Submitted July 16, 2008
Accepted December 23, 2008
Increased T-bet+ cytotoxic effectors and type I interferon-mediated processes in chronic graft versus host disease of the oral mucosa
Matin M. Imanguli, William D. Swaim, Stacy C. League, Ronald E. Gress, Steven Z. Pavletic, and Frances T. Hakim*
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, United States
* Corresponding author; email: hakimf{at}mail.nih.gov.
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 IL-15, type I IFN inducible factors which 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 Stat-1 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 interferon-driven immigration, proliferation and differentiation of Th1/Tc1 differentiated effectors. The clinical trials are registered at www.clinicaltrials.gov as NCT00331968.
