X. Lu, Önder Alpdoğan, Janine Lin, Robert Balderas, Roberto Campos‐González, Xiao Wang, Guo‐Jian Gao, David Suh, Christopher King, Melanie Chow, Odette M. Smith, Vanessa M. Hubbard, Johanne L. Bautista, Javier Cabrera-Pérez, Johannes L. Zakrzewski, Adam A. Kochman, Andrew Chow, Grégoire Altan‐Bonnet, Marcel R.M. van den Brink,

Immune Cell Function and Interaction

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.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.