Selective targeting of the LIGHT-HVEM costimulatory system for the treatment of graft-versus-host disease

Abstract

Decoy lymphotoxin ␤ receptor (LT␤R) 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 LT␤-LT␤R and LIGHT-HVEM/LT␤R, 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 IntroductionThe functional network of tumor necrosis factor (TNF) and TNF receptor superfamily members is composed of complex cross-talk between multiple ligands and multiple receptors, which regulate pleiotropic functions in the immune system. 1 LIGHT, standing for homologous to lymphotoxins, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes, is a type II transmembrane glycoprotein belonging to the TNF ligand superfamily. 2 LIGHT is expressed on immature dendritic cells (DCs) and activated T cells 2,3 and interacts with 2 functional receptors, lymphotoxin-␤ receptor (LT␤R) and HVEM. 2 LIGHT interaction with LT␤R triggers the production of proinflammatory mediators, 4,5 up-regulates adhesion molecule expression, 6 and induces apoptotic cell death in certain tumors. 7 On the other hand, by signaling through HVEM, LIGHT costimulates T-cell activation. 8 In vivo experiments demonstrated that transgenic expression of LIGHT leads to spontaneous progression of inflammatory autoimmunity such as Crohn disease, 9-11 while genetic disruption of LIGHT results in impaired T-cell activation, particularly in CD8 ϩ T cells, [12][13][14][15] and renders mice less vulnerable to pathogenic inflammation, as shown in acute hepatitis models. 16 Thus, LIGHT regulates multiple immune functions of innate and adaptive immunity through interactions with LT␤R and HVEM.There are numerous reports demonstrating therapeutic effects of decoy protein of LT␤R in various immunologic diseases, including autoimmunity, inflammation, and transplantation, 17,18 indicating that decoy LT␤R could be a potential biologic for clinical immunotherapy, analogous to a decoy form of TNF-receptor. 19 Prolonged administration of decoy LT␤R, however, might become a double-edged sword since it abrogates the maintenance of DC and natural killer/natural killer T (NK/NKT) cells 20,21 and inhibits the microstructure formation of lymphoid organs, 22 thus disrupting immune homeostasis. Therefore, it is of great interest to discover novel approaches that separate the therapeutic effects of decoy LT␤R from the potential adverse effects. While decoy LT␤R interferes with 3 molecular interactions-LT␤-LT␤R, LIGHT-LT␤R, and LIGHT-HVEM-the antihomeostatic effects are largely dependent on LT␤-LT␤R functions since the corresponding phenotypes are observed in LT␤-or LT␤R-KO mice but not in LIGHT-KO mice. [12][13][14][15][23][2...

Unexpected Role of B and T Lymphocyte Attenuator in Sustaining Cell Survival during Chronic Allostimulation

“…HVEM Ϫ/Ϫ and LIGHT Ϫ/Ϫ donor T cells showed decreased survival and reduced antihost CTL activity compared with wild type donor cells 7-10 days following transfer (64). Previously, blockade of LIGHT using soluble LT␤R-Ig or anti-LIGHT Ab was found to reduced severity of GVHD in this system (12).…”

“…Previously, blockade of LIGHT using soluble LT␤R-Ig or anti-LIGHT Ab was found to reduced severity of GVHD in this system (12). Notably, cotransfer of WT and LIGHT Ϫ/Ϫ T cells showed that wild-type donor cells had a significant survival advantage after 11 days (64).…”

“…HVEM activity was shown recently to be required for manifestation of disease in a similar parental-into-F 1 nonirradiated model of GVHD (64). HVEM Ϫ/Ϫ and LIGHT Ϫ/Ϫ donor T cells showed decreased survival and reduced antihost CTL activity compared with wild type donor cells 7-10 days following transfer (64).…”

New perspectives on the biology of acute GVHD

“…Other CTL-killing mechanisms involve TNF death ligand receptor-triggered apoptosis by activation of the TNF/TNFR, TRAIL, TWEAK and LTb/LIGHT pathways. [132][133][134][135][136][137][138][139] The CD4 effector T cells exerts their effect mainly through the Fas/FasL pathway and secondarily through the granzyme pathway.…”

Pathophysiology of acute graft-versus-host disease: recent advances

“…Experimental data suggests that this pathway is crucial for GI GVHD (discussed more below). Recently, several additional TNF family apoptosis-inducing receptors/ligands have been identified, including TWEAK, TRAIL and LTβ/LIGHT have all been proposed to play a role in GVHD and GVL responses (2,(232)(233)(234)(235)(236)(237)(238). However whether these distinct pathways play a more specific role for GVHD mediated by distinct T cell subsets in certain situations remains unknown.…”