Biodistribution and Modes of Action of Multipotent Adult Progenitor Cell therapy in Murine Models of Transplant Rejection

T cell homeostatic proliferation (HP) and Graft versus Host Disease (GvHD) are major barriers to the success of transplantation. Multipotent Adult Progenitor Cells (MAPC cells) have demonstrated promising safety and therapeutic profiles in experimental models and small clinical trials of transplantation and acute GvHD (aGvHD), however, the mechanisms by which MAPC cells mediate these effects is not entirely clear. Thus, the aim of this thesis was to develop our understanding of the modes of action and biodistribution of MAPC cells in in vivo models of GvHD and HP. MAPC cells were capable of delaying aGvHD onset when delivered 7 days after peripheral blood mononuclear cell (PBMC) delivery. MAPC cells were not significantly effective when administered along with PBMC, however interferon (IFN)-γ licensing improved this, and increased the biodistribution of MAPC cells towards GvHD target organs. PPARδ was identified as a key modulator of MAPC cell function, as activation of PPARδ hampered the efficacy of MAPC cells in the aGvHD model, while antagonism of PPARδ had the opposite effect. In vitro studies suggest that PPARδ may impart an inhibitory effect on COX-2 expression in MAPC cells In an IL-7 driven HP model MAPC cells suppressed T cell proliferation and function and modulated splenic myeloid and B cell populations, however their effects were dependent on the administrative route applied (intravenously (IV) or intraperitoneally (IP)). Whole animal biodistribution studies demonstrated that MAPC cells delivered IP persisted in vivo for longer than MAPC cells delivered IV, and accumulated in the omentum, while MAPC cells IV accumulated predominantly in the lung. In a lymphodepletion driven model of HP, MAPC cells delivered IP suppressed IFN-γ production by T cells and enhanced Treg. Importantly, MAPC cells mediated their suppressive effects on HP through production of PGE2. The data presented herein contributes to a broader understanding regarding the activity of MAPC cells during transplant rejection. These findings provide a platform for future studies regarding the use and optimisation of MAPC cells for transplant rejection.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

National University of Ireland Maynooth

Year dc:date.issued

2018

Author dc:creator

• Carty, Fiona

Language dc:language

en