SEARCH:   Advanced

Blood, 9 April 2009, Vol. 113, No. 15, pp. 3620-3630. Prepublished online as a Blood First Edition Paper on January 23, 2009; DOI 10.1182/blood-2008-07-168351. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2008-07-168351v1 113/15/3620    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Imanguli, M. M. Articles by Hakim, F. T. Search for Related Content PubMed PubMed Citation Articles by Imanguli, M. M. Articles by Hakim, F. T. Related Collections Transplantation Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  TRANSPLANTATION Increased T-bet+ cytotoxic effectors and type I interferon–mediated processes in chronic graft-versus-host disease of the oral mucosa Matin M. Imanguli1, William D. Swaim2, Stacy C. League1, Ronald E. Gress1, Steven Z. Pavletic1,*, and Frances T. Hakim1,* 1 Experimental Transplantation and Immunology Branch, National Cancer Institute (NCI), and 2 Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD Although chronic graft-versus-host disease (cGVHD) is a major long-term complication of allogeneic hematopoietic stem cell transplantation, little is known of its pathogenesis. We have systematically examined oral mucosa among cGVHD patients and determined that the clinical severity of oral cGVHD was correlated with apoptotic epithelial cells, often found adjacent to infiltrating effector-memory T cells expressing markers of cytotoxicity and type I cytokine polarization. Accumulation of T-bet+ T-cell effectors was associated with both increased proliferation and the expression of the type I chemokine receptor CXCR3. Concurrently, in both infiltrating cells and keratinocytes, we observed increased expression of the CXCR3 ligand MIG (CXCL9) and interleukin-15 (IL-15), type I interferon (IFN)–inducible factors that support the migration, type I differentiation, and expansion of alloreactive effectors. In severely affected mucosa, we observed high levels of MxA, a protein specifically induced by type I IFN, and signal transducer and activator of transcription 1 (STAT1) phosphorylation, a critical step in the IFN-signaling pathway, along with increased numbers of plasmacytoid dendritic cells. These data challenge the current paradigm of cGVHD as a type II cytokine–driven disorder and support the model that oral cGVHD results from type I IFN–driven immigration, proliferation, and differentiation of T-bet+ type I T effectors. The clinical trials are registered at http://www.clinicaltrials.gov as NCT00331968 [ClinicalTrials.gov] . CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

	Copyright © 2009 by American Society of Hematology         Online ISSN: 1528-0020