Interaction of vascular endothelial cells with CD8+ T-cells in vivo.
PhD Thesis, University of Basel,
Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_8498
Transplantation of organs and cells saves and prolongs thousands of lives every year. Surgical techniques were significantly improved but major problems remain, in particular the host’s immune system. Despite advances in immunosuppressive therapies, chronic allograft rejection still occurs which is characterized by intimal thickening in the arteries and the replacement of graft parenchyma, a phenomenon called chronic transplant vasculopathy (CTV). Within three years after transplantation 45% of transplant patients are affected by CTV which leads to the failure of allografts of about 5% each year post transplantation. The reasons for its development and the mechanistic basis inducing CTV are still not clearly understood. In graft versus host disease (GVHD) and vascular rejection of solid organ transplants, vascular endothelial cells (EC) have been recognized as important targets for alloreactive cytotoxic T-lymphocytes (CTL) and the presence of CTL has been associated with CTV. Therefore, T-cell-mediated immunity and subsequent inflammation appear to be important features of the initiation and progression of CTV. The contribution of EC to CD8+ T-cell activation and therefore their role in the development of chronic vascular rejection is still controversially discussed. For that reason and the fact that after transplantation of vascularised organs EC are the first graft cells encountered by host lymphocytes, the detailed interaction of vascular EC with CD8+ T-cells has been assessed in vivo in the first part of our study, in order to find out whether EC are able to activate or tolerize naive CD8+ T-cells. Using a transgenic mouse model with beta-galactosidase (β-gal) expression confined to the vascular endothelium (Tie2-LacZ mice) and the help of β-gal TCR transgenic CD8+ T-cells (Bg1 mice), the capacity of EC presenting a minor histocompatibility antigen (mhAg) to induce a CD8+ T-cell response was studied. We could show that mhAg presentation on EC was ignored by CD8+ T-cells and was neither sufficient to activate nor to tolerize CD8+ T-cells. Moreover, the mhAg was cross-presented by BM-derived CD11c+ DC and led to spontaneous activation of β-gal-specific CD8+ T-cells in Tie2-LacZ mice. This identifies the priming of mhAg-specific CD8+ T-cells via DC as the critical step in the generation of alloimmune responses. Furthermore, no β-gal-specific CD8+ T-cell activation was induced after transplantation of fully vascularised heart or liver grafts from Tie2-LacZ mice into non-transgenic recipients confirming that CD8+ T-cell responses against mhAg cannot be initiated by EC.
In the second part of the study the major aim was to develop an experimental system that facilitates in vivo studies on the interaction of EC with activated CTL in a heart transplantation model. To this end, Tie2-LacZ hearts were heterotopically transplanted into C57BL/6 recipients. Tie2-LacZ hearts were accepted and showed no vascular inflammatory changes or neointima formation until day 100 post transplantation. Repetitive priming with β-gal peptide loaded DC induced a long-term β-gal-specific CTL response resulting in the induction of vascular inflammatory disease with neointima formation and vascular occlusion. Infection with β-gal recombinant mouse cytomegalovirus (MCMV-LacZ) however, led to a shorter activation of β-gal-specific CTL and thus to a less significant vascular inflammation in Tie2-LacZ hearts. Taken together, we suggest that it is the prolonged presentation of mhAg within secondary lymphoid organs that is responsible for the activation of EC-specific CTL and that activated CTL recognize thereafter mhAg specifically expressed on EC, leading to the development of chronic vascular rejection.
|Committee Members:||Rolink, Antonius G.|
|Faculties and Departments:||03 Faculty of Medicine > Departement Biomedizin > Further Research Groups at DBM > Developmental and Molecular Immunology (Rolink)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||116|
|Last Modified:||30 Jun 2016 10:41|
|Deposited On:||13 Feb 2009 16:49|
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