dc.contributor.author | Hart-Matyas, Michael | |
dc.date.accessioned | 2014-01-24T19:23:40Z | |
dc.date.available | 2014-01-24T19:23:40Z | |
dc.date.issued | 2014-01-24 | |
dc.identifier.uri | http://hdl.handle.net/10222/43957 | |
dc.description.abstract | Long-term survival of cardiac transplant recipients continues to be severely limited by the development of a pathological, chronic rejection process, termed allograft vasculopathy (AV). This remains to be the case despite dramatic improvements in the areas of surgical techniques, pre- and post-operative care, and immunosuppression.
To model the clinical setting we used calcineurin inhibitor (CNI) immunosuppression, the cornerstone of post-transplant immunosuppression, in a murine aortic interposition transplant model for our analysis of AV development. This model mimics the presentation of AV in human cardiac transplants through the development of a progressively occlusive neointimal lesion. Our previous work in this model has demonstrated that CD8+, but not CD4+, T cells play a role in neointimal lesion formation. Further investigation also highlighted a specific requirement for either CD8+ T cell-derived IFN-γ or direct cytotoxicity in the development of lesion formation. In the current study we confirmed that CD8+ T cell-derived IFN-γ also leads to the loss of medial smooth muscle cells, an event which inversely correlates with lesion formation. The Fas/FasL direct cytotoxic pathway was also significantly involved in neointimal lesion formation and medial remodeling. This work clarified the pathways utilized by CD8+ T cells in their role as mediators of AV development.
Recognizing the threat that CD8+ T cells pose to cardiac transplant recipients in the presence of CNI immunosuppression, and a growing concern with the presence of anti-donor memory T cells in transplant recipients, we next explored the development of memory CD8+ T cells in the presence of CNI immunosuppression. We first established that memory CD8+ T cells could not develop when CNI immunosuppression was initiated immediately post-challenge. Next, we hypothesized that the clinical practice of CNI delay post-transplant would permit the development of de novo memory CD8+ T cells. Immediate and early initiation was sufficient to prevent the development of de novo memory CD8+ T cells. However, later delay to within a clinically practiced timeframe did permit the development of de novo memory CD8+ T cells. Our analysis revealed that this population demonstrated equivalent functionality to de novo memory CD8+ T cells generated in the absence of CNI immunosuppression. | en_US |
dc.language.iso | en_US | en_US |
dc.subject | CD8+ T cell | en_US |
dc.subject | Memory T cell | en_US |
dc.subject | Allograft Vasculopathy | en_US |
dc.subject | Immunosuppression | en_US |
dc.title | CD8+ T cells in the development of Allograft Vasculopathy and de novo allospecific memory formation | en_US |
dc.type | Thesis | en_US |
dc.date.defence | 2014-01-15 | |
dc.contributor.department | Department of Pathology | en_US |
dc.contributor.degree | Doctor of Philosophy | en_US |
dc.contributor.external-examiner | Dr. Reginald Gorczynski | en_US |
dc.contributor.graduate-coordinator | Dr. Wenda Greer | en_US |
dc.contributor.thesis-reader | Dr. Jennifer Merrimen | en_US |
dc.contributor.thesis-reader | Dr. David Hoskin | en_US |
dc.contributor.thesis-supervisor | Dr. Tim Lee, Dr. Greg Hirsch | en_US |
dc.contributor.ethics-approval | Received | en_US |
dc.contributor.manuscripts | No | en_US |
dc.contributor.copyright-release | Yes | en_US |