The cytolytic molecules Fas ligand and TRAIL are required for murine thymic graft-versus-host disease.
Data(s) |
01/01/2010
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Formato |
343 - 356 |
Identificador |
http://www.ncbi.nlm.nih.gov/pubmed/19955659 39395 J Clin Invest, 2010, 120 (1), pp. 343 - 356 http://hdl.handle.net/10161/4323 1558-8238 |
Idioma(s) |
ENG en_US |
Relação |
J Clin Invest 10.1172/JCI39395 Journal of Clinical Investigation |
Tipo |
Journal Article |
Cobertura |
United States |
Resumo |
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. |
Palavras-Chave | #Animals #Bone Marrow Transplantation #CASP8 and FADD-Like Apoptosis Regulating Protein #Cell Movement #Fas Ligand Protein #Graft vs Host Disease #Lymphocyte Activation #Mice #Mice, Inbred BALB C #Mice, Inbred C57BL #Receptors, OX40 #Receptors, TNF-Related Apoptosis-Inducing Ligand #Stromal Cells #T-Lymphocytes #TNF-Related Apoptosis-Inducing Ligand #Thymus Gland #Transplantation, Homologous |