Abstract |
Decoy lymphotoxin beta receptor (LTbetaR) 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 LTbeta-LTbetaR and LIGHT-HVEM/LTbetaR, 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 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 LIGHT-HVEM costimulation in the pathogenesis of GVHD and illustrate a novel target for selective immunotherapy in allogeneic bone marrow transplantation.
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Authors | Yanhui Xu, Andrew S Flies, Dallas B Flies, Gefeng Zhu, Sudarshan Anand, Sarah J Flies, Haiying Xu, Robert A Anders, Wayne W Hancock, Lieping Chen, Koji Tamada |
Journal | Blood
(Blood)
Vol. 109
Issue 9
Pg. 4097-104
(May 01 2007)
ISSN: 0006-4971 [Print] United States |
PMID | 17179227
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antibodies, Monoclonal
- Receptors, Tumor Necrosis Factor, Member 14
- Tnfrsf14 protein, mouse
- Tumor Necrosis Factor Decoy Receptors
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Topics |
- Animals
- Antibodies, Monoclonal
(immunology, pharmacology)
- Apoptosis
(drug effects, immunology)
- Autoimmune Diseases
(immunology, pathology, therapy)
- Bone Marrow Transplantation
- Graft vs Host Disease
(immunology, pathology, therapy)
- Immunotherapy
- Inflammation
(immunology, pathology, therapy)
- Lymphocyte Transfusion
- Mice
- Mice, Inbred BALB C
- Receptors, Tumor Necrosis Factor, Member 14
(immunology)
- Transplantation Chimera
(immunology)
- Transplantation, Homologous
- Tumor Necrosis Factor Decoy Receptors
(immunology)
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