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Title: Regulatory T cells in experimental solid organ transplantation
Author: Chan, Thomas
ISNI:       0000 0004 8502 8888
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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Clinical transplantation outcome has been improved significantly over the last few decades by powerful immunosuppressive drugs. However, transplant recipients are subjected to non-specific immunosuppression, which increases the risks of malignancy, opportunistic infections, and drug associated toxicities. Alternative strategies that provide more selective immunosuppression are currently being investigated. The possibility of harnessing regulatory T cells as cellular therapeutic agents has been proposed based on the evidence obtained from a number of pre-clinical studies. We have developed an in vitro protocol that could generate an enriched population of CD4+ Foxp3+ regulatory T cells (IFN-γ Treg) by stimulating CD4+ T cells with allogeneic APC in the presence of exogenous IFN-γ. We found that these Treg could suppress alloresponses following adoptive transfer to immunodeficient, as well as immunocompetent hosts in the presence of a sub-optimal costimulation blockade treatment in vivo. When compared to Treg generated by other in vitro protocols, IFN-γ Treg appeared to be superior in their suppressive function on a cell-to-cell basis. Alloantigen-driven IFN-γ Treg prolong allograft survival in a dose-dependent manner. More importantly, Treg delivered prior to the transplant resulted in the induction of tolerance but they had no impact on graft survival when given post-transplant. We demonstrated that IFN-γ Treg control alloresponses via the action of CTLA-4 and are partially dependent on IL-10 in vivo. Using an in vitro suppression assay, we showed that IFN-γ Treg controlled the proliferation of naïve CD4+CD25- T cells in vitro. Tolerance was only partially reversed following the depletion of IFN-γ Treg suggesting that the persistence of IFN-γ Treg was not a prerequisite for the induction of tolerance long-term, but that tolerance was maintained via infectious tolerance in vivo. However, IFN-γ Treg were less efficacious in controlling memory responses in sensitized recipients compared to naïve hosts at a given cell dose. IFN-γ Treg were more resistant to expansion in response to polyclonal or allogeneic stimulation in the presence of exogenous IL-2 compared to naturally-occurring Treg (nTreg) in vitro. However, at the same cell dose, IFN-γ Treg were more potent than freshly-isolated nTreg or expanded nTreg. Cryopreservation is a permissible solution to various logistic issues; however, Treg function could be discounted following the freeze and thaw processes. Activation status of Treg appeared to be crucially important for their suppressive function and we found that activated nTreg were equally effective in controlling allograft rejection in immunocompetent recipients as IFN-γ Treg, in the presence a sub-optimal costimulation blockade. Furthermore we developed a novel in vivo magnetic resonance imaging technique that provided a non-invasive method to assess graft function. In conclusion, we propose that alloantigen-driven Treg are potential candidates as alternative to nTreg for controlling allograft rejection after transplantation.
Supervisor: Wood, Kathryn Sponsor: National Medical Research Council ; Singapore
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available