Oxidized low-density lipoprotein (oxLDL) triggers hypoxia-inducible factor-1alpha (HIF-1alpha) accumulation via redox-dependent mechanisms.

Abstract

Decoy lymphotoxin receptor (LTR) haspotent immune inhibitory activities andthus represents a promising biologic forthe treatment of inflammation, autoimmunediseases, and graft-versus-host disease(GVHD). As this reagent interruptsmultiple molecular interactions, includingLT-LTR and LIGHT-HVEM/LTR, underlyingmolecular mechanisms have yetto be fully understood. In this study, wedemonstrate that blockade of the LIGHTHVEMpathway is sufficient to induceamelioration of GVHD in mouse models.Antihost cytotoxic T lymphocyte (CTL)activity following in vivo transfer of allogeneiclymphocytes was completely abrogatedwhen LIGHT- or HVEM-deficient(KO) T cells were used as donor cells.Accordingly, survival of the recipient micefollowing the transfer of allogeneic bonemarrow cells plus LIGHT-KO or HVEM-KOT cells was significantly prolonged. In theabsence of LIGHT-HVEM costimulation,alloreactive donor T cells undergo vigorousapoptosis while their proliferativepotential remains intact. Furthermore, weprepared a neutralizing monoclonal antibody(mAb) specific to HVEM and showedthat administration of antiHVEM mAbprofoundly ameliorated GVHD and led tocomplete hematopoietic chimerism withdonor cells. Collectively, our results demonstratean indispensable role of LIGHTHVEMcostimulation in the pathogenesisof GVHD and illustrate a novel target forselective immunotherapy in allogeneicbone marrow transplantation. (Blood.2007;109:4097-4104)