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Welcome to the Regenerative Medicine Institute (REMEDI®)

Prof. Thomas Ritter

Personal Professor in Medicine
Phone: 
+353-91-495329
thomas.ritter@nuigalway.ie

Personal Professor in Medicine
Vice-Dean for Research, College of Medicine, Nursing and Health Sciences

Cellular Immunology, Cornea Transplantation, Gene Therapy.

Researcher in

Research Project Area: 

Novel therapeutic approaches to improve corneal allograft survival by cell and gene therapy and insights into the mechanism of action.
Science Foundation Ireland

Abstract:
With more than 100.000 procedures annually, cornea transplantation is the most frequent procedure of human tissue. However, long-term allograft survival is limited by immunological problems and reports on incidence of graft rejection vary between 5% and 40%. Therefore, continued therapeutic efforts are required to improve prognosis after cornea transplantation.
This proposal addresses a clinically relevant question, namely how corneal allograft survival can be improved by novel cell and gene therapeutic approaches. It consists of two research strands: Strand one will investigate whether the immunomodulatory properties of mesenchymal stem cells (MSCs) can be utilised to improve corneal allograft survival and to study the mechanisms behind. Strand two will further investigate the mechanism of Programmed Death-Ligand-1 induced prevention of corneal graft rejection and if this therapeutic effect can be further improved. Key impacts include the identification of novel mechanisms of MSC-mediated immunomodulation, the generation of optimised protocols for MSC purification and delivery, dosing and mode of action for preparation of a phase I clinical trial and Proof-of-Concept efficacy data for MSCs in prevention of cornea graft rejection. The proposal represents the continuation of a previously SFI funded programme and will strengthen the investigation of basic mechanisms and translation toward clinical application.

 

Novel topical treatment for inflammatory diseases of the skin and eye using vesicles released from human mesenchymal stem cells.
Health Research Board

Abstract:
This project targets a clinically significant problem and has the potential to be rapidly translated into a clinical application. Many people suffer from wound healing deficiencies which very much affects their quality of life. Moreover, the financial burden for the society is significant. Mesenchymal stem or stromal cells (MSCs) are a heterogeneous population of non-hematopoietic cells with multi-lineage potential. Despite their regenerative potential, it has been also demonstrated that MSCs possess immunomodulatory properties. Although MSCs have been administered to many patients in various clinical trials the potential risks of cell-based therapies such as immunogenicity or ectopic tissue formation by injected cells should not be underestimated. Drugs which are derived from cells but are devoid of cellular components would be a major breakthrough for therapeutic applications.
Interestingly, it has been shown that injection of conditioned medium alone was sufficient to mediate therapeutic effects and more recently it has been hypothesized that extracellular vesicles derived from MSCs mediate at least some of their trophic effects. Several studies have shown that extracellular vesicles (exosomes) released from MSCs contributed to improve myocardial infarction or kidney injury, however their role for the topical treatment of diabetes mediated skin ulcer or ocular surface disorders is not known.
Exosomes will be purified from human MSCs and topically applied in different concentrations in pre-clinical models for diabetes mediated skin ulcer and corneal surface disorders. Disease regression and immunomodulatory effects resulting from this treatment will be analysed. Finally it will be studied if exosomal preparations derived from “licenced” hMSCs or gene-modified hMSCs expressing the immunosuppressive protein PD-L1 will have enhanced therapeutic effects.
Successful completion of the project will result in the development a novel topical treatment for patients with diabetic skin ulceration and ocular surface disorders.

 

Innovative approaches to address adverse immune reactions to biomedical devices, implants and transplant tissues. Adverse Immune Signatures and their Prevention in Corneal Transplantation (VISICORT).
FP7 Collaborative Project

Abstract:
Immune system response is the most complex barrier to long-term success of tissue transplants/implants from allogeneic and bio-artificial sources. While newly developed tissue transplant procedures are not yet performed frequently enough for robust analysis of adverse immune responses in humans, corneal transplantation (CT) is a well-established allogeneic tissue transplant with >100,000 full- and partial-thickness procedures performed annually. Adverse immune responses occur in up to 30% of CT recipients causing rejection and failure. The high levels of CT clinical activity and immune complications create an ideal opportunity to comprehensively profile immune responses associated with adverse tissue transplant outcomes and to develop new approaches for their prevention or early diagnosis.
VISICORT is a multi-disciplinary project with expertise in basic immunology, bio-sampling, systems biology/immune profiling, bioinformatics, clinical tissue transplantation and cell therapy. It will complete the first systematic immune profiling of biological samples from animal and human CT recipients with diverse outcomes. Clinical data and bio-specimens from over 700 CT recipients at 5 leading transplant centres will be centrally collated and distributed to cutting-edge university- and SME-based laboratories for multi-platform profiling and integrated bioinformatics analyses. Profiling data will generate better understanding of adverse immune reactions to tissue transplants. This knowledge will be used to develop novel biomarker-based surveillance strategies and, coupled with SME-based expertise in cell product development, will also inform the design and initiation of an optimised clinical trial strategy of immunomodulatory stromal stem cell therapy in high-risk human CT recipients. VISICORT research will strongly impact multiple EU research/scientific communities, patient cohorts and SMEs and will have high commercialisation value for the biopharmaceutical and biotechnology industries.

Positions Held: 

01/2015 - Present
Personal Professor in Medicine
Department of Medicine/REMEDI,
NUI Galway
Immunology, Gene Therapy, Transplantation

07/2009 - 12/2014
Senior Lecturer
Department of Medicine/REMEDI,
NUI Galway
Immunology, Gene Therapy, Transplantation

03/2005 - 06/2009
Lecturer
Department of Medicine/REMEDI,
NUI Galway
Immunology, Gene Therapy, Transplantation

2003 - 2005
Associate Professor (C2)
Institute of Medical Immunology,
CharitÄ—-University Medicine Berlin, Germany
Immunology, Gene Therapy, Transplantation

1995 - 2003
Group Leader
Institute of Medical Immunology,
CharitÄ—-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: 

Treacy, O., O’Flynn, L., Ryan, A.E., Morcos, M., Lohan, P., Schu, S., Wilk, M., Fahy, G., Griffin, M.D., Nosov, M., Ritter, T. Mesenchymal stem cell therapy promotes corneal allograft survival in rats by local and systemic immunomodulation. Am. J. Transplant. 2014 Sep;14(9):2023-36.
http://www.ncbi.nlm.nih.gov/pubmed/25307035

Lohan, P., Coleman, C.M., Murphy, M.J., Griffin, M.D., Ritter, T., Ryan, A.E. Changes in immunological profile of MSC after differentiation: should we be concerned? Stem Cell Res Ther. 2014 Aug 19;5(4):99. doi: 10.1186/scrt488.
http://www.ncbi.nlm.nih.gov/pubmed/25158057

Ryan AE, Lohan P, O’Flynn L, Treacy O, Coleman C, Shaw G, Murphy M, Ceredig R, Griffin MD, Ritter T. Chondrogenic differentiation of mesenchymal stem cells alters cellular immunogenicity in vitro and in vivo. Mol Ther. 2014 Mar;22(3):655-67.
http://www.ncbi.nlm.nih.gov/pubmed/24184966

O’Flynn, L., Nosov, M., Ryan, A., Treacy, O., Cregg, M., Fahy, G., Morcos, M., Ritter, T. Donor bone marrow derived dendritic cells prolong corneal allograft survival and promote an intragraft immunoregulatory milieu. Mol Ther. 2013 Nov;21(11):2102-12.
http://www.ncbi.nlm.nih.gov/pubmed/23863882

Ritter, T., Wilk, M., Nosov, M. Gene therapy approaches to prevent corneal graft rejection: Where do we stand? Invited review. Ophthalmic Res, 2013;50(3):135-40.
http://www.ncbi.nlm.nih.gov/pubmed/23941996

Griffin, M.D., Elliman, S., Cahill E., English, K., Ceredig, R., Ritter, T. Adult mesenchymal stromal cell therapy for inflammatory diseases: How well are we joining the dots? Stem Cells 2013 Jun 14. doi: 10.1002/stem.1452. [Epub ahead of print]
http://www.ncbi.nlm.nih.gov/pubmed/23766124

Griffin MD, Ryan AE, Alagesan S, Lohan P, Treacy O, Ritter T. Anti-donor immune responses elicited by allogeneic mesenchymal stem cells: What have we learned so far? Immunol Cell Biol. 2013 Jan;91(1):40-51.
http://www.ncbi.nlm.nih.gov/pubmed/23207278

Schu, S., Nosov, M., O’Flynn, L., Shaw, G., Treacy, O., Barry, F., Murphy, M., O’Brien, T., Ritter, T. Immunogenicity of allogeneic mesenchymal stem cells. J. of Cellular and Molecular Medicine 2012 Sep;16(9):2094-103. http://www.ncbi.nlm.nih.gov/pubmed/22151542

Nosov, M., Wilk, M., Morcos, M., Cregg, M., O’Flynn, L., Treacy, O., Ritter, T. Role of lentivirus-mediated overexpression of Programmed Death Ligand-1 on corneal allograft survival. Am. J. of Transplant, 2012 May;12(5):1313-22. http://www.ncbi.nlm.nih.gov/pubmed/22300371

Treacy, O., Ryan, A., Heinzl, T., O’Flynn, L., Cregg, M., Wilk, M., Odoardi, F., Lohan, P., O’Brien, T., Nosov M., Ritter, T. Adenoviral transduction of mesenchymal stem cells: In vitro responses and in vivo immune responses after cell transplantation. PLoS One, 2012;7(8):e42662.
http://www.ncbi.nlm.nih.gov/pubmed/22880073

Griffin, M., Ritter, T., Mahon, B. Immunological aspects of allogeneic mesenchymal stem cell therapies. Invited Review. Human Gene Therapy. 2010 Dec;21(12):1641-55.
http://www.ncbi.nlm.nih.gov/pubmed/20718666

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.

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.

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

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

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.

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-gamma accelerates chronic graft injury in a rat renal allograft model. J. Am. Soc. Nephrol. 2003. 14: 214-225.

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.

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.

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.

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.

 

 

Research Funding: 

FP7 Collaborative Project (Small or Medium-scale Focused Research Project) FP7-Health-2013.1.3-2: Innovative approaches to address adverse immune reactions to biomedical devices, implants and transplant tissues. Adverse Immune Signatures and their Prevention in Corneal Transplantation (VISICORT). PI Prof. Matthew Griffin, NUIG. €5,989,587, Co-PI, WP1 leader, 04/14-03/19
€800,000

PROJECT GRANT: Novel topical treatment for inflammatory diseases of the skin and eye using vesicles released from human mesenchymal stem cells. PI, 1 Post-doc position, Health Research Board, Patient Oriented Research. HRA-POR-2013-341, 10/13-09/16
€330,000

PROJECT GRANT: Novel therapeutic approaches to improve corneal allograft survival by gene and cell therapy and insights into the mechanism of action. PI, 1 Post-doc position, 2 Ph.D. positions, 1 Research assistant, Science Foundation of Ireland, Investigators Programme Award 12/IA/1624, 04/13-03/18
€1,003,000

Professional and Personal Interests: 

IMMUNOLOGY, TRANSPLANTATION, IMMUNOMODULATION, MESENCHYMAL STEM CELLS, GENE THERAPY, CORNEAL TRANSPLANTATION, OSTEOARTHRITIS

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