Abstract
AbstractChronic graft-versus-host disease (cGVHD) is a complication after minor antigen mismatched bone marrow transplantation (BMT) characterized by an autoimmune-type reaction in various organs. Aberration in T cell regulation is involved, with donor mesenchymal stem cells (MSCs) playing a possible role in immunomodulation. In a minor-antigen mismatched mouse BMT model, transplantation of mismatched, but not syngeneic MSCs triggered the onset of cGVHD, and was associated with fibrosis, increased IL-6 secretion, decreased Foxp3+ regulatory T cells and increased Th17 in the peripheral blood. Mismatched MSCs alone were sufficient to induce cGVHD, while removal of donor MSCs rescued mice from cGVHD. RAG2 knockout recipient mice did not suffer cGVHD, indicating that host T cells were involved. Residual host-derived T cells were significantly higher in cGVHD patients compared to non-cGVHD patients. In conclusion, donor MSCs react with residual host T cells to trigger the progression of cGVHD.
Highlights
Chronic graft-versus-host disease is a complication after minor antigen mismatched bone marrow transplantation (BMT) characterized by an autoimmune-type reaction in various organs
Minor antigen mismatched HSC and mesenchymal stem cells (MSCs) co-transplantation In order to elucidate the role of donor-derived fibroblasts, we first established a modified Chronic graft-versus-host disease (cGVHD) model by co-transplanting isolated hematopoietic stem cells (HSCs) and MSCs
Cells double positive for the fibroblast marker HSP47 and EGFP were detected in cGVHD tissue when EGFP+ PαS-MSCs were transplanted with wild type B10.D2 side population (SP) cells (Fig. 1c, d)
Summary
Chronic graft-versus-host disease (cGVHD) is a complication after minor antigen mismatched bone marrow transplantation (BMT) characterized by an autoimmune-type reaction in various organs. Chronic GVHD (cGVHD) has distinct clinical findings, which resemble features of autoimmune disease such as systemic sclerosis or Sjögren’s syndrome involving exocrine glands [1,2], and is believed to be distinct from the potentially lethal acute form of GVHD. This autoimmune phenotype has been attributed to donor-derived T cells that escape negative selection by the host thymus damaged by acute GVHD 3,4. Accumulation of donor-derived fibroblasts in fibrotic lesions surrounding exocrine ducts was observed (Supplementary Fig. 1d), which was similar to human patients as shown in our previous report 6. We sought to answer the debated role of donor MSCs in the pathogenesis of the autoimmune-like phenotype of cGVHD using prospectively isolated MSCs and HSCs in a mouse model of cGVHD
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