@article {542571, title = {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).}, journal = {Blood}, volume = {105}, number = {8}, year = {2005}, month = {2005 Apr 15}, pages = {3372-80}, abstract = {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.}, keywords = {Animals, Antibodies, Monoclonal, Antigens, CD28, Antigens, Differentiation, T-Lymphocyte, Bone Marrow Transplantation, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, DNA-Binding Proteins, Down-Regulation, Graft Rejection, Graft Survival, Graft vs Host Disease, Inducible T-Cell Co-Stimulator Protein, Lymphoid Tissue, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Mutant Strains, Signal Transduction, STAT4 Transcription Factor, STAT6 Transcription Factor, Trans-Activators, Transplantation, Homologous}, issn = {0006-4971}, doi = {10.1182/blood-2004-10-3869}, author = {Taylor, Patricia A and Panoskaltsis-Mortari, Angela and Freeman, Gordon J and Sharpe, Arlene H and Noelle, Randolph J and Rudensky, Alexander Y and Mak, Tak W and Serody, Jonathan S and Blazar, Bruce R} }