Presidential Symposium – Monday 31 August, 14:30 – 16:00H, Auditorium 1
EBMT 2020 Basic Science Award: Antonia Müller
This year’s basic science award goes to Antonia Müller of University Hospital Zurich, for her study “JUN activation in dermal fibroblasts promotes fibrosis and inflammation in sclerodermatous graft-vs-host disease in mice and humans”.
To view Antonia’s winning abstract, see: https://www.professionalabstracts.com/ebmt2020/iPlanner/#/presentation/777
Q: Congratulations on receiving this year's basic science award Antonia. How did you feel when you received the news?
A: Thanks! We were very excited when we learned that our work has been selected for this prestigious award. We feel honoured not only because of this truly collaborative effort but also feel that this award is an appreciation of the unmet clinical need in treating patients with chronic graft-versus-host disease.
Q: Can you tell our delegates a little about you. Where are you based, and the specialist areas that you work in?
A: Currently, I am a transplant and CAR-T physician at the University Hospital in Zurich, where one of my clinical focuses is running a chronic GvHD clinic. Before I moved to Switzerland, I spent more than 6 years as a postdoc in Judy Shizuru’s lab at Stanford where I studied blood formation, immune function and graft-versus host disease in preclinical transplant models.
Q: Tell us about the background to your study?
A: During my time at Stanford I studied many different mouse models for their clinical manifestations of chronic GvHD. In fact – this is a pretty challenging task, as there are few models that resemble a) transplant conditions, and b) clinical features of GvHD that actually resemble the scenario as observed in humans.
By chance we discovered a model with impressive sclerodermatous skin changes. This is when we teamed up with Gerlinde Wernig and her group in the Institute for Stem Cell Biology and Regenerative Medicine at Stanford. She has a long history of studying fibrogenesis in the context of different diseases, including myelofibrosis, pulmonary fibrosis and other conditions. Her group recently described the impact of the transcription factor JUN in end-stage fibrotic diseases. She showed that induction of JUN in mice was sufficient to induce severe fibrosis in multiple organs, and her data suggested that JUN is a central molecular mediator of most fibrotic conditions.
Having a preclinical model and a tissue bank of sclerodermatous GvHD lesions, plus a clinic with patients suffering from this condition post-allogeneic transplant with an unmet need of therapies, it was obvious we should examine the role of the transcription factor JUN in chronic GVHD.
Q: What were the main findings of the study?
A: First, we went back to our tissue bank of sclerodermatous skin lesions from mice that we had collected in the previous years and examined whether sclerodermatous GvHD was associated with JUN activation. We observed a strong expression of JUN in the disease, but not in controls without GvHD.
Next, we studied archived samples from human tissues from the pathology department and confirmed that also human sclerodermatous GvHD lesions have a very strong JUN expression.
After that, we obtained fresh material from GvHD patients who were biopsied in their skin lesions and studied chromatin accessibility for JUN and some downstream immune regulators. We found that JUN regulates the immune mediators CD47 and IL-6 as well as members of the hedgehog pathway.
Finally, we implanted fresh human skin cells from patients under the kidney capsule of immunocompromised mice to study features of their cells in vivo. Such xenograft models of sclerodermatous GvHD also allows testing different agents targeting pathway members downstream of JUN and their capacity to resolve manifested scleroderma.
Q: What are the implications of the findings going forward?
A: Our studies identified a new profibrotic signature for sclerodermatous chronic GvHD that presumably can result from different chronic inflammatory conditions. We believe this is important to ultimately treat the disease, as it is unlikely that targeting just one graft cell type (such as T cells or B cells) would be able to resolve established tissue fibrosis. We hope that targeting a profibrotic process downstream of JUN may help to better treat scleroderma in patients in the near future.
Thanks Antonia, and many congratulations to you and your collaborators for receiving this award.