- Dr. Thomas J. Dengler, Principal Investigator
- Prof. Stefan Meuer, Research Associate
- Prof. Jordan Pober, Research Associate
- Medizinische Universitätsklinik, Heidelberg, Germany
- Immunological Properties and Therapeutic Potential of Endothelial Precursor Cells in Transplantation
Alloimmune endothelial injury appears to be the initial lesion of transplant vasculopathy. Circulating endothelial progenitor cells (EPC) have recently been identified as capable of neovascularization and vascular protection through regeneration. Recent studies have documented cellular chimerism in allograft vessels, suggesting a physiological repair mechanism involving such EPCs. We hypothesize that the prevention of developing vasculopathy depends on efficient repair of endothelial cell loss in graft vessels.
Rapid recovery from endothelial defects will inhibit the inflammatory cascade initiating neointima formation, and may facilitate graft adaptation through immune-modulating effects. The current project investigates the antigen-presenting and immuno-modulatory capacity of autologous EPC. It also tests if exogenous application of EPC can achieve cellular chimerism in the endothelium, and confer protection against transplant-related vascular injury. Different protocols for adhesion and flow cytometry sorting will be compared. Cells will be characterized by expression analysis of endothelial-cell-specific antigens, T cell co-stimulators and antigen uptake receptors, and by examination of angiogenic potential. The allogenic T-cell-stimulatory capacity of EPC to differentiate human umbilical vein endothelial cells (EC) will be compared in several read-out systems. Differences in T cell stimulation will be investigated for anergy or tolerogenic effects. Antigen presentation and activation of autologous T cells by EPC will subsequently be investigated in the same systems. Two hybrid vascular models (human EC in SCID mouse) will be used to study the replacement of resident endothelium by EPC: implantation of gels with 3-dimensional EC tubes and aortic interposition of human artery segments. In both models, endothelial chimerism will be assessed for native conditions and states of endothelial damage. In the EC gel model, damage and EC loss are induced by antibody-mediated complement action or alloimmune CTL attack. For the aortic interposition graft ischemia/reperfusion injury and CTL attack will be studied.
The project aims to define the therapeutic role of human endothelial precursor cells in the prevention of transplant-related vascular damage and to elucidate the T cell-stimulatory and potential tolerogenic properties of EPC. Finally, potential therapy-enhancing effects of genetic modification of EPC will be studied. Beyond transplant immunology, our expected findings will contribute to the understanding of vascular pathogenesis and vascular protection (vasculitis, atherosclerosis).