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Yoko Ogawa, Shigeto Shimmura, Saori Yaguchi, Takaaki Inaba, Kazuo Tsubota; Donor MSCs expressing MHC class II molecule trigger immune responses in an animal model of lacrimal gland chronic graft versus host disease. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3226. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
To examine using a cGVHD mouse model whether donor MSCs expressing MHC class II have a potential to trigger lacrimal gland cGVHD.
We chose a MHC-compatible, minor antigen (miHA)-incompatible model of cGVHD involving bone marrow transplantation (WBMT) with 8 week-old donor B10.D2 (H-2d) mice and recipient BALB/c mice (H-2d). We first modified the cGVHD model by co-transplanting prospectively isolated HSCs with prospectively isolated MSCs. This model closely mimics clinical findings of patients suffering from cGVHD. We examined lacrimal gland inflammation and fibrosis, expression of MHC class II on MSCs, T cell subsets and cytokine production in peripheral blood after the co-transplantation.
We found that serum levels of IL-6 increased in recipient mice transplanted with mismatched MSCs starting at 3 weeks after transplantation. This coincided with the appearance of lacrimal gland inflammation and fibrosis and MSC-derived cells in the peripheral blood of recipients starting at 3 weeks after transplantation and gradually increasing up to 7 weeks. Interestingly, these MSC-derived cells in the peripheral blood expressed MHC class II antigens.Flowcytometry revealed that both MSCs and T cells from mismatched MSC-transplanted recipients produce IL-6. Proliferated T cells are predominantly recipient derived CD4+ T cells. MHC class II molecule was expressed in a subset of MSC cells, but the frequency was significantly increased after co-culture with recipient T cells.
These data suggest that mismatched MSCs and host T cells stimulate each other via the MHC class II molecule. Our results show that donor MSCs expressing MJHC class II molecule trigger immune responses in cGVHD related dry eye, challenging current paradigms on the pathogenesis of the disease.
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