Allogeneic cell therapy for osteoarthritis

Osteoarthritis is a debilitating multi-factorial joint disease which currently has no cure. Due to the significant immune cell mediated component in this disease a therapy which can modulate this inflammation and promote cartilage healing is urgently required. An allogeneic cell therapy could be particularly beneficial in OA. One such allogeneic cell is the mesenchymal stem cell (MSC). MSC, in addition to their chondrogenic differentiation capacity, possess potent immunomodulatory capabilities in the undifferentiated state. The first part of this work focused on the immune properties of allogeneic MSC after differentiation to a chondrogenic lineage. The work found that after chondrogenic differentiation MSC upregulate immunogenic cell surface molecules such as MHCI, MHCII, CD80 and CD86 and are functionally more immunogenic in vitro. Additionally these cells were found to lose their ability to modulate allogeneic lymphocyte proliferation in in vitro co-culture assays, possibly due to the loss of PGE2 and nitric oxide secretion. In vivo, it was shown that chondrogenically differentiated MSC, implanted subcutaneously, elicit significantly more infiltration of mononuclear phagocytes than their undifferentiated counterparts. Allogeneic differentiated MSC also resulted in higher memory T cell and allo-antibody responses compared to undifferentiated MSC, highlighting their immunogenicity. An alternative cell type for allogeneic cell therapy in OA is the chondrocyte itself. To test the immune properties of allogeneic chondrocytes, cartilage was excised and chondrocytes cultured from it in vitro. These cells were termed culture expanded primary chondrocytes (CEPC). In vitro CEPC were shown to be non-immunogenic, eliciting equivalent allogeneic T cell proliferation as undifferentiated MSC. This immunogenicity was not affected by culturing the cells in hypoxic conditions or exposing the cells to an inflammatory environment in vitro. Additionally CEPC could modulate both T cell and macrophage activity in vitro. This T cell immunomodulatory capacity was shown to be nitric oxide dependent. In summary, allogeneic chondrogenically differentiated MSC lose their immunomodulatory ability and become more immunogenic, while allogeneic CEPC are not immunogenic and have potent immunomodulatory activity in vitro.

Funder

European Union FP7 BMERM programme

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Attribution-NonCommercial-NoDerivs 3.0 Ireland

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University of Galway Theses (PhD Theses)