Inhibition of T cell costimulation by VCAM-1 prevents murine graft-versus-host disease across minor histocompatibility barriers.
Activation of T cells leading to graft-vs-host disease (GVHD) requires two signaling events: the Ag-specific signal generated through the engagement of the TCR/CD3 complex with antigenic peptide fragments presented by MHC molecules on APCs and the second signal provided through additional costimulatory ligands. T cells have preferential costimulatory requirements depending on their state of activation-induced maturation. In the present study, we investigated the role of the receptor-ligand pair VLA-4 (alpha 4 beta 1) and VCAM-1 in allogeneic T cell responses in vitro and in vivo. Anti-VCAM-1 mAb effectively inhibited mixed lymphocyte culture (MLC) across several major MHC barriers and secondary MLC across minor histocompatibility Ags (95.5% and 90.0% inhibition, respectively). In contrast, anti-VLA-4 mAb inhibited a CD8(+)-mediated primed CTL response in vitro by 100%, yet had little effect on proliferative responses. In the B10.D2/nSnJ-->BALB/c (both H-2d) system of GVHD, BALB/c received anti-VCAM-1, or anti-VLA-4 or controls NS-1 or Y13-259 for the first 5 wk after transplant. Anti-VLA-4 mAb delayed the onset of GVHD, but failed to reduce incidence, severity or GVHD-related mortality. In contrast, anti-VCAM-1 reduced the incidence of GVHD from 100% (18/18) in control animals to 53.3% (8/15) (p < 0.01) on day 70 post-transplant and significantly decreased GVHD-related mortality. Sixty percent (9/15) of anti-VCAM-1 recipients survived more than 180 days after transplant. Long-term engraftment of allogeneic bone marrow was documented in all transplanted mice by PCR analysis of a microsatellite region in the IL-1 beta gene.
Schlegel
P G
PG
Bone Marrow Transplant Program H1353, Stanford University School of Medicine, CA 94305, USA.
Vaysburd
M
M
Chen
Y
Y
Butcher
E C
EC
Chao
N J
NJ
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000627:therapeutic use; D003602:Cytotoxicity, Immunologic; D006086:Graft vs Host Disease / Q000401:mortality / Q000517:prevention & control* / Q000628:therapy; D006649:Histocompatibility Antigens / Q000276:immunology; D006825:Hybridomas; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D015778:Minor Histocompatibility Antigens / Q000276:immunology*; D008969:Molecular Sequence Data; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D017186:Titrimetry; D019010:Vascular Cell Adhesion Molecule-1 / Q000627:therapeutic use*
D015815:Cell Adhesion Molecules; D006649:Histocompatibility Antigens; D015778:Minor Histocompatibility Antigens; D019010:Vascular Cell Adhesion Molecule-1