Understanding the Pathophysiology of Acute and Chronic GVHD


Yi-Bin Chen, MD: Let’s talk about graft versus host disease [GVHD] himself. Nelson, can you briefly tell us about the symptoms of acute GVHD and what we think is the pathophysiology behind it?

Nelson J. Chao, MD, MBA: We know it’s a mutated T-cell disease, so if you do extensive T-cell ablation, you don’t see it. Of course you end up with non-transplantation and relapse issues if you don’t have T-cells either, but that’s mediated by T-cells. It depends on T-cell recognition of allogeneic peptides presented by the CMH [major histocompatibility complex]. In the acute setting, it’s much more of an acute inflammatory response, which isn’t much different from the cytokine release type symptoms where you end up having significant damage to your gut, skin, and gut. liver. We think it’s the gut microbiota that causes the donor T cells to be activated, and then from the gut they could go to the other organs, but it’s mainly a disease of the skin, the intestine and liver. However, we can also sometimes see CNS [central nervous system] disease and lung disease.

Yi-Bin Chen, MD: I think we have all accepted this form of pathophysiology for acute GVHD. I think the discussion around the pathophysiology of chronic graft versus host disease is a bit more complicated. Hana, can you briefly tell us about the symptoms of chronic graft versus host disease? What do you think of in terms of pathology there?

Hana F. Safah, MD: You’re right. Exactly. There is a big difference between how the patient presents with acute GVHD and those who present with chronic GVHD. For those with a chronic condition, I usually like to tell them to expect something like an autoimmune disease, where symptoms can come on slowly. We don’t have that kind of angry reaction that we see with a sharp rash all over and it’s angry and red. For chronic conditions, you see changes in the skin such as sclerotic changes, then this will progress to damage to the joint, with limited range of motion. Some patients come because they can’t do the work they used to do. For example, if the patient is a hairdresser and he can no longer use his hand as before, or if he has dry eyes, dry mouth or perhaps mouth ulcers; these are usually the symptoms. You’ll see mucocutaneous symptoms, then when you start looking at other organ damage, you might see liver damage. Usually patients also have weight loss. Whenever a patient starts complaining of weight loss, I always think it is chronic GVHD. The interesting part is that chronic GVHD can mimic anything, so when I see a patient who has had a stem cell transplant in the past and comes in with a strange symptom, I think of chronic GVHD. I have had patients with nephrotic syndrome who presented with chronic GVHD. The mechanism is somewhat different from acute GVHD, but it is related. It starts in the intestine, with the activation of T cells, and then we have the loss of the thymus with the dysregulation of the immune system. It causes less TREX [Three prime repair exonuclease 1]

also, and then we have these follicular helper T cells in the lymph nodes that are related to the expansion of these aberrant B cells. I think B cells play a very important role when it comes to chronic GVHD. These aberrant B cells are anti-host B cells. They evolve into plasma cells which secrete these antibodies, so here is the humeral effect of chronic GVHD, then comes the activation of the macrophage, the fibroblast, and we end up with the fibrotic part of chronic GVHD. That’s what’s making our patient sick. When you think of these phases, you are trying to stop it before it reaches the final part, or the third phase, of GVHD. This phase is also known as the fibrotic phase because it carries the burden of symptoms and diminished quality of life, whether physiological or functional. I hope to have been clear.

Yi-Bin Chen, MD: I think it’s clearly unclear because there are so many pathways involved. It is a very heterogeneous disease that can involve almost any organ. Due to the multiple pathways involved, therapy has shifted to target some of these pathways which we will discuss.

Transcript edited for clarity.