The VISICORT team meets in Nantes

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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!

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VISICORT discussed at A FACTT meeting

screen-shot-2016-10-06-at-19-33-02VISICORT 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 Partners Present at 7th EU Cornea Congress in Copenhagen

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.

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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.

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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.

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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 represented at the launch of Cúram’s €68m Centre for Research in Medical Devices

VISICORT took part in a poster session to mark the launch of Cúram’s €68m Centre for Research in Medical Devices at NUIG Galway.

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VISICORT at the World Biobanking Lisbon Summit

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.

New VISICORT research published

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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 features in The Consultant

VISICORT’s Connor Murphy talks to about the project.

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VISICORT Plenary, Dublin

The VISICORT consortium gathered at the Royal Victoria Eye and Ear Hospital in Dublin on May 26th and 27th to attend the fourth bi-annual VISICORT plenary meeting. Hosted by Prof. Conor Murphy and Diana Malata from the Royal College of Surgeons, and attended by representative from each project partner, the meeting was an opportunity to present and review progress on all project work packages. There was also an opportunity to focus on three pivotal project areas: Clinical Trial Design and Progress; Sample Collection and Processing and Proteomic and Transcriptomic Data Analysis.
Prof Murphy emphasised project progress thus far noting “it was my pleasure to welcome my colleagues from the VISICORT consortium to Dublin for this Plenary meeting. It is clear that significant progress is being made across all aspects of the project. In particular, data from the pre-clinical work is contributing greatly to the optimal design of the clinical trial of immunomodulatory stromal cells in high risk corneal transplantation which will commence in 2 years’ time. We look forward to making continued progress towards the identification of corneal transplant outcome biomarkers and higher success rates for transplant recipients in the future”

VISICORT project coordinator, Prof. Matthew Griffin of the Regenerative Medicine Institute (REMEDI), National University of Ireland, Galway added: “With VISICORT now reaching its two year time-point, our recent all-partner meeting in Dublin provided an excellent forum for reviewing our progress across a range of project strands including pre-clinical experiments, human subject bio-sampling, technological/logistical protocols, clinical data capture, development of a clinical trial protocol and dissemination activities. Among the achievements to date, the consortium has been very successful in building large cross-sectional and longitudinal patient cohorts linked to a centralised biological repository that is integrated with a clinical database. As a result, we are now entering the exciting phase of performing a range of profiling- and bioinformatics-based analyses to identify immune signatures of corneal transplant rejection and other complications.”

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STEM CELL REVOLUTIONS documentary screening, NUI Galway

Featuring beautiful hand-drawn animations and interviews with leading stem cell scientists, STEM CELL REVOLUTIONS charts the history and scientific evolution of stem cell research – from the earliest experiments that first revealed stem cells in the body, to leading current scientific and clinical developments. Watch the trailer here

Question & answer session to follow led by Profs Tim O’ Brien and Matt Griffin

WHEN
WHERE
Clinical Science Institute (CSI) Lecture Theatre – Costelloe Road NUI Galway, H91 YR71 Galway – View Map

For more details and to book tickets click here.

 

Bigger, Bedouins, and a blind gazelle – Ireland’s contribution to corneal transplantation

VISICORT is an Irish-led European project, which is carrying out groundbreaking research that will help to improve the outcomes of corneal transplantation. This is not the first time that Ireland has led the field in corneal transplantation. In fact, the first recorded successful experimental corneal allograft was carried out in the early 19th century by Samuel Bigger, an Irish ophthalmic surgeon.

Bigger’s surgical breakthrough took place in unusual circumstances. While travelling in Egypt in 1837, he was captured and held for ransom by a Bedouin tribe. For the intrepid Dr Bigger, a period of captivity in the Egyptian desert was an opportunity for, and not an obstacle to scientific discovery. A footnote to his article ‘An Inquiry into the Possibility of transplanting the Cornea’, published in the Dublin Journal of Medical Science in 1837 laconically reports his success:

The first time Dr Bigger had an opportunity of trying this experiment on one of the inferior animals, occurred in 1835, at a period when he was a prisoner with a Nomadic tribe of Arabs, about twelve or fourteen day’s journey from Grand Cairo. The subject of the operation was a pet gazelle, who had lost one eye from inflammation, and the power of seeing with the other, from a wound of the cornea. The cornea was taken from another animal of the same species, brought in wounded, but not quite dead; adhesion took place, and ten days after the operation the animal gave unequivocal signs of vision, the upper part of the transplanted cornea remaining perfectly transparent.

On his return from Egypt in November 1835, Bigger continued his experiments with rabbits, and continued to refine his approach, adjusting the knife used, the position and number of sutures, and the post-operative treatment of the animals.

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The title of Bigger’s article, as it appeared in the Dublin Journal of Medical Science

Bigger’s work followed on from the research of Johann Dieffenbach (1792–1847), whose disappointing results led him to conclude that keratoplasty was ‘an audacious fantasy’, which would never be achieved. Bigger’s success reinvigorated efforts to successfully carry out corneal transplants into humans. In 1838, Robert Sharp Kissam attempted the transplant of a pig’s cornea into the eye of a young man who was practically blind as a result of a leucomatous cornea. The graft was initially successful, but became opaque after 2 weeks.

Throughout the remainder of the nineteenth century, numerous efforts to achieve a successful corneal allograft in humans continued. These all ended in disappointment, until 7 December 1905 when the Austrian surgeon Eduard Konrad Zirm (1887–1944) performed the first successful penetrating keratoplasty in a human where the graft remained clear. A cornea from an 11-year-old boy who had been blinded by a penetrating scleral injury, was transplanted into the eye of Alois Glogar, a 45-year-old labourer, who had been blinded by severe alkali burns. Zirm’s success proved difficult to replicate – and after reporting the first successful transplant, Zirm himself did not publish any other work on keratoplasty.

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4 Eduard Zirm and his patient Alois Glogar

Over the first half of the twentieth century, significant contributions to the development and refinement of keratoplasty techniques were made by a number of prominent ophthalmologists, and an infrastructure for the donation of corneal tissue was established in Europe, the United States, and beyond.

Dramatic technical improvements have been made since Dr Bigger took his scalpel to the Egyptian gazelle. But, in spite of these developments, corneal allograft rejection continues to be the greatest limitation in corneal graft survival. VISICORT’s research addresses this challenge directly, and will provide a clearer understanding of the mechanisms of corneal rejection and new clinical tools and therapies to improve the outcomes of corneal transplantation. Dr Bigger would have approved!

Mark Sweetnam

You can find a more detailed history of corneal transplantation here.