PhD Research Summary - Dr. Gysemans
This thesis investigated the complex interactions between transplanted pancreatic islets and the immune system in experimental models of type 1 diabetes, aiming to identify key mediators of β-cell destruction in vivo. A deeper understanding of these mechanisms is essential for designing new, well-tolerated therapeutic regimens to achieve donor-specific β-cell tolerance following islet transplantation.
In chapter IV, the study explored the dual role of the interferon-γ (IFN-γ) signaling pathway in β-cell sensitivity to immune-mediated destruction. Using knockout mouse models, it was shown that IFN-γ itself is not essential for β-cell destruction in vivo, but loss of the transcription factor IRF-1 increases β-cell susceptibility, suggesting a protective function of IRF-1 in maintaining β-cell defense mechanisms.
In chapter V, the focus was on the fate of xenogeneic (rat) islets transplanted into diabetic NOD mice. Xenografts in autoimmune NOD mice showed rapid rejection and a higher incidence of primary non-function, associated with elevated interleukin-1 (IL-1) and reduced transforming growth factor-β (TGF-β) mRNA expression in the grafts. These findings indicate that local inflammatory conditions in autoimmune hosts strongly affect graft viability.
In chapter VI, the potential of combined immunotherapy was evaluated. Treatment with mouse interferon-β (rIFN-β) or cyclosporine A (CsA), each combined with the vitamin D analog TX527, was tested in NOD mice after syngeneic islet transplantation. The combination of rIFN-β and TX527 effectively prevented autoimmune diabetes recurrence and prolonged graft survival, linked to reduced inflammatory cytokine expression and increased IL-10 in the grafts.
In chapter VII, a humanized mouse model (hu-PBL-SCID) was used to study human T-cell responses to xenogeneic islet grafts. The work demonstrated that pre-activation of human peripheral blood lymphocytes (hu-PBL) is essential for consistent xenograft infiltration and β-cell destruction, highlighting the importance of immune activation in this humanized system.
Overall, this research advances understanding of β-cell–immune interactions in type 1 diabetes and transplantation, providing valuable insights for the development of targeted, tolerogenic therapies to protect transplanted islets and restore insulin-producing capacity.