Infusion of anti-B7.1 (CD80) and anti-B7.2 (CD86) monoclonal antibodies inhibits murine graft-versus-host disease lethality in part via direct effects on CD4+ and CD8+ T cells.
Efficient T cell proliferation requires costimulation via CD28/B7 or other pathways. Graft-vs-host disease (GVHD) is caused by activated donor T cells. We have found that the infusion of anti-B7.1 (CD80) + anti-B7.2 (CD86) mAb is effective in eliminating GVHD lethality induced by either CD8+ or CD4+ T cells. Donor CD4+ and CD8+ T cell expansion was inhibited by almost 100-fold as measured by enumerating thoracic duct lymphocytes (TDL) obtained early post-transplant. TDL retained anti-host responsiveness indicating that not all T cells were anergic. Although anti-CD80 or anti-CD86 mAb individually were ineffective in preventing CD8+ T cell GVHD lethality, each mAb was partially effective in CD4+ T cell-mediated GVHD. Because CD80 expression was found to be up-regulated on donor CD4+ TDL post-transplant, the GVHD capacity of donor CD4+ T cells deficient in CD80 was tested and found to be reduced similarly to that seen with anti-CD80 mAb. These studies demonstrate that anti-CD80 + anti-CD86 mAb infusion is effective in preventing GVHD lethality by inhibiting donor CD4+ or CD8+ T cell expansion and provide the first evidence that CD80 expression on donor T cells is critical for optimal GVHD lethality.
Blazar
B R
BR
Department of Pediatrics, University of Minnesota, Minneapolis 55455, USA.
Sharpe
A H
AH
Taylor
P A
PA
Panoskaltsis-Mortari
A
A
Gray
G S
GS
Korngold
R
R
Vallera
D A
DA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D015703:Antigens, CD / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology*; D051940:B7-2 Antigen; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007262:Infusions, Intravenous; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016513:Mice, SCID
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D000949:Histocompatibility Antigens Class II; D008562:Membrane Glycoproteins