1. STAT-3 and ERK 1/2 phosphorylation are critical for T-cell alloactivation and graft-versus-host disease.
- Author
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Lu SX, Alpdogan O, Lin J, Balderas R, Campos-Gonzalez R, Wang X, Gao GJ, Suh D, King C, Chow M, Smith OM, Hubbard VM, Bautista JL, Cabrera-Perez J, Zakrzewski JL, Kochman AA, Chow A, Altan-Bonnet G, and van den Brink MR
- Subjects
- Animals, Flow Cytometry, Mice, Phosphorylation immunology, Transplantation, Homologous, Bone Marrow Transplantation immunology, Graft vs Host Disease, Lymphocyte Activation, Mitogen-Activated Protein Kinase 3 metabolism, STAT3 Transcription Factor metabolism, T-Lymphocytes immunology
- 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.
- Published
- 2008
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