Dr. Paul Lohan and Prof. Thomas Ritter from NUIGalway and Visicort partner Prof. Conor Murphy from RCSI in Dublin presented several posters at the ARVO 2017 Annual Meeting in Baltimore from May 7th to May 11th. More than 10,000 delegates around the world participated in the meeting which is the most important meeting on eye research showing latest research in eye research. Dr. Lohan’s poster on the establishment of a “high-risk” corneal transplant model in the rat and his work on modulating allograft rejection using mesenchymal stem cells was well received and many leaders in the field of ocular immunology visited the poster and asked interesting questions. Overall the meeting was a great success!
The VISICORT consortium partners met in Edinburgh, UK on Thursday, April 27th and Friday, April 28th to review progress towards the project’s major goals following three years of collaborative research. The meeting was jointly hosted at Nine, Edinburgh BioQuarter by VISICORT partners Fios Genomics Ltd. and University of Edinburgh’s SynthSys Laboratory and was attended by 25 team members from 10 partner sites.
The group was also joined by Scientific Advisory Group member, Prof. John Forrester who is Cockburn Professor of Ophthalmology University of Aberdeen and is an internationally recognised leader in immune-mediated eye disease and corneal transplantation.
The meeting focused on the consortium’s progress and future plans in its two main research activities:
Biological profiling of immune complications in corneal transplantation
Over the past three years VISICORT has successfully developed a multi-site clinical research network involving five centres of excellence for corneal transplantation (Aarhus, Berlin, Bristol, Dublin and Nantes); a central logistics and sample collection facility (Biostór Ireland, Ltd.) and specialised profiling technology / bioinformatics laboratories (Edinburgh and Nantes). To date, this network has enrolled almost 1000 corneal transplant recipients and control patients into three separate observational studies which uniquely link their biological profiles with current and future transplant outcomes.
During the first year of the project, a specially-designed secure database – VISICORT Information Management System (VIMS) – was developed by team members at Biostór Ireland Ltd. and Aarhus University Hospital in collaboration with Belfast-based company PathXL (now part of Philips Digital Pathology Solutions). VIMS has uniquely facilitated the flow of samples and linked clinical information across project sites while ensuring the highest level of data protection for study participants. This has allowed us to reach an exciting milestone in the project at which gene expression, protein abundance and blood immune cell profiles have been generated for a large number of European corneal transplant recipients and are now being linked to complications such as acute and chronic rejection.
Over the next year, much of this profiling information will be analysed in detail to reveal new details about the immunological processes that drive transplant rejection and to identify new approaches to testing for rejection risk. We will also continue to longitudinally follow over 300 recently transplanted recipients to learn more about the individual factors that contribute to the development of complications.
Development of an early-phase clinical trial of stromal stem cells in high risk corneal transplantation
One of the greatest remaining challenges to successful corneal transplantation is the safe prevention of rejection and transplant failure in those whose cornea is already inflamed or who have previously rejected a transplant. Under these “high immunological risk” conditions, rejection commonly occurs and extended use of strong immune suppressive medications is frequently necessary.
Laboratory research carried out over the past 3 years by VISICORT researchers at the National University of Ireland, Galway and Orbsen Therapeutics Ltd. has now shown that stromal stem cells (often called mesenchymal stem cells or MSCs) from an unrelated donor given intravenously in the week before a high-risk corneal transplant greatly reduce the frequency of rejection by modulating the anti-donor immune response. We are now excited to have begun the process of testing the safety and feasibility of this new treatment approach in an early-phase clinical trial involving patients who will be receiving a second or greater corneal transplant at the Charité University Hospital in Berlin.
Development of the clinical trial protocol and procedures will be a major part of the VISICORT research agenda for the next 6 months. This will bring together expertise in therapeutic stromal cell manufacture at NUI Galway’s Centre for Cell Manufacture Ireland (CCMI); in early-phase clinical trial and regulatory affairs at Charité University Hospital and in clinical high-risk corneal transplantation at Charité, Aarhus University Hospital, Royal College of Surgeons of Ireland, University of Bristol and Centre Hospitalier Universitaire de Nantes.
Reflecting on the meeting, VISICORT coordinator, Prof. Matt Griffin of NUI Galway’s Regenerative Medicine Institute (REMEDI) commented: “It has been an exciting journey to reach the point at which we are now in a position to drive toward the major goals of the project that was conceived over three years ago. Our greatest resources have been the diverse expertise and, especially, the energy and collaborative spirit among the research teams that we have built at each partner site. I am greatly looking forward to keeping our momentum going in the same fashion over the next year so that we can deliver strongly on the promise of this project.”
VISICORT team members Prof. Matthew Griffin, Prof. Thomas Ritter and Dr. Siobhan Gaughan visited Prof. Uwe Pleyer at Charité in Berlin on Friday 17th February 2017.
A successful and informative meeting with the team from CRO Charité Research Organisation was held to progress the Clinical Trial work package. http://www.charite-research.org/en
The VISICORT team met in Nantes on Thursday 20 and Friday 21 of October, hosted by the INSERM team. The consortium enjoyed a very productive meeting. The team were particularly pleased to welcome two members of the VISICORT scientific advisory board – Prof. Miguel Soares of University of Lisbon and Principal Investigator at the Instituto Gulbenkian de Ciencia, Oeiras, Portugal and Ms. Rita Lawlor, founder and the project manager of the ARC-NET cancer research centre at the University of Verona, Italy.
The team reported the progress being made in each of the project’s workpackages and made plans for the next phase of the project.
There was also a little time to put a convenient foosball table to good use!
VISICORT was one of a number of projects discussed at the A FACTT meeting in Galway this week. A FACTT is an Action to Focus and Accelerate Cell-based Tolerance-Inducing Therapies, funded through the COST (European Cooperation in Science and Technology) Programme. The meeting is being hosted by NUIG and runs from 5-7 October.
VISICORT was strongly represented at the 7th annual congress of EU Cornea – the European Society of Cornea and Ocular Surface Disease Specialists – which was held at the Bella Center in Copenhagen between September 9th and 10th 2016.
In a focus session on “Immunology in Corneal Transplantation”, members of the VISICORT consortium gave individual presentations to congress attendees on key issues related to the project’s goal of increasing understanding of adverse immune responses to corneal allografts.
Prof. Matthew Griffin (NUI Galway, VISICORT Coordinator) presented a Keynote Lecture entitled “What has been learned from immunological profiling in kidney transplantation? “ in which he summarised developments that have occurred over the past 10-15 years in whole-genome microarray and peripheral blood immune cell profiling in the field of kidney transplantation. Emphasising the progress of these discovery-based profiling technologies towards novel diagnostic and prognostic assays for kidney transplant rejection and tolerance, he reflected upon the potential benefits of similar immunological profiling projects to future management of corneal allograft recipients at risk for rejection or chronic graft dysfunction.
Prof. Uwe Pleyer (Charité University Hospital, Berlin), in a presentation entitled “The role of immune-modulatory stromal cell therapy in prevention of corneal graft rejection”, described the emergence of mesenchymal stromal cells (MSCs) as an immunomodulatory therapy of potential value in preventing allograft rejection. He reviewed experimental evidence from animal model studies performed in the laboratory of Prof. Thomas Ritter (NUI Galway) and others that MSCs from unrelated (“third party”) individuals, delivered intravenously around the time of corneal transplantation module the anti-donor immune response to favour graft acceptance. He then presented the current progress of the VISICORT consortium toward a Phase 1 clinical trial at Charité University Hospital of third party MSCs in human corneal allograft recipients at high risk for rejection.
Mr. Derek Tole (University of Bristol and Bristol Eye Hospital, University Hospitals Bristol NHS Foundation Trust, UK) addressed “Immunosuppression in high-risk keratoplasty” with an emphasis on the outcomes and potential adverse effects associated with the use of the potent anti-rejection drugs tacrolimus and mycophenole mofetil in corneal transplant recipients with one or more risk factors for rejection. With reference to 5-year follow-up results from the Bristol Eye Hospital, he demonstrated the value of a dedicated immunosuppression clinic for maximising the long-term safety and efficacy of these agents in keratoplasty recipients.
Prof. John Armitage (University of Bristol and Bristol Eye Bank) summarised the recent results for one of the largest studies of the influence of tissue type (HLA) matching on corneal transplant outcomes in a presentation entitled “Conclusions of high-risk HLA matching study-CTFS II”. In a large cohort of allograft recipients from the UK, this study concluded that there was no clear overall benefit associated with higher degree of HLA matching. Interestingly, a sub-analysis of data for high-risk recipients compared with an historical control cohort suggested a possible benefit for matching at Class I HLA loci. However, as Prof. Armitage pointed out, further prospective research will be needed to determine whether HLA matching could provide a bona fide immunological advantage in high-risk corneal transplantation.
Commenting after the session, Prof. Jesper Hjortdal (EU Cornea Board Member and VISICORT partner, Aarhus University Hospital, Denmark) noted: “Improving corneal transplantation outcomes is one of the key-issues for the European Society of Cornea and Ocular Surface Disease Society (EuCornea). In-depth exploitation of immune profiles and development of new, safe immunolomodulatory therapies are promising ways to do this. Hopefully, the VISICORT project will bring corneal transplantaion significantly further, being able, on a patient level, to predict who will do well and target mechanistically-informed immunomodulatory therapy to those that have a higher risk profile”.
VISICORT took part in a poster session to mark the launch of Cúram’s €68m Centre for Research in Medical Devices at NUIG Galway.
Peadar Mac Gabhann, from VISICORT partner Biostór Ireland will be speaking at the World Biobanking Lisbon Summit in Lisbon, Portugal on the 9th & 10th February 2017. The summit brings together senior professionals from biobanking. The summit consists of moderated interactive sessions and panel discussions. Peadar will be presenting an overview of the VISICORT project.
More information about the Summit can be found here.
VISICORT researchers Nicolas Degauque and Sophie Brouard from INSERM UMR1064 and Université de Nantes (France) have recently published two articles which were supported in part through the VISICORT project.
A review of cross-reactivity of the TCR repertoire has been published in the Journal Frontiers in Immunology and looks at the implications of cross-reactivity for allotransplantation. The ability to track donor reactive T cells during organ transplantation can improve graft survival, prevent graft dysfunction and help in tailoring immunosuppressive treatment and is therefore of great advantage to transplant immunologists. However the vast size of the alloreactive T cell repertoire has hampered attempts in this area. The authors review progress in this area including the evolution of the concept of cross-reactivity of the TCR repertoire and the development of techniques to track anti-donor response. It is now expected that each T cell can recognise a large array of peptides (cross-reactivity) resulting in more efficient immunological protection for individuals. The necessity of TCR cross-reactivity is explored using allotransplantation as a functional and efficient example. The benefits of using low resolution techniques such as PCR and flow cytometry or high resolution techniques such as next generation sequencing to track anti-donor response via the TCR Vβ repertoire is also summarised in the review article. Effective donor-specific T cell tracking has not yet been translated to the clinical management of transplant patients despite advances in the area.
In a separate article, a brief communication published in the American Journal of Transplantation, the similarities and differences of three subsets of CD8 T cells were investigated from peripheral blood mononuclear cell (PBMC) samples of kidney transplant patients with stable grafts on standard immunosuppressive regimes. CD8 cells have long been implicated in transplant rejection and memory cells are considered one of the main hurdles in achieving transplantation success. Bearing in mind both assay functionality and limitations with flow cytometry techniques, it is important to choose the right CD8 markers for specific studies. The article reported on the use of CD45RA and CCR7/ CD27/ CD28 markers to identify CD8 subsets. The authors found that use of CD45RA and CD28 markers offer several benefits for characterisation of the CD8 compartment in kidney transplant patients including the identification of early and late differentiated Effector Memory CD8 T cells.
Speaking on the two articles and their relation to VISICORT Dr Degauque said “VISICORT represents a unique opportunity to compare the imprint on the immune systems induced by two different types of transplantations (Kidney or Corneal Transplantation), by looking at the selection of the TCR to the modification of the phenotype of T cells. The monitoring of large clinical cohorts requires the use of multi-colour flow cytometry panels in which the numbers of the tracked markers will define the accuracy of the depiction of the immune system. Using advanced multicolour panels, we aim to improve our understanding of the adaptive immune cells in corneal rejection and to identify biomarker of graft rejection in order to improve patients standard care.”
The full text of the article in Frontiers in Immunology can be found here. Work on VISICORT work packages 4 and 5 is continuing at INSERM UMR1064 and Université de Nantes.
VISICORT’s Connor Murphy talks to about the project.
This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no 602470. The material presented and views expressed here are the responsibility of the author(s) only. The EU Commission takes no responsibility for any use made of the information set out.