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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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TRANSPLANTATION
Targeting of inducible costimulator (ICOS) expressed on alloreactive T cells down-regulates 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
From the University of Minnesota Cancer Center and Department of Pediatrics, Division of BMT, Minneapolis, MN; the USA Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; the Department of Pathology, Brigham and Women's Hospital, Boston, MA; the Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH; the Department of Immunology, University of Washington School of Medicine, Seattle, WA; the Department of Medical Biophysics and Immunology, Advanced Medical Discovery Institute, Toronto, ON; and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC.
Inducible costimulator (ICOS), a CD28/cytotoxic T lymphocyte antigen 4 (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 up-regulated on antigen-presenting cells (APCs) and some nonlymphoid tissues by tumor necrosis factor  (TNF) or lipopolysaccharide (LPS). Thus, ICOS: ICOS ligand (ICOSL) blockade could reduce alloreactive T cell-APC interactions responsible for graft-versus-host disease (GVHD) and bone marrow (BM) graft rejection. ICOS blockade, achieved with ICOS-/- mice or anti-ICOS monoclonal antibody (mAb) administration, resulted in significant inhibition of GVHD in multiple strain combinations whether mediated by CD4+ and/or CD8+ T cells, alloantigen-specific T-cell receptor (TCR) transgenic (Tg) T cells, or CD28-, T helper 1 (Th1)-, or Th2-deficient T cells. Anti-ICOS significantly delayed GVHD mortality even when mAb infusions were delayed until day 5 after transplantation. ICOS blockade reduced the number of alloantigen-specific effector cells but did not prevent their activation. Imaging of green fluorescent protein-positive (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-/- versus wild-type (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. (Blood. 2005; 105:3372-3380)
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