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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, 2005; DOI 10.1182/blood-2005-01-0410.

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TRANSPLANTATION

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, Glen Heller, George F. Murphy, Chen Liu, Onder Alpdogan, and Marcel R. M. van den Brink

From the Department of Medicine and Immunology, Department of Pediatrics, and Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY; Department of Pathology, Brigham and Women's Hospital, Boston, MA; and Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville.

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 up-regulated on alloreactive T cells in recipients of an allogeneic hematopoietic stem cell transplantation (allo-HSCT) with GVHD. We compared ICOS-/- T cells with wild-type (WT) T cells in 2 GVHD models. In both models, recipients of ICOS-/- T cells demonstrated 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 interferon-{gamma} (IFN-{gamma}), while interleukin-4 (IL-4) and IL-10 levels were increased, suggesting that alloreactive ICOS-/- T cells are skewed toward T helper-2 (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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