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Blood, 1 November 2005, Vol. 106, No. 9, pp. 3285-3292.
Prepublished online as a Blood First Edition Paper on June 23, 2005June 14, 2005; DOI 10.1182/blood-2005-01-0410.
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Submitted February 1, 2005
Accepted May 11, 2005
Absence of inducible costimulator on alloreactive T cells reduces graft-versus-host disease and induces Th2 deviation
Vanessa M Hubbard, Jeffrey M Eng, Teresa Ramirez-Montagut, Kartono H Tjoe, Stephanie J Muriglan, Adam A Kochman, Theis H Terwey, Lucy M Willis, Rafaella Schiro, Glenn Heller, George F Murphy, Chen Liu, Onder Alpdogan, and Marcel R van den Brink*
Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, NY, NY, USA
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, NY, NY, USA
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, NY, NY, USA
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL, USA
* Corresponding author; email: vandenbm{at}mskcc.org.
Inducible costimulator (ICOS) is expressed on activated and memory T cells, and is involved in the regulation of cytokine production. We studied the role of ICOS on alloreactive T cells in graft-versus-host disease (GVHD), and determined that ICOS expression was upregulated on alloreactive T cells in recipients of an allogeneic hematopoietic stem cell transplantation (allo-HSCT) with GVHD. We compared ICOS-/- T cells to wild type (WT) T cells in two GVHD models. In both models, recipients of ICOS-/- T cells exhibited significantly less GVHD morbidity and mortality, which was associated with less intestinal and hepatic GVHD, but increased cutaneous GVHD. In addition, recipients of ICOS-/- donor T cells displayed a slight decrease in graft-versus-leukemia (GVL) activity. Further analysis of alloreactive ICOS-/- T cells showed no defect in activation, proliferation, cytotoxicity, and target organ infiltration. Recipients of ICOS-/- T cells had decreased serum levels of IFN- , while IL-4 and IL-10 levels were increased, suggesting that alloreactive ICOS-/- T cells are skewed towards Th2 differentiation. These data suggest a novel role for ICOS in the regulation of Th1/Th2 development of activated T cells. In conclusion, alloreactive ICOS-/- donor T cells induce less GVHD due to a Th2 immune deviation while GVL activity is slightly diminished.
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