The Changing Landscape of Chronic Graft vs. Host Disease - Episode 2

Role of Early Intervention in GVHD Treatment

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Dr John DiPersio discusses an early intervention approach to the management of chronic and acute GVHD.

John DiPersio, MD, PhD: My feeling about how to intervene for both of these diseases is that for acute GVHD [graft-vs-host disease]—that initial recognition of the antigen and the expansion of the donor T cells—if you want to prevent severe GVHD, you’ve got to intervene relatively early, not late. For chronic GVHD, the initial defect is occurring early on. The stem cells that become T cells in the recipient are educated in the peripheral lymph nodes and the thymus of the recipient. Even though the thymus is involuted in adults, it still functions a little. That process of clonal deletion, peripheral tolerance, or central tolerance is abnormal because the cells that do that selection have been damaged.

What cells damage those? It turns out those are donor T cells. There’s a lot of evidence in the mouse that the cells that damage the organs, which are responsible for differentiating stem cells into T cells and proper clonal deletion, are the T cells of the donor. You have to prevent the donor T cells from damaging those specialized tissues in the thymus and the peripheral lymph nodes of the recipients. Otherwise, the stem cells that come into the recipient are going to be made, and a lot of autoreactive T cells are going to come out the back end. They’re going to engage B cells, and you’re going to get this autoreactivity and alloreactivity, which we define as chronic GVHD.

My bias is that all these treatments to intervene late in the process of these diseases can only keep a lid on something that’s already 90% out of the bag. That’s the best we can do. That’s what we see in a lot of these treatments. They modify the disease but don’t prevent the disease. If you want to prevent it, you might have to start thinking about earlier interventions. That’s been my pet peeve with testing a lot of the reagents in GVHD. We give them too late, and they have a very minor temporizing effect. With earlier treatments, they may have a bigger effect.

The problem with earlier treatments is people worry that that would result in a reduction in graft-vs-leukemia. That can be tested only in randomized clinical trials.

Transcript Edited for Clarity