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Blood, 1 May 2007, Vol. 109, No. 9, pp. 4097-4104. Prepublished online as a Blood First Edition Paper on December 19, 2006; DOI 10.1182/blood-2006-09-047332. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2006-09-047332v1 109/9/4097    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Xu, Y. Articles by Tamada, K. Search for Related Content PubMed PubMed Citation Articles by Xu, Y. Articles by Tamada, K. Related Collections Transplantation Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  TRANSPLANTATION Selective targeting of the LIGHT-HVEM costimulatory system for the treatment of graft-versus-host disease Yanhui Xu1, Andrew S. Flies2, Dallas B. Flies2, Gefeng Zhu2, Sudarshan Anand2, Sarah J. Flies2, Haiying Xu2, Robert A. Anders2, Wayne W. Hancock3, Lieping Chen2, and Koji Tamada2 1 Department of Molecular Biology and Biochemistry, Mayo Clinic College of Medicine, Rochester, MN; 2 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD; 3 Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia Decoy lymphotoxin ß receptor (LTßR) 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 LTß-LTßR and LIGHT-HVEM/LTßR, 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. W. Steinberg, O. Turovskaya, R. B. Shaikh, G. Kim, D. F. McCole, K. Pfeffer, K. M. Murphy, C. F. Ware, and M. Kronenberg A crucial role for HVEM and BTLA in preventing intestinal inflammation J. Exp. Med., June 9, 2008; 205(6): 1463 - 1476. [Abstract] [Full Text] [PDF] C. A. Nelson, M. D. Fremont, J. R. Sedy, P. S. Norris, C. F. Ware, K. M. Murphy, and D. H. Fremont Structural Determinants of Herpesvirus Entry Mediator Recognition by Murine B and T Lymphocyte Attenuator J. Immunol., January 15, 2008; 180(2): 940 - 947. [Abstract] [Full Text] [PDF]

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