Date of Award

2-2015

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Professor Peter Conlon

Second Supervisor

Dr. Nader Najafian

Funder/Sponsor

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).

Keywords

Transplantation, Cell Differentiation, Receptors, Notch

Abstract

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.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

File Size

19.7 MB

Comments

A thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2015.

Available for download on Saturday, December 02, 2017

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