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Modulation of the murine lymphatic system to decipher its role in the allo-immune response

Student thesis: Doctoral ThesisDoctor of Philosophy

The adaptive immune response to an allograft is initiated when donor-derived foreign antigens are recognised by the host immune system. This process relies on efficient trafficking of immune cells out of the graft to secondary lymphoid organs which provide a suitable niche for interactions between antigen presenting cells and allo-reactive T cells. The role of the lymphatic system in the allo-response is poorly understood, and there is evidence that lymphatics can have either a negative or a positive impact on graft survival, depending on a variety of complex factors.
The contribution of lymphatics to the allo-response has been studied using mouse models of skin, heart and kidney transplantation, in conjunction with pharmacological or genetic modulation of lymphatic function. Allogeneic kidney graft survival was significantly prolonged following treatment of recipients with anti-ICAM-1, an effect which correlated with reduced density of donor passenger leukocytes within recipients' draining lymph nodes in the immediate post-transplantation period. In addition, skin, heart and kidney grafts with lymphatic deletion of ephrin B2 benefitted from prolonged survival compared with wild-type grafts. This could not be attributed to reduced trafficking of donor cells to the draining lymph nodes and was likely a result of a local protective effect of ephrin B2 deficiency in the graft. The draining lymph node lymphatic response to heart transplantation was assessed; however, no significant changes were detected.
Varied models and organ types have been used to provide evidence for the role of donor and recipient lymphatics in allogeneic transplantation. Disruption of lymphatics resulted in delayed rejection or even permanent graft survival in some models. The mechanisms involved are complex, and may be independent of leukocyte trafficking. Future research focus should concentrate on elucidating the mechanisms involved so that they can be harnessed and translated into clinically applicable protocols to prolong allograft survival in the clinic.
Original languageEnglish
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Award date2018

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