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

Citation

Xu, Y and Flies, AS and Files, DB and Zhu, G and Anand, S and Flies, Sj and Xu, H and Anders, RA and Hancock, WW and Tamada, K, Selective targeting of the LIGHT-HVEM costimulatory system for the treatment of graft-versus-host disease, Blood , 109, (9) pp. 4097-4104. ISSN 0006-4971 (2006) [Refereed Article]

Copyright Statement

Copyright 2007 by The American Society of Hematology

Official URL: http://dx.doi.org/10.1182/blood-2006-09-047332

DOI: doi:10.1182/blood- 2006-09-047332

Abstract

Decoy lymphotoxin  receptor (LTR) 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-LTR and LIGHT-HVEM/LTR, underlying molecular mechanisms have yet to be fully understood. In this study, we demonstrate that blockade of the LIGHTHVEM 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 LIGHTHVEM costimulation in the pathogenesis of GVHD and illustrate a novel target for selective immunotherapy in allogeneic bone marrow transplantation. (Blood. 2007;109:4097-4104)

Item Details

Item Type:Refereed Article
Keywords:immunology
Research Division:Medical and Health Sciences
Research Group:Immunology
Research Field:Cellular Immunology
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Immune System and Allergy
Author:Flies, AS (Dr Andy Flies)
ID Code:102360
Year Published:2006
Web of Science® Times Cited:46
Deposited By:Menzies Institute for Medical Research
Deposited On:2015-08-16
Last Modified:2016-10-18
Downloads:0

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