Mehler, Vera Josefa;
(2020)
Assessing the cell-mediated immune response towards iPSC-derivatives.
Doctoral thesis (Ph.D), UCL (University College London).
Abstract
Clinical trials have, and continue to, evaluate induced-pluripotent stem cell (iPSC)-derived cells as a cellular therapy in the field of regenerative medicine. The widespread clinical utility of iPSCs is expected to be realised using allogeneic cells that have undergone thorough safety evaluations, including assessment of their immunogenicity. IPSC-derivatives, including neural crest stem cells (NCSCs) and smooth muscle cells (SMCs) have significant potential as cellular therapies in regenerative medicine. iPSC-derived NCSCs are considered a promising candidate in the treatment of neurocristopathies and iPSC-derived SMCs in the treatment of cardiovascular diseases. However, the application of iPSC-derived NCSCs in cellular therapy has not been widely studied to date and no reports on their potential immunogenicity have been published so far. On the other hand, iPSC-derived SMCs as a cellular therapy have been the subject of several pre-clinical models, especially in the field of cardiovascular medicine, but only a handful have addressed their immunogenicity. In this study, we generated NCSCs and SMCs from iPSCs and evaluated their immune profile. This characterisation comprised an assessment of the expression of immune-related antigens in iPSC-NCSCs and iPSC-SMCs, including HLA class I and II, the expression of co-stimulatory molecules, and testing functional immunogenicity, using a one-way mixed lymphocyte reaction. We showed for the first time that iPSC-NCSCs are non-immunogenic in-vitro, reflected by undetectable immune-related antigen expression and negligible levels of T cell stimulation. On the other hand, iPSC-SMCs exhibited some level of immunogenicity, although this was not consistent across our evaluations, reflected by variations in the read outs for molecular as well as functional immunogenicity. We further investigated whether mesenchymal stromal cells (MSCs) as an immunosuppressive strategy, could mitigate the immune response provoked by iPSC-SMCs. Our results suggest that MSCs do indeed represent a viable approach to reduce iPSC-stimulated T cell proliferation in vitro. Taken together, these results are encouraging for the potential future use of iPSC-derived cells , such as NCSCs, as a cellular therapy, and suggest that the expected immune response provoked by some iPSC-derived cell types, for instance iPSC-derived SMCs, may be mitigated by the simultaneous therapeutic application of MSCs.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Assessing the cell-mediated immune response towards iPSC-derivatives |
| Event: | UCL |
| Language: | English |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10096648 |
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