Selective targeting of the LIGHT-HVEM costimulatory system for the treatment of graft-versus-host disease.
Decoy lymphotoxin beta receptor (LTbetaR) has potent immune inhibitory activities and thus represents a promising biologic for the treatment of inflammation, autoimmune diseases, and graft-versus-host disease (GVHD). As this reagent interrupts multiple molecular interactions, including LTbeta-LTbetaR and LIGHT-HVEM/LTbetaR, underlying molecular mechanisms have yet to be fully understood. In this study, we demonstrate that blockade of the LIGHT-HVEM pathway is sufficient to induce amelioration of GVHD in mouse models. Anti-host cytotoxic T lymphocyte (CTL) activity following in vivo transfer of allogeneic lymphocytes was completely abrogated when LIGHT- or HVEM-deficient (KO) T cells were used as donor cells. Accordingly, survival of the recipient mice following the transfer of allogeneic bone marrow cells plus LIGHT-KO or HVEM-KO T cells was significantly prolonged. In the absence of LIGHT-HVEM costimulation, alloreactive donor T cells undergo vigorous apoptosis while their proliferative potential remains intact. Furthermore, we prepared a neutralizing monoclonal antibody (mAb) specific to HVEM and showed that administration of anti-HVEM mAb profoundly ameliorated GVHD and led to complete hematopoietic chimerism with donor cells. Collectively, our results demonstrate an indispensable role of LIGHT-HVEM costimulation in the pathogenesis of GVHD and illustrate a novel target for selective immunotherapy in allogeneic bone marrow transplantation.
Xu
Yanhui
Y
Department of Molecular Biology and Biochemistry, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Flies
Andrew S
AS
Flies
Dallas B
DB
Zhu
Gefeng
G
Anand
Sudarshan
S
Flies
Sarah J
SJ
Xu
Haiying
H
Anders
Robert A
RA
Hancock
Wayne W
WW
Chen
Lieping
L
Tamada
Koji
K
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology / Q000628:therapy; D016026:Bone Marrow Transplantation; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D007167:Immunotherapy; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000628:therapy; D017710:Lymphocyte Transfusion; D051379:Mice; D008807:Mice, Inbred BALB C; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000276:immunology*; D018183:Transplantation Chimera / Q000276:immunology*; D014184:Transplantation, Homologous; D053319:Tumor Necrosis Factor Decoy Receptors / Q000276:immunology*
D000911:Antibodies, Monoclonal; D053240:Receptors, Tumor Necrosis Factor, Member 14; C506029:Tnfrsf14 protein, mouse; D053319:Tumor Necrosis Factor Decoy Receptors