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Dr. Thomas Ritter

Senior Lecturer in Medicine (Gene Therapy)
Phone: 
+353-01-495329
thomas.ritter@nuigalway.ie

Senior Lecturer in Medicine (Gene Therapy)

Cellular Immunology, Cornea Transplantation, Gene Therapy.

Researcher in

Research Project Area: 

 

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.

 

Positions Held: 

2009-present
Senior Lecturer
Department of Medicine/REMEDI,
NUI Galway
Immunology, Gene Therapy, Transplantation

2005-2008
Lecturer
Department of Medicine/REMEDI,
NUI Galway
Immunology, Gene Therapy, Transplantation

2003-2005
Associate professor (C2)
Institute of Medical Immunology,
Charitė-University Medicine Berlin, Germany
Immunology, Gene Therapy, Transplantation

1995-2003
Group leader
Institute of Medical Immunology,
Charitė-University Medicine Berlin, Germany
Immunology, Gene Therapy, Transplantation

1994-1995
Post-Doc
Centre d’Immunology de Marseille-Luminy, France
T-cell receptor signalling

1989-2004
Ph.D.
Max-Planck Society, Clinical Research Units of Rheumatology and Connective Tissue Research, University Erlangen-Nuremberg
Immunology, connective tissue, T-cell receptor signalling

1988-1989
Diploma
Institute of Clinical and Molecular Virology, University Erlangen-Nuremberg.
Molecular Biology, Virology

Awards & Honours: 

Awards and External Assignments:

2008 Grant assessor for Action Medical Research (UK).
 

2007 Grant assessor for Welcome trust (UK) and NUI Galway, Millenium Fonds, Minor project applications

2006 Grant assessor for German Research Foundation (DFG)

2007-present Editorial Board Member of the journal Transplantation

2000-present Referee for the following journals: Am. J. Transplantation, Biomaterials, Biotechniques, Brit. J.
Ophthalmology, Curr. Gene Ther. (Reviews only), Gene Therapy, Invest. Ophthal. Vis. Sci. (IOVS), J.
Gene Medicine, Transplantation, Transplant Immunology, Transplant International

2003-2005 Member of the Promotion Committee, Charité-University Medicine Berlin, Germany
 

1996-2005 Member of the Research Committee, Charité-University Medicine Berlin, Germany

1992 Three month's fellowship at the Centre of Immunology at Marseille, France

1994-1995 Postdoctoral education at the Centre of Immunology at Marseille, France funded by a grant of the
European Community

Selected Publications: 

1.Gong, N., Pleyer, U., Vogt, K., Anegon, I., Fluegel, A., Volk, H.-D., Ritter, T. Local over-expression of nerve growth factor in corneal transplants improves allograft survival. Invest. Ophthal. Vis. Sci. 2007. 48: 1043-1052.

2.Kuttler, B., Wanka, H., Kloting, N., Gerstmayer, B., Volk, H.D., Sawitzki, B., Ritter, T. Ex-vivo gene transfer of viral interleukin-10 to BB rat islets: No protection after transplantation to diabetic BB rats. J. Cell Mol Med. 2007 Jul-Aug;11(4):868-80.

3.Gong, N., Pleyer, U., Volk, H.-D., Ritter, T. Effects of local and systemic viral Interleukin-10 gene transfer on corneal allograft survival. Gene Ther. 2007 Mar;14(6):484-90. 2006 Nov 9 online publication

4.Gong, N., Pleyer, U., Yang, J., Vogt, K., Hill, M., Anegon, I., Volk, H.-D., Ritter, T. Influence of local and systemic CTLA4Ig gene transfer on corneal allograft survival. J. Gene Med. 2006. Apr;8(4):459-67

5.Brandt C, Yang J, Hammer M, Schmitt-Knosalla I, Siepert A, Hammer MH, Vogt K, Sawitzki B, Lehmann M, Volk HD, Ritter T. Allo-specific T-cells encoding for viral IL-10 exert strong immunomodulatory effects in vitro but fail to prevent allogeneic graft rejection. Am J Transplant, 2005. Feb;5(2):268-81.

6.Yang J, Reutzel-Selke A, Steier C, Jurisch A, Tullius SG, Sawitzki B, Kolls J, Volk HD, Ritter T. Targeting of macrophage activity by adenovirus -mediated intragraft over-expression of TNFRp55-Ig, IL-12p40, and vIL-10 ameliorates whereas stimulation of macrophages by over-expression of IFN- accelerates chronic graft injury in a rat renal allograft model. J. Am. Soc. Nephrol. 2003. 14: 214-225.

7.Hammer MH, Schröder G, Flügel A, Risch K, Volk HD, Lehmann, M, Ritter T. Antigen-dependent transgene expression in transplantation: a novel approach using gene-modified T lymphocytes. J. Am. Soc. Nephrol. 2002. 13: 511-518.

8.Ritter T, Brandt C, Proesch S, Vogt K, Kolls J, Volk HD. Stimulatory and inhibitory action of cytokines on the regulation of hCMV-promoter activity in human cell lines. Cytokine 2000. 12: 1163-1170.

9.Ritter T, Schröder G, Risch K, Vergopoulos A, Shean MK, Kolls J, Brock J, Lehmann M, Volk HD. Ischemia/Reperfusion injury mediated downregulation of adenovirus-mediated gene expression in a rat heart transplantation is inhibited by co-application of a TNFRp55-Ig chimeric construct. Gene Therapy 2000. 7: 1238-1243.

10.Hammer M, Flügel A, Seifert M, Lehmann M, Brandt C, Volk HD, Ritter T. Potential of allospecific gene-engineered T-cells in transplantation gene therapy: Specific T-cell activation determines transgene expression in vitro and in vivo. Human Gene Therapy 2000. 11: 1303-1312.

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