Protection from graft-versus-host disease with a novel B7 binding site-specific mouse anti-mouse CD28 monoclonal antibody.
We studied the role of CD28 in T-cell biology and T cell-mediated pathology using a novel mouse anti-mouse CD28 antibody, E18, which recognizes an epitope close to the B7 binding site. In vitro, this antibody completely blocked binding of B7 molecules to CD28 expressed on mouse thymocytes but enhanced anti-CD3-induced proliferation of peripheral T cells. Injections of E18 monoclonal antibody into normal BALB/c mice in vivo, however, led to a reversible reduction in Treg cell frequencies among CD4(+) cells, both in the thymus and in secondary lymphoid organs, suggesting that E18 acted as an inhibitor of CD28 signaling under these conditions. Antagonistic activity of E18 in vivo was further implied by suppressed responses of conventional CD4(+) T cells to stimulation with the superantigen staphylococcal enterotoxin B and in a model of acute graft-versus-host disease. In contrast to healthy mice, intact monoclonal antibody E18, but not its nonstimulatory Fab fragment, increased the frequencies of Treg cells among CD4(+) T cells in these pro-inflammatory settings allowing for efficacious protection from acute graft-versus-host disease. Thus, the agonistic signal generated by conventional, ie, nonsuperagonistic, anti-CD28 antibodies is important for their immunotherapeutic potential in vivo.
Beyersdorf
Niklas
N
Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany. niklas.beyersdorf@vim.uni-wuerzburg.de
Ding
Xin
X
Blank
Gregor
G
Dennehy
Kevin M
KM
Kerkau
Thomas
T
Hünig
Thomas
T
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D018122:B7-1 Antigen / Q000276:immunology*; D001666:Binding Sites, Antibody / Q000276:immunology*; D016026:Bone Marrow Transplantation / Q000379:methods; D018106:CD28 Antigens / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology; D004195:Disease Models, Animal; D004768:Enterotoxins / Q000494:pharmacology; D006086:Graft vs Host Disease / Q000276:immunology* / Q000517:prevention & control*; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D011485:Protein Binding / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D018122:B7-1 Antigen; D018106:CD28 Antigens; D017252:CD3 Complex; D004768:Enterotoxins; D007140:Immunoglobulin Fab Fragments; C031818:enterotoxin B, staphylococcal