Interleukin-13 as a master regulator of alternative microglia/macrophage activation: modulation of allograft- and pathology-associated immune responses
8 juni 2017
UAntwerp Campus Drie Eiken, Building Q, Promotiezaal - Universiteitsplein 1 - 2610 WILRIJK (route: UAntwerpen, Campus Drie Eiken
Prof P. Ponsaerts & Prof Z. Berneman
PhD defence Chloé Hoornaert - Faculty of Medicine and Health Sciences
Transplantation of mesenchymal stem cells (MSCs) into injured or diseased tissue –for the in situ delivery of a wide variety of MSC-secreted therapeutic proteins– is an emerging approach for the modulation of the clinical course of several diseases and traumata. From an emergency point-of-view, allogeneic MSCs have numerous advantages over patient-specific autologous MSCs since ‘off-the-shelf’ cell preparations could be readily available for instant therapeutic intervention following acute injury.
Although we could confirm the –widely accepted– in vitro immunomodulatory capacity of allogeneic MSCs on antigen-presenting cells with standard co-culture experiments, allogeneic MSC grafts were irrevocably rejected by the host’s immune system upon either intramuscular or intracerebral transplantation. In an attempt to modulate MSC allograft rejection in vivo, we transduced MSCs with an interleukin-13 (IL13)-expressing lentiviral vector. Our data clearly indicate that prolonged survival of IL13-expressing allogeneic MSC grafts in muscle tissue coincided with the induction of an alternatively activated M2a macrophage phenotype in vivo and a reduced number of alloantigen-reactive interferon gamma (IFNγ)- and/or interleukin-2 (IL2)-producing CD8+ T cells compared to non-modified allografts.
Likewise, intracerebral IL13-expressing MSC allografts exhibited prolonged survival and induction of an M2a macrophage phenotype, although a peripheral T cell component was absent. In a final study, we investigated whether targeted central nervous system transplantation of autologous/allogeneic IL13-expressing MSCs would be able to modulate pathology-associated immune responses in the cuprizone (CPZ) mouse model, i.e. a well-established animal model of neuroinflammation and demyelination. Using a multimodal imaging approach, we demonstrated that transplantation of both autologous and allogeneic IL13-expressing MSCs (MSCs-IL13) efficiently limited CPZ-induced microgliosis, oligodendrocyte death and focal demyelination.
In summary, this doctoral study clearly illustrates that the localized production of IL13 by allogeneic MSCs has the potential to effectively modulate innate and adaptive immune responses in vivo. Upon transplantation of IL13-expressing MSCs, the pleiotropic actions of IL13 –potentially aided by the intrinsic secretion of MSC-associated proteins– significantly promoted MSC allograft survival in vivo and/or conferred (partial) protection against CPZ-induced demyelination and neuroinflammation.