Analyzing Risk Factors for Acute and Chronic Graft-Versus-Host Disease

Ernst Holler, MD, University Medical Center Regensburg, Regensburg, Bavaria, Germany, provides insights into the latest data on the risk factors for the development of acute and chronic graft-versus-host disease (GVHD), including human leukocyte antigen (HLA) matching, the presence of certain microbiota, and age of the patients. 

Transcript:

Welcome. I'm Professor Ernst Holler. I'm working at the University of Regensbug in Germany. I am a hematologist oncologist, and I was the former leader of the stem cell transplantation unit. Now I'm working as a research professor on questions of GVHD, translational research in GVHD. 

I have been engaged in GVHD [research] since almost 1982, working on the pathophysiology and new treatment concepts and new prophylaxis concepts. And this is my pleasure today, to talk about risk factors, concepts of risk factors of acute and chronic GVHD.

Now, if we talk about GVHD, we have to be aware that the central event is activation of donor T-cells from a different donor by recipient antigen-presenting cells. This is the center of GVHD. You always need a donor which is genetically different to the recipient, and you need immunocompetent T-cells of the donors. This concept was already established in the [1960s] by Billingham formulating the requests for GVHD.

We have to think about factors which contribute to this activation of these 2 cell populations. On one hand, of course, T-cells play a role. So if we transplant, for instance, peripheral blood stem cells, we have a higher number of T-cells than bone marrow cells. And correspondingly, there is a higher incidence of chronic GVHD. 

The age of the patient is a risk factor. So, very young patients have less acute and chronic GvHD than older patients. And this has been explained by the attack of the donor T-cells against the recipient's thymus. Young people can recover thymic functions, but older patients are unable. And so, the donor T-cells cannot acquire tolerance. So, the major risk factor for GVHD is HLA-difference.

If you have donors, from non-related donors, and they have different HLA genes, then you get 100% [incidence of] GVHD. That's the reason why transplantation is either done with conventional immunosuppression by HLA [identical] siblings or by HLA matched unrelated donors. There's also GVHD within siblings, and this is explained by so-called HLM minor antigens. For instance, if a male patient receives T-cells from a female donor, then this female immune system recognizes minor antigen as associated with the Y chromosome. That's why [this] induces more GVHD. 

We have been now on the T-cell side, and there are also risk factors on the antigen-presenting side. Antigen-presenting cells need to be activated, and one mechanism that these cells are stronger activated is conditioning-induced inflammation, so, very intense conditioning induces more GVHD.

And in the last years, there was an additional concept recognizing that the microbiota sitting in in the gut, in the skin, are contributing to activation of antigen-presenting cells. In former times, we were all only thinking about [lipopolysaccharide bacteria] LPS, but we now know that we have millions of different bacteria which can send signals to immune cells and contribute to activation. And this is another factor, recognized as a risk factor of GVHD.

These main factors explain acute GVHD, but they also contribute to chronic GVHD, because chronic GvHD is a continuum arising from acute GvHD. Mainly arising by thymic damage, as I already mentioned, but also by damage to other niches of the immune system. B-cells are hyperactivated in chronic GVHD. Again, acute damage to the B-cell niche contributes to chronic GVHD. This would be major risk factors of GVHD. Thank you for your attention.