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Blood, 1 November 2007, Vol. 110, No. 9, pp. 3094. This Article Full Text (PDF) 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 Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Yu, X.-Z. Articles by Anasetti, C. Search for Related Content PubMed Articles by Yu, X.-Z. Articles by Anasetti, C. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  TRANSPLANTATION Comment on Taylor et al, page 3480 FTY720 prevents GVHD: the host perspective Xue-Zhong Yu, and Claudio Anasetti H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE In this issue of Blood, Taylor and colleagues report that FTY720 hinders the initiation of GVHD by reducing the number of host DCs in the spleen, rather than by trapping T cells in secondary lymphoid tissues. Sphingosine 1-phosphate (S1P) is a biologically active lysophospholipid that controls cellular differentiation, survival, and migration of several cell types. S1P is produced by mast cells, platelets, and macrophages, and is secreted in the extracellular fluid.1 S1P binds a family of G-protein–coupled receptors with a diverse pattern of expression on immune cells, thus mediating the emigration of thymocytes from the thymus and the trafficking of lymphocytes and dendritic cells (DCs) in secondary lymphoid organs.1 S1P1 is the most abundant S1P receptor on T cells and is also expressed on DCs. T cells from S1P1-deficient mice or mice treated with S1P1-downregulating drug FTY720 (FTY) rapidly leave the blood, are sequestered in the lymph nodes, and mount a diminished response to immune challenges in tissues. FTY also inhibits DC function, thereby preventing IgE secretion and asthma in experimental animals.2 In patients with multiple sclerosis, oral FTY reduces the number of lesions and the amount of clinical disease activity.3 In de novo renal transplantation, FTY is as effective as mycophenolate mofetil in preventing graft rejection when used in combination with cyclosporine. Therefore, FTY appears to be a very promising immune-modulating agent. Graft-versus-host disease (GVHD) is mediated by donor T cells that recognize host allo-antigens, and is associated with beneficial graft-versus-tumor (GVT) effects in recipients of allogeneic hematopoietic cell transplantation. In murine bone marrow transplantation (BMT) models, administration of FTY inhibits GVHD without abrogating GVT. It has been accepted that FTY prevents GVHD by trapping T cells in secondary lymphoid organs.4 In this issue of Blood, Taylor and colleagues present an elegant approach to visualize donor GFP-expressing T cells migrating to various recipient organs after transplantation. In the early phase of GVHD development, greater numbers of donor effector T cells accumulated in Peyer patches and mesenteric lymph nodes in FTY-treated recipients, but such an accumulation quickly diminished. Consistent with these data is the concept that FTY facilitates activation-induced T-cell death in the lymph nodes.5 Taylor and colleagues found fewer donor effector T cells in spleen, inguinal, and axillary lymph nodes, and in the gut-associated lymphoid tissues in FTY-treated recipients. In contrast, FTY did not reduce donor effector T cells in the liver or lung, implying that FTY does not prevent effector T cells from reaching epithelial organs targeted by GVHD. The other novel finding presented in the article is that FTY reduced host DCs in recipient spleen before transplantation, and that pretreatment of the host alone was sufficient to inhibit GVHD. After transplantation, expansion of donor CD4+ and CD8+ effector cells was blunted by the same magnitude as host DCs were depleted by FTY before transplantation. Because host DCs are also required for optimal GVT, it was no surprise that FTY therapy impaired GVT. FTY alone appeared modestly immune suppressive, and combination therapy was required to prevent GVHD. FTY was additive with adoptively transferred donor T regulatory cells (Tregs), providing the rationale for testing the combination for GVHD prevention in humans. Footnotes Conflict-of-interest disclosure: The authors declare no competing financial interests. REFERENCES Rosen H and Goetzl EJ. Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nat Rev Immunol 2005; 5:560–570.[CrossRef][Medline] [Order article via Infotrieve] Idzko M, Hammad H, van Nimwegen M, et al. Local application of FTY720 to the lung abrogates experimental asthma by altering dendritic cell function. J Clin Invest 2006; 116:2935–2944.[CrossRef][Medline] [Order article via Infotrieve] Kappos L, Antel J, Comi G, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 2006; 355:1124–1140.[Abstract/Free Full Text] Kim YM, Sachs T, Asavaroengchai W, Bronson R, Sykes M. Graft-versus-host disease can be separated from graft-versus-lymphoma effects by control of lymphocyte trafficking with FTY720. J Clin Invest 2003; 111:659–669.[CrossRef][Medline] [Order article via Infotrieve] Hashimoto D, Asakura S, Matsuoka K, et al. FTY720 enhances the activation-induced apoptosis of donor T cells and modulates graft-versus-host disease. Eur J Immunol 2007; 37:271–281.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Insights into the mechanism of FTY720 and compatibility with regulatory T cells for the inhibition of graft-versus-host disease (GVHD) Patricia A. Taylor, Michael J. Ehrhardt, Christopher J. Lees, Jakub Tolar, Brenda J. Weigel, Angela Panoskaltsis-Mortari, Jonathan S. Serody, Volker Brinkmann, and Bruce R. Blazar Blood 2007 110: 3480-3488. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) 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 Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Yu, X.-Z. Articles by Anasetti, C. Search for Related Content PubMed Articles by Yu, X.-Z. Articles by Anasetti, C. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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