Project 1:  Funded by: Health Research Board (Project Grant 2007)

Title: Overcoming the immune system: Mesenchymal stem cells as an immunosuppressive agent in transplantation

Abstract
Mesenchymal stem cells (MSCs) with their multi-lineage differentiation potential and known immunosuppressive properties provide exciting new therapeutic options for the treatment of degenerative, inflammatory and autoimmune diseases as well as for tolerance induction accompanying allogenic transplantation. However, recent findings suggest that MSCs might be immunogenic when transplanted into an allogenic host, which would be a major drawback to their universal application. Therefore, the possibility of immune rejection and/or activation of immune cells by MSCs in vivo need further investigation.
The objectives of this proposal are
1) to analyse the (extent of) immunogeneicity of MSCs in vitro and in vivo,
2) to investigate whether the immunogeneicity of MSCs can be influenced by transgenic expression of immunomodulatory molecules which modulate the immune recognition of MSCs by the recipients’ immune system,
3) to test whether wild type or transgenic MSCs can prolong the survival of syngenic or allogenic islet grafts in a rat model of autoimmune diabetes (BB).
Both molecular and cellular experiments will be performed to elucidate whether MSCs are subject of allogenic rejection in vivo. Moreover, genetic modification of MSCs by over-expression of an intracellular MHC-class I retaining molecule ('intrabody') and by cell surface expression of Fas ligand (FasL/CD95L) will be performed to generate MSCs with a low immunogenic profile. The effects of this novel approach will be tested in a pancreatic islet transplant model. Type I diabetes has a high prevalence and the only available cure to date is allogenic transplantation of islet cells. However, long term engraftment is rarely seen since β-cells are destructed by recurrence of autoimmunity and rejection processes. If co-transplantation of MSCs (gene-modified or wild type) leads to prolonged islet graft survival without the need for additional immunosuppression, this will be of the greatest importance for a successful treatment of this prevalent disease.

Project 2:  Funded by Science Foundation of Ireland (SFI PI 2007)

Title: Novel therapeutic approaches for the induction of tolerance in cornea transplantation
 

Abstract:  With more than 60.000 procedures a year, penetrating keratoplasty is the most frequent transplantation procedure of human tissue. Technical advances in microsurgery have played a key role in improving the quality of keratoplastic results. However, long term graft survival is limited by immunological problems. Reports on the incidence of graft rejection after penetrating keratoplasty vary between 5% and 40 %. In the presence of risk factors the 5-year prognosis for penetrating keratoplasty is even worse and estimated to be approximately 50%. This outcome is worse than that observed for transplantation of parenchymatous organs. Continued preventive and therapeutic efforts are required to improve the prognosis after keratoplasty. Less toxic treatment protocols need to be introduced into the transplant setting to prevent the rejection of allogeneic grafts. The genetic modification of the graft or cells prior to transplantation is an attractive approach to protect the graft from allogeneic rejection and for the induction of tolerance. In this proposal novel strategies using either viral (Adenoviruses and/or Adeno-Associated Viruses as gene therapy vehicle) or cell-based (genetically modified dendritic cells) therapies to protect the graft from rejection will be investigated. These strategies focus on gene transfer of therapeutic molecules which interfere with co-stimulation required for full activation of T cells. Moreover, in vivo mechanisms of immunomodulation and graft protection by these different approaches will be analysed. The results are expected to significantly prolong corneal graft survival and to result in novel strategies for the prevention of graft rejection which could be of value for other transplant models as well.