The Use of Mesenchymal Stromal Cells in Renal Transplantation

Ben Jones (2010). The Use of Mesenchymal Stromal Cells in Renal Transplantation PhD Thesis, School Of Medicine, The University of Queensland.

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Author Ben Jones
Thesis Title The Use of Mesenchymal Stromal Cells in Renal Transplantation
School, Centre or Institute School Of Medicine
Institution The University of Queensland
Publication date 2010-10
Thesis type PhD Thesis
Supervisor Dr Steven McTaggart
Dr Gary Brooke
Total pages 161
Total colour pages 10
Total black and white pages 151
Subjects 11 Medical and Health Sciences
Abstract/Summary Mesenchymal stromal cells (MSC) are multipotent adult stem cells that have been identified as important contributors to tissue repair and regeneration. In addition, they are both non-immunogenic and immunosuppressive making them potential candidates for systemic immunosuppression. Although traditionally isolated from bone marrow, this is invasive and therefore limits the supply of MSC. We investigated the isolation of MSC from novel sources (bone and placenta) and particularly focused on placenta as a potential source of non-invasive and more readily obtained MSC. We were able to show that MSC can be isolated from placental tissue (pMSC) and share common phenotypic characteristics with bone marrow-derived MSC (bMSC). We demonstrated that pMSC have an equivalent immunosuppressive capacity to bMSC and this was reversed through addition of the IDO specific blocker 1-MT. Thus we were able to show that suppression of allogeneic T-cell proliferation by placental MSC is IDO dependent. Furthermore, IDO activity could be induced by IFN- treatment leading to enhanced immunosuppression by MSC. While many published papers have demonstrated the immunosuppressive capacity of MSC in culture, few studies have looked at their ability to suppress systemic immune responses in vivo, and there is no literature on MSC in renal transplantation. In order to test the effectiveness of MSC in a solid organ transplant model, we undertook further experiments in a rodent model of transplantation. We first examined the ability of MSC to migrate to the transplanted kidney and were able to show that MSC migrate to the transplanted kidney. Additionally, there was no difference in MSC migration between allogeneic and syngeneic transplants suggesting that ischaemic injury rather than alloimmune stimuli are predominantly responsible for MSC migration to the kidney. While we were able to demonstrate MSC migration to the transplanted kidney, this was not associated with systemic immune changes or prolongation of transplant survival. While there are several potential reasons why MSC did not alter the outcome in this animal model of solid organ transplantation, we believe that the severity of donor-recipient allogeneic mismatch overwhelmed any potential benefits induced by MSC. In order to compare and contrast the results obtained for MSC, we then studied another cellular therapy, donor specific transfusion (DST) of dendritic cells (DC). In contrast to previous studies, DST of DC was ineffective in this model and supports the contention that this model is too severe to see subtle changes that may result from cellular treatments, such as MSC. While there was no impact on clinical rejection, changes in the dendritic cell populations were observed suggesting that DST may be modulating the immune system. Our characterization of DC populations in the rat transplant model will provide focus for further studies, with limited literature regarding dendritic cell populations/function in rat models of renal transplantation. We were able to not only define distinct sub-populations of OX62+ DC but showed DST of DC resulted in a significant drop in CD4- DC and increase in CD4+ DC, possibly indicating a shift to a TH2 immune phenotype.
Keyword kidney transplantation, mesenchymal stromal cells, IDO, dendritic cells, immunosuppression
Additional Notes 19, 33, 57, 60, 66, 97, 98, 105, 115, 158

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Created: Tue, 26 Oct 2010, 06:13:46 EST by Mr Ben Jones on behalf of Library - Information Access Service