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Final Report Summary - MSC_GVHD_ENHANCE (Enhancement of mesenchymal stem cell therapy for graft versus host disease)

The MC CIG (321697) MSC_GvHD_Enhance project is focused on enhancing the therapeutic efficacy of mesenchymal stem cell (MSC) therapy for graft versus host disease (GvHD).

State of the art and project objectives
Steroid resistant acute GvHD is a very serious complication associated with allogeneic haematopoietic stem cell transplantation. There is no established consensus on therapy for this disease and patient prognosis is poor. Early reports of MSC therapy for acute GvHD involving small numbers of patients were promising, however, results from large phase III trials have questioned the therapeutic efficacy of MSC therapy for GvHD. Our hypothesis is that MSC require licensing (by pro-inflammatory signaling molecules, like IFN-gamma) for therapeutic efficacy in GvHD. This project addresses a number of very important and clinically relevant questions; Why are IFN-gamma licensed MSC more efficacious in the treatment of acute GvHD in pre-clinical models? What are the differences between licensed and unlicensed MSC that facilitates the enhanced efficacy? Can correlates of MSC therapeutic efficacy be identified and translated into the clinic?

Scientific Progress to date (End point of the study)
Using highly specialized tools (microarray), this study has identified a number of genes associated with immune modulation and cell migration, which are significantly increased in MSC following licensing with IFN-gamma. In vitro assays (tests performed in cells in the lab), have validated the increased expression and the function of these genes in licensed MSC.
We have developed a sophisticated humanized mouse model (a mouse with a functional human immune system) of Graft versus host disease. This model has allowed us to investigate the therapeutic efficacy of MSC and licensed MSC. We have demonstrated that licensed MSC but not resting MSC can prolong the survival of GvHD mice when administered on day 0 (the same day the mice receive human immune cells). Importantly, resting MSC were demonstrated to have the same therapeutic efficacy as licensed MSC when administered on Day 7 (1). In addition, the project has elucidated a number of mechanisms utilised by MSC to prolong survival in this acute GvHD model. MSC impaired CD4+ T cell proliferation, significantly reduced T cell production of TNF-alpha, reduced apoptosis and enhanced the number of regulatory T cells present in GvHD target organs.
This project has also investigated the bio-distribution (location in the body) of MSC and licensed MSC in the GvHD model with specific emphasis on GvHD target organs (liver, spleen and lungs). By utilizing novel whole mouse cryo-imaging technology (CryoViz) to examine differences in MSC bio-distribution in GvHD this study has shown a significant increase in MSC present in target organs in GvHD mice compared to healthy mice. Furthermore, this project has demonstrated that significantly increased numbers of MSC licensed with IFN-gamma migrate to GvHD target organs in comparison to unstimulated MSC. Utilising specific adhesion molecule inhibitors the project is currently investigating the role of MSC adhesion factors in this enhanced migration to GvHD target organs. It is hypothesised that this data will identify a biomarker assocaited with MSC migration to GvHD target organs.

Potential Impact and Socio-economic impact
This research is both internationally competitive and innovative in that no correlates have been identified for MSC therapeutic efficacy and the provision of such information would transform the field of MSC therapy for the treatment of GvHD.
MSC therapy is already in clinical trials for the treatment of steroid refractory GvHD. Currently, MSC therapy for GvHD is sub-optimal and this project focused on elucidating the mechanisms utilized by MSC in vivo in the inflammatory setting of GvHD. This knowledge of mechanism in conjunction with detailed information on MSC in vivo bio-distribution will allow us to enhance/optimize MSC therapy for GvHD. The findings generated thus far have demonstrated the enhanced migration of licensed MSC to GvHD target organs. Scientifically, these data (some published/un-published) add important new data to the field of MSC in GvHD research and may identify novel biomarkers associated with MSC therapeutic efficacy. Technically, the cryoviz technology is the first of its kind in Europe and is leading the way in terms of quantification of stem cell therapy in disease specific target organs. This technology has facilitated the investigation of MSC therapy down to the single cell level and therefore is highly innovative and novel to the field. In terms of commercial relevance, this GvHD model has the potential to provide a platform for the development of novel therapies for GvHD and in this context we have a couple of on-going industry sponsored projects. The societal impact of this project is also high, given that this project will contribute to the generation of a more optimal MSC therapy for aGvHD.

(1) Tobin LM, Healy ME, English K and Mahon BP. Human Mesenchymal Stem Cells suppress donor CD4+ T cell proliferation and reduce pathology in a humanised mouse model of acute Graft versus Host Disease. Clinical and Experimental Immunology. 2013 May;172(2):333-48.

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