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Yoko Ogawa, Shigeto Shimmura, Kazuo Tsubota; Development of autoimmune type lacrimal gland GVHD in adoptively transferred mice with recipient derived T cells. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):878.
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Lacrimal gland chronic graft-versus-host disease (cGVHD) is a complication following bone marrow transplantation, which resembles autoimmune disease such as Sjogren’s syndrome. T cells are believed to play a possible role in immunomodulation. However, the precise source and role of T cells in lacrimal gland cGVHD are unknown. Here we show using a MHC compatible, minor antigen mismatched cGVHD model that donor mesenchymal stem cells (MSC), and recipient T cells play a role in the pathogenesis of lacrimal gland cGVHD. This study was undertaken to investigate whether recipient derived T cells are capable of inducing autoimmune lesions in cGVHD lacrimal gland.
We obtained freshly isolated MSCs and hematopoietic stem cells (HSCs) by established methods by Morikawa S, and Matsuzaki Y, et al. To confirm the function of mismatched MSC-transplanted recipient derived T cells, we adoptively transferred splenic T cells from mismatched MSC-transplanted recipient into naïve nude mice (BALB/c background) and compared with that of the wild type control. The animals were analyzed 45 days after transfer. Analyses of tissue samples from lacrimal glands including other target organs were performed by using immunohistochemistry and immunofluorescence. Splenic cells were collected and stained with anti-CD4 and anti-IL-17 antibody for flowcytometry. Purified donor-derived and mismatched B10.D2 MSCs were co-cultured with T cells isolated from mismatched MSC-transplanted recipient mice. Cells were treated with either blocking anti-MHC class II antibody or isotype control.
We found that cGVHD-like inflammation and fibrosis occurred in the target organs including lacrimal glands as well as systemic organs. The number of HSP47+ fibroblasts per field in the target organs was significantly increased in the adoptively transferred nude mice compared with that of the wild type control. FACS analysis of splenic PBMC of the adoptively transferred recipients revealed that CD4+Th 17 cells were markedly elevated compared with wild type BALB/c background nude mice. Effector T cells proliferation co-cultured with mismatched MSC was blocked by anti MHC Class II antibody in vitro.
Our results show that donor MSCs express MHC Class II following transplantation, and trigger immune responses in residual host T cells in the pathogenesis of autoimmune pathology in lacrimal gland cGVHD.
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