Blockade of LIGHT/LTbeta and CD40 signaling induces allospecific T cell anergy, preventing graft-versus-host disease.
Previous studies have shown that blockade of LIGHT, a T cell costimulatory molecule belonging to the TNF superfamily, by soluble lymphotoxin beta receptor-Ig (LTbetaR-Ig) inhibits the cytotoxic T lymphocyte (CTL) response to host antigenic disparities and ameliorates lethal graft-versus-host disease (GVHD) in a B6 to BDF1 mouse model. Here, we demonstrate that infusion of an mAb against CD40 ligand (CD40L) further increases the efficacy of LTbetaR-Ig, leading to complete prevention of GVHD. We further demonstrate that alloantigen-specific CTLs become anergic upon rapid expansion, and persist in the tolerized mice as a result of costimulatory blockade. Transfer of anergic CTLs to secondary F1 mice fails to induce GVHD despite the fact that anergic CTLs can be stimulated to proliferate in vitro by antigens and cytokines. Our study provides a potential new approach for the prevention of lethal GVHD.
Tamada
Koji
K
Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Tamura
Hideto
H
Flies
Dallas
D
Fu
Yang-Xin
YX
Celis
Esteban
E
Pease
Larry R
LR
Blazar
Bruce R
BR
Chen
Lieping
L
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D023201:CD40 Ligand / Q000276:immunology*; D017635:Clonal Anergy; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D007165:Immunosuppression Therapy / Q000379:methods; D007519:Isoantigens; D008233:Lymphotoxin-alpha / Q000037:antagonists & inhibitors*; D053308:Lymphotoxin-beta; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D000911:Antibodies, Monoclonal; D007519:Isoantigens; C505887:Ltb protein, mouse; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D008565:Membrane Proteins; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand