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Blockade of LIGHT/LTbeta and CD40 signaling induces allospecific T cell anergy, preventing graft-versus-host disease.

Abstract
Previous studies have shown that blockade of LIGHT, a T cell costimulatory molecule belonging to the TNF superfamily, by soluble lymphotoxin beta receptor-Ig (LTbetaR-Ig) inhibits the cytotoxic T lymphocyte (CTL) response to host antigenic disparities and ameliorates lethal graft-versus-host disease (GVHD) in a B6 to BDF1 mouse model. Here, we demonstrate that infusion of an mAb against CD40 ligand (CD40L) further increases the efficacy of LTbetaR-Ig, leading to complete prevention of GVHD. We further demonstrate that alloantigen-specific CTLs become anergic upon rapid expansion, and persist in the tolerized mice as a result of costimulatory blockade. Transfer of anergic CTLs to secondary F1 mice fails to induce GVHD despite the fact that anergic CTLs can be stimulated to proliferate in vitro by antigens and cytokines. Our study provides a potential new approach for the prevention of lethal GVHD.
AuthorsKoji Tamada, Hideto Tamura, Dallas Flies, Yang-Xin Fu, Esteban Celis, Larry R Pease, Bruce R Blazar, Lieping Chen
JournalThe Journal of clinical investigation (J Clin Invest) Vol. 109 Issue 4 Pg. 549-57 (Feb 2002) ISSN: 0021-9738 [Print] United States
PMID11854328 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antibodies, Monoclonal
  • Isoantigens
  • Ltb protein, mouse
  • Lymphotoxin-alpha
  • Lymphotoxin-beta
  • Membrane Proteins
  • Tnfsf14 protein, mouse
  • Tumor Necrosis Factor Ligand Superfamily Member 14
  • Tumor Necrosis Factor-alpha
  • CD40 Ligand
Topics
  • Animals
  • Antibodies, Monoclonal (pharmacology)
  • CD40 Ligand (immunology)
  • Clonal Anergy
  • Female
  • Graft vs Host Disease (etiology, immunology, prevention & control)
  • Immunosuppression Therapy (methods)
  • Isoantigens
  • Lymphotoxin-alpha (antagonists & inhibitors)
  • Lymphotoxin-beta
  • Membrane Proteins (antagonists & inhibitors)
  • Mice
  • Mice, Congenic
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Transgenic
  • T-Lymphocytes (immunology)
  • T-Lymphocytes, Cytotoxic (immunology)
  • Tumor Necrosis Factor Ligand Superfamily Member 14
  • Tumor Necrosis Factor-alpha (antagonists & inhibitors)

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