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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 (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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 15, 2006 Accepted December 12, 2006 Selective targeting of the LIGHT-HVEM co-stimulatory system for the treatment of graft-versus-host disease 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, and Koji Tamada* Department of Molecular Biology and Biochemistry, Mayo Clinic College of Medicine, Rochester, MN The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia, PA * Corresponding author; email: ktamada1{at}jhmi.edu. 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 LIGHT-HVEM pathway is sufficient to induce amelioration of GVHD in mouse models. Anti-host 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 co-stimulation, allo-reactive 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 ameliorates GVHD and leads to complete hematopoietic chimerism with donor cells. Collectively, our results demonstrate an indispensable role of LIGHT-HVEM co-stimulation 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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