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

journal contribution
posted on 2023-05-24, 11:49 authored by Xu, Y, Andrew FliesAndrew Flies, Files, DB, Zhu, G, Anand, S, Flies, Sj, Xu, H, Anders, RA, Hancock, WW, Tamada, K
Decoy lymphotoxin B receptor (LTBR) 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 LTB-LTBR and LIGHT-HVEM/LTBR, 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)

History

Publication title

Blood

Volume

109

Issue

9

Pagination

4097-4104

ISSN

0006-4971

Department/School

Menzies Institute for Medical Research

Publisher

American Society of Hematology

Place of publication

United States

Rights statement

Copyright 2007 by The American Society of Hematology

Repository Status

  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified

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