%0 Journal Article %J Blood %D 2005 %T 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). %A Taylor, Patricia A %A Panoskaltsis-Mortari, Angela %A Freeman, Gordon J %A Sharpe, Arlene H %A Noelle, Randolph J %A Rudensky, Alexander Y %A Mak, Tak W %A Serody, Jonathan S %A Blazar, Bruce R %K Animals %K Antibodies, Monoclonal %K Antigens, CD28 %K Antigens, Differentiation, T-Lymphocyte %K Bone Marrow Transplantation %K CD4-Positive T-Lymphocytes %K CD8-Positive T-Lymphocytes %K DNA-Binding Proteins %K Down-Regulation %K Graft Rejection %K Graft Survival %K Graft vs Host Disease %K Inducible T-Cell Co-Stimulator Protein %K Lymphoid Tissue %K Mice %K Mice, Inbred BALB C %K Mice, Inbred C57BL %K Mice, Mutant Strains %K Signal Transduction %K STAT4 Transcription Factor %K STAT6 Transcription Factor %K Trans-Activators %K Transplantation, Homologous %X 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 alpha (TNFalpha) 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. %B Blood %V 105 %P 3372-80 %8 2005 Apr 15 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/15618467?dopt=Abstract %R 10.1182/blood-2004-10-3869