| 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 αE and β7, 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 apoptosisinducing 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. |
| Keywords: |
controlled study; transplantation, homologous; drug potentiation; nonhuman; t lymphocyte; t-lymphocytes; animal cell; mouse; animal; cytology; animals; mice; cell function; carcinoembryonic antigen related cell adhesion molecule 1; radiation; fas ligand; animal experiment; animal model; cell motion; protein interaction; mice, inbred balb c; mice, inbred c57bl; physiology; c57bl mouse; immunology; lymphocyte activation; donor; bagg albino mouse; pre t lymphocyte; thymus; thymus gland; death receptor 5; tumor necrosis factor related apoptosis inducing ligand; graft versus host reaction; cell movement; cytolysis; caspase 8; fas ligand protein; upregulation; bone marrow transplantation; graft vs host disease; stroma cell; stromal cells; cd134 antigen; receptors, ox40; chemokine receptor ccr2; graft recipient; allotransplantation; lymphocyte function; alloimmunity; tnf-related apoptosis-inducing ligand; p selectin glycoprotein ligand 1; alpha integrin; beta7 integrin; chemokine receptor ccr9; chemokine receptor cxcr3; inhibitor protein; l selectin; flice inhibitory protein; tnfrsf4 protein, mouse; tnfsf10 protein, mouse; tumor necrosis factor related apoptosis inducing ligand receptor; conditioning; cytoarchitecture; thymus graft; casp8 and fadd-like apoptosis regulating protein; receptors, tnf-related apoptosis-inducing ligand
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