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EBMT 2021 Annual Meeting - Basic Science Award


EBMT 2021 Basic Science Award: Duc-Dung Le

GS2 Presidential Symposium - Monday, March 15, 14:30 - 16:00, Auditorium 1 

This year’s basic science award goes to Dr Duc-Dung Le of University Hospital Würzburg, Germany for his study “Host intestinal tissue resident macrophages protect against murine intestinal acute graft-versus-host-disease.”

To see the winning abstract, go to:

Q: Congratulations on receiving this year's basic science award Duc-Dung! Can you tell our delegates a little about you. Where are you based, and the specialist areas that you work in? 

A: I am a postdoctoral researcher at Andreas Beilhack’s Lab at the Department of Medicine II at Würzburg University Hospital in Germany. Originally, I am from Vietnam. I moved to Germany for my undergraduate study and then PhD. I have specialised in immunology and immunotherapy. Our very international research team focuses on dynamic immune cell interactions after allogeneic hematopoietic cell transplantation. We use preclinical models to identify novel therapeutic targets for GvHD as well as for cancer and infectious diseases in patients undergoing allogeneic hematopoietic cell transplantation.

In one of my research projects we investigate the role of radio-resistant host intestinal macrophages in acute GvHD. Our project is embedded in a research consortium between three universities in Germany - Würzburg, Regensburg and Erlangen.

Q: Tell us about the background to your study?

A: Acute GvHD is a complication in patients undergoing hematopoietic cell transplantation. It affects 30 – 50% of these patients. 14 % of the patients develop even severe forms of acute GvHD, which are life-threatening. Acute GvHD has a huge impact on the quality of life of patients and remains a leading cause of mortality.

Acute GvHD is mediated by donor T cells infused into the recipient. In the initiation phase of acute GvHD, donor T cells will be activated by host antigen presenting cells in lymphatic tissues, such as lymph nodes and the spleen. Then, there is a striking phenomenon about acute GvHD: once alloreactive donor T cells are activated, they predominantly attack certain tissues, namely the gastrointestinal tract, the liver and the skin. This causes tissue damage and inflammation. Why T cells attack these particular organs and cause such a massive immune response is not really understood.

To better understand what’s going on during the effector phase in this immune response we turned to mouse models of GvHD and made quite a startling observation: during this acute GvHD-effector phase - this is the time when the freshly activated donor T cells migrate into the gut mucosa and start to attack healthy tissues in the intestinal tract – and we observed in mouse models for aGvHD that almost all infiltrating donor T cells colocalised with myeloid cells.

Even days after irradiation, it turned out that these myeloid cells were radio-resistant and originated from the recipient and not from the donor. This striking observation immediately opened a lot of questions. Our first and immediate thought was that these radio-resistant host-type myeloid cells within the intestinal tissues may be essential to lure pathogenic T cells into the intestinal tract. We even speculated that these cells could be essential to further enhance GvHD and could be the reason for persisting GvHD in the gut.

Our initial observation and all these ideas prompted a series of functional experiments in the research lab – and these turned into truly humbling moments as all our initial hypotheses and predictions proved wrong.  But, of course, as you can imagine, this made this project for us even more exciting and we started to dissect layer by layer what’s going on!

Q: What were the main findings of the study?

A: First, we found that the radio-resistant host myeloid cells in the intestinal tract were not pathogenic but, on the contrary, protected from acute GvHD. So, for example if you specifically deplete these cells with different techniques, acute GvHD immediately spins out of control, alloreactive T cells get hyper-activated, more inflammatory cytokines are released, more T cells are recruited, tissue damage follows and within a short time period you end up in a fatal situation.

Now, it had become clear that these cells are not triggers of but, instead, protect from acute GvHD. This immediately begged the question whose are these radiation resistant host myeloid cells? Where do they come from? This was of course essential to know if we would like to enhance the function of these cells to prevent or cure acute GvHD.

In short, we found out that these are tissue resident cells in the intestinal tract - that they are special intestinal macrophages and that they originate from embryo-derived and bone marrow-derived progenitors.

Next, we wanted to know how these cells regulate alloreactive T cells and why are they so essential to prevent intestinal GvHD. Again, there were many mechanisms conceivable. We were struck that the expression of PD-L1 on these radiation resistant intestinal macrophages appeared to be critical to control alloreactive T cells.

PD-L1-PD-1 was shown before to be an important regulator also of alloreactive T cells. But now it seems that we identified the dominant cell type that uses this pathway in controlling intestinal GvHD. As a matter of fact, when we started to investigate biopsies from transplantation patients together with our clinical colleagues we found that the specific lack of PD-L1 expressing intestinal macrophages clearly correlated with acute GvHD.

This emphasizes the importance of this intestinal macrophage population also in the clinical situation. It also shows to us how really important it is to do comparative studies and how important it is that basic researchers work closely together with clinical scientists.

Q: What are the implications of the findings going forward?

A: Our findings that host type tissue resident macrophages persist even longer time periods after transplantation and that they are so important to control alloreactive T cells highlight several issues.

First, we need to understand how we can foster their function, which is of course very relevant from a therapeutic perspective. To do this, we need to better understand what are the triggers that they differentiate into this phenotype and acquire their functions. Developing strategies to boost these cells could truly benefit patients.

Then we want to know whether similar tissue resident cells can control alloreactive T cells in other tissues. As mentioned, it is remarkable that acute GvHD dominates in certain tissues, but usually is not apparent in other organs, such as the pancreas or the thyroid gland.

Of course, we would also like to understand, how these cells differ from macrophages in the tumor microenvironment.

This brings me back to how important international and interdisciplinary research is. Together, we can tackle these challenges. Be it within our wonderful DFG research consortium, where we dissect mechanism of GvHD and graft-versus-leukemia responses or be it at the EBMT meeting, where we exchange our newest results and ideas, which ultimately will benefit our patients.

Q: Will you have the chance to view many sessions at this year’s EBMT meeting? What will be some of the highlights for you?

A: Definitely, this year provides the great opportunity to follow talks in different – even in parallel sessions. As difficult and challenging the COVID-19 pandemic is for all of us, in the virtual meeting we can easily and quickly join different sessions.

Beside the basic studies, I am very much interested in the clinical sessions to learn more about inovative therapy, recent findings and issues in the treatment of blood diseases and in hematopoietic cell transplantation as well. Therefore, the sessions of hematopoietic cell transplantation, cellular and immuno-therapy and experimental transplantation will be in my focus.

Thanks Duc-Dung, and many congratulations to you and your collaborators for receiving this award.

Watch the EBMT TV interview