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Blood, 15 April 2005, Vol. 105, No. 8, pp. 3372-3380.
Prepublished online as a Blood First Edition Paper on December 23, 2004; DOI 10.1182/blood-2004-10-3869.
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Submitted October 7, 2004
Accepted December 18, 2004
Targeting of inducible costimulator (ICOS) expressed on alloreactive T cells downregulates graft-versus-host disease (GVHD) and facilitates engraftment of allogeneic bone marrow (BM)
Patricia A Taylor, Angela Panoskaltsis-Mortari, Gordon J Freeman, Arlene H Sharpe, Randolph J Noelle, Alexander Y Rudensky, Tak W Mak, Jonathan S Serody, and Bruce R Blazar*
Department of Pediatrics, Division of BMT, University of Minnesota Cancer Center, Minneapolis, MN, USA
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH, USA
Department of Immunology, University of Washington School of Medicine, Seattle, WA, USA
Department of Medical Biophysics and Immunology, Advanced Medical Discovery Institute, Toronto, Ontario, Canada
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
* Corresponding author; email: blaza001{at}umn.edu.
ICOS, a CD28/CTLA-4 family member, is expressed on activated T cells. ICOS Ligand, a B7 family member, is constitutively expressed on B cells, macrophages and dendritic cells and is upregulated on APCs and some nonlymphoid tissues by TNF or LPS. Thus, ICOS:ICOSL blockade could reduce alloreactive T cell-APC interactions responsible for GVHD and BM graft rejection. ICOS blockade, achieved with ICOS-/- mice or anti-ICOS mAb administration, resulted in significant inhibition of GVHD in multiple strain combinations whether mediated by CD4+ and/or CD8+ T cells, alloantigen-specific TCR Tg T cells or CD28-, Th1- or Th2-deficient T cells. Anti-ICOS significantly delayed GVHD mortality even when mAb infusions were delayed until d5 after transplantation. ICOS blockade reduced the number of alloantigen-specific effector cells but did not prevent their activation. Imaging of GFP+ effectors indicated that ICOS blockade inhibited expansion of GVHD-causing effector T cells in secondary lymphoid and GVHD target organs. Engraftment rates were significantly higher in ICOS-/- vs WT mice receiving allogeneic BM; and ICOS blockade significantly inhibited expansion of host antidonor alloantigen-specific BM graft rejecting T cells. These data suggest that the ICOS pathway may be a beneficial therapeutic target for GVHD inhibition, GVHD therapy and BM graft promotion.
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