The cytolytic molecules Fas ligand and TRAIL are required for murine thymic graft-versus-host disease.

Abstract

Thymic graft-versus-host disease (tGVHD) can contribute to profound T cell deficiency and repertoire restriction after allogeneic BM transplantation (allo-BMT). However, the cellular mechanisms of tGVHD and interactions between donor alloreactive T cells and thymic tissues remain poorly defined. Using clinically relevant murine allo-BMT models, we show here that even minimal numbers of donor alloreactive T cells, which caused mild nonlethal systemic graft-versus-host disease, were sufficient to damage the thymus, delay T lineage reconstitution, and compromise donor peripheral T cell function. Furthermore, to mediate tGVHD, donor alloreactive T cells required trafficking molecules, including CCR9, L selectin, P selectin glycoprotein ligand-1, the integrin subunits alphaE and beta7, CCR2, and CXCR3, and costimulatory/inhibitory molecules, including Ox40 and carcinoembryonic antigen-associated cell adhesion molecule 1. We found that radiation in BMT conditioning regimens upregulated expression of the death receptors Fas and death receptor 5 (DR5) on thymic stromal cells (especially epithelium), while decreasing expression of the antiapoptotic regulator cellular caspase-8-like inhibitory protein. Donor alloreactive T cells used the cognate proteins FasL and TNF-related apoptosis-inducing ligand (TRAIL) (but not TNF or perforin) to mediate tGVHD, thereby damaging thymic stromal cells, cytoarchitecture, and function. Strategies that interfere with Fas/FasL and TRAIL/DR5 interactions may therefore represent a means to attenuate tGVHD and improve T cell reconstitution in allo-BMT recipients.

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Citation

Published Version (Please cite this version)

10.1172/JCI39395

Publication Info

Na, Il-Kang, Sydney X Lu, Nury L Yim, Gabrielle L Goldberg, Jennifer Tsai, Uttam Rao, Odette M Smith, Christopher G King, et al. (2010). The cytolytic molecules Fas ligand and TRAIL are required for murine thymic graft-versus-host disease. J Clin Invest, 120(1). pp. 343–356. 10.1172/JCI39395 Retrieved from https://hdl.handle.net/10161/4323.

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Scholars@Duke

Sempowski

Gregory David Sempowski

Professor in Medicine

Dr. Sempowski earned his PhD in Immunology from the University of Rochester and was specifically trained in the areas of inflammation, wound healing, and host response (innate and adaptive).  Dr. Sempowski contributed substantially to the field of lung inflammation and fibrosis defining the roles of pulmonary fibroblast heterogeneity and CD40/CD40L signaling in regulating normal and pathogenic lung inflammation.  During his postdoctoral training with Dr. Barton F. Haynes at Duke University, Dr. Sempowski focused on human immunology and more specifically immune reconstitution in settings of immune deficiency.  This resulted in publication of seminal findings regarding the cellular and molecular mechanisms that drive attenuation of immune function in the elderly. 

Since joining the Duke School of Medicine faculty in 2000, Dr. Sempowski has developed an independent research program studying immune deficiency associated with aging and radiation exposure. Dr. Sempowski is highly collaborative and works closely with investigators across the US, Europe, Australia and Japan and is internationally recognized as a thought leader in thymic aging, immunosenescence and multiplex biomarker analysis.

In 2017 Dr. Sempowski assumed Directorship of the Duke Global Health Research Building, a division of the Duke Human Vaccine Institute.  This state-of-the-art Regional Biocontainment Laboratory (RBL) was built with funding from the NIH to support basic research to develop drugs, diagnostics and vaccines for emerging/reemerging infections and biodefense.  The Duke RBL has a comprehensive safety and operations program to provide the Duke and RTP communities biocontainment facilities for BSL2, BSL3, and Select Agent research.  The facility is home to a portfolio of sponsored research programs focused on biosafety and biopreparedness, vaccine and therapeutic development, host response and immune monitoring and assay proficiency and quality assurance. 


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