The Changing Landscape of Chronic Graft vs. Host Disease - Episode 1

Overview of Graft vs Host Disease (GVHD)

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John DiPersio, MD, PhD, and Michael Bishop, MD, define acute and chronic graft-vs-host disease (GVHD).

John DiPersio, MD, PhD: My name is John DiPersio, and I’m from Washington University School of Medicine in St. Louis, Missouri, and I’m the chief of the division of oncology and the deputy director of the Siteman Cancer Center at Washington University. I’m going to be working with my colleague Mike Bishop from The University of Chicago Pritzker School of Medicine. He’s the head of the transplant and cellular therapies program at the University of Chicago.

We’re going to be discussing some of our viewpoints of diagnosis and management of acute and chronic graft-vs-host disease [GVHD]. As an introduction, for those of you who take care of patients who are undergoing transplantation, and those of you who have referred patients to transplant centers, you’ve had the opportunity to see how complicated and devastating graft-vs-host disease can be. You’ve probably also been exposed to a number of relatively new treatments that have emerged over the past several years for the management of both acute and chronic graft-vs-host disease.

The way I would describe graft-vs-host disease is that it’s a disease in which the donor T cells recognize host antigens as nonself. When you think about it, what’s the recognition? The recognition is that donor T cells must see some antigen expressed on host tissues that’s different from what that donor T-cell has been developed to see itself. That usually means it’s a different HLA [human leukocyte antigen] antigen and a different minor histocompatibility antigen. Or it’s simply a different minor histocompatibility antigen where the donor and recipient are matched so that the sequence of the HLA of the donor and recipient are the same, and the recipients express a host antigen that’s recognized by the donor T cells. That host antigen is expressed in the context of host HLA, either class 1 or 2.

That minor histocompatibility antigen could be a single nucleotypic polymorphism from any protein— beta-2 microglobulin, albumin. We all have different SNPs [single nucleotide polymorphisms] that we’re born with that are encoded in chromosomes, aside from the chromosomes, and encode the HLA locus, and these protein-specific differences are unique to each of us. Even though you may have a match sib that’s a DNA identical to you at the HLA locus, the minor histocompatibility antigens will be different, and they can be presented in the context of antigen-presenting cells of the host so that the T cells of the donor can recognize them and cause a reaction that results in graft-vs-host disease.

There are many theories about which T cell is the most important and which T cells contribute most of the pathology of acute graft-vs-host disease. To simplify it, acute GVHD is best defined as this allogeneic reaction—donor T cells reacting against host, major and minor histocompatibility antigens in which the T cells are contributing to the illness.

With chronic GVHD, these are passively transferred T cells that have already seen antigen and are primed in the donor. They can see these antigens in the host as nonself. Chronic GVHD is due to T cells again, but instead of coming from the donor T cells, they come from donor stem cells. Normally, when you do a transplant—in a mouse, for instance—the stem cells become T cells. But when they become T cells, they lose their ability to recognize self-antigens. In a recipient animal, those allogeneic-reactive T cells are deleted. It’s called clonal deletion, central deletion, or anergy.

In the context of chronic GVHD, what we think is happening is that some T cells that are normally deleted to the host antigens leak out. They leak out over time. The T cells that are generated from the host, from the donor stem cells, engage B cells and induce this B-cell reaction. You have B-cell proliferation, B-cell activation, and the production of antibodies. Some of those antibodies can result in antibodies that bind to host tissues and cause disease.

To simplify that, acute GVHD—whether it happens a week after transplant, a month after transplant, or 3 years after transplant—is due to the maturity cells that come from the donor graft. Initially, chronic GVHD is due to the T cells that are leaking out of the host from the donor stem cells that are not appropriately clonally deleted. Those T cells recognize a host as nonself, and they engage B-cells, and you get this combined effect of T-cell reactivity and B-cell reactivity, and you get a disease called chronic GVHD. If it’s mostly B cells, autoimmune B cells, and autoimmune antibodies, you get a very pure B-cell–appearing disease like scleroderma, or a patient who has a mixed connective tissue disease.

If you have more of an inflammatory component, it’s mostly because of T cells that are still around. That’s what’s called an overlap syndrome. An overlap syndrome would be somebody who has a bit of acute GVHD from residual donor T cells that are still reacting to host APCs [antigen-presenting cells] and minor histocompatibility antigen. These new T cells from the donor stem cells are improperly clonally deleted and are autoreactive that engage B cells, and you have this mixed T-cell alloreactivity and B-cell autoreactivity, so you get this mixed overlap syndrome.

That’s the way chronic GVHD and acute GVHD work. We’ve never worked this out completely in humans, but through a number of experimental models in the mouse, this is the best model to think of the physiology of acute and chronic GVHD. When you see someone a year after transplant, and they look perfect, you taper their immunosuppression. They get a very red rash and some diarrhea from those donor T cells that came in from the graft initially and stuck around all that time and were reactivated.

But if someone has an esophageal dysplasia or pulmonary toxicity, that’s most likely because of T cells developed from the stem cells of the donor in the peripheral lymph nodes in the thymus of the recipient, which are improperly clonally deleted and so they engage B cells. The B cells make antibodies, and you get this disease, which is akin to either a mixed connective tissue disease or a sclerodermatous-like illness. That’s chronic GVHD.

Transcript Edited for Clarity