The Role of Notch Receptors in the Alloimmune Response
Notch receptors are a family of highly conserved transmembrane receptors crucial to cell development and fate: Notch-1 plays a critical role in normal T cell development, and is further involved in T cell activation and differentiation, while Notch-2 is known to be important to B cell development. The ability to influence T and B cell fate is of great interest in the field of transplantation; however, limited data exist on the importance of Notch-1 and Notch-2 in immune regulation. The primary aim of this study was to investigate the role of Notch-1 and Notch-2 in the alloimmune response using an in vivo mouse model of solid organ transplantation and selective human anti-Notch-1 (aNotch-1) and anti-Notch-2 (aNotch-2) antibodies, with particular reference to their roles in T and B cell development and behaviour, respectively.
Inhibition of Notch-1 prolonged cardiac graft survival, primarily by expanding natural regulatory T cells (Tregs), but also by reducing effector T cells; use of aNotch-1 decreased Treg apoptosis whilst increasing Treg proliferation and suppressive function. The protective effect of aNotch-1 was abrogated by Treg depletion but not by prior thymectomy, indicating a principal effect on peripheral T cells. Furthermore, selective genetic deletion of Notch-1 on Tregs increased the proportion, proliferation and suppressive function of Tregs in vitro and in vivo. Lastly, transient Notch-1 inhibition combined with single-dose CTLA4-Ig induced long-term graft tolerance.
Notch-2 blockade also prolonged cardiac allograft survival, an effect that was associated both with a reduction in T effector cells and, most strikingly, marked changes in the B cell subsets. Near-complete loss of the marginal zone B cell subset and reduction in the plasma cell population resulted in a highly significant reduction in the levels of donor-specific antibodies.
These data reveal a promising, novel approach for immune modulation in transplantation by selectively targeting Notch-1 and Notch-2.
I would also like to acknowledge funding and grant support from the American Society of Transplantation (AST/One Lambda Basic Science Fellowship Grant) and the Irish Nephrology Society (INS Research Bursary).
First SupervisorProfessor Peter Conlon
Second SupervisorDr. Nader Najafian
CommentsA thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2015.
Published CitationMagee CN. The Role of Notch Receptors in the Alloimmune Response. [PhD Thesis]. Dublin: Royal College of Surgeons in Ireland; 2015.
- Doctor of Philosophy (PhD)