Graft-versus-host disease

Definitions & Key takeaways

Graft-versus-host disease (GVHD) is an immunological reaction associated with transplantation, which occurs when T cells in the graft tissue react against the tissues of the graft recipient. It is commonly seen in hematopoietic stem-cell transplantation recipients and presents with symptoms like skin rashes, diarrhea, and liver damage.

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Introduction0:00–0:22

With “graft-versus-host disease”, “graft” refers to a section of transplanted, or donated tissue, like bone marrow or peripheral blood, and “host” refers to the tissues of the person receiving the transplant.
In this disease, immune cells in the donated tissue attack the recipient’s body cells. Normally, the immune system’s job is to fight against anything foreign that might cause harm, without harming the body’s own cells.

Physiology0:22–2:19

To make that work, the immune system cells are trained early on to distinguish the body’s own cells called “self” cells from foreign cells called “non-self” cells.
Recognizing whether a cell is foreign or not involves a set of genes called histocompatibility genes, which make up the major histocompatibility complex, or MHC proteins.
These MHC proteins also go by the name human leukocyte antigens, or HLA. The histocompatibility genes actually code for two classes of proteins, MHC class I and MHC class II.
MHC class I molecules are found on all nucleated cells throughout the body, while MHC class II molecules are only expressed on antigen presenting cells like monocytes, macrophages, dendritic cells, and B cells.
But because the genes coding for them are so variable in the population, two different individuals will have major differences in the antigens expressed on their cells, even siblings - unless, of course, they’re identical twins.
When surgeons do a tissue transplantation, the transplant usually comes from a different person with different genes, and it’s called an allograft.
If there are immune cells within that allograft, they will see the MHC proteins that coat every cell of the recipient body as foreign.
In fact, that’s why transplantation donors are really carefully selected, to make sure that they share as many of the same HLA antigens with the host as possible.
But even between HLA-identical individuals, other antigens, called minor histocompatibility antigens, can be recognized as foreign and trigger an immune response between the donor and the recipient.

Pathophysiology2:19–6:02

In graft versus host disease there are three key elements. First, the graft must contain immune cells.
This is usually the case in hematopoietic stem cell transplantations, which contain hematopoietic stem cells that can give rise to all types of blood cells, including immune cells.
Hematopoietic stem cell are derived from bone marrow which is the spongy tissue inside some bones, where new blood cells are formed.
Alternatively, hematopoietic stem cells can come from the peripheral blood or umbilical cord blood from a newborn baby. Typically hematopoietic stem cell transplantations are needed by individuals whose own bone marrow doesn’t function properly, for example, those suffering from leukemia.
The second element is that the host’s immune system must be suppressed so that it doesn’t destroy the grafted immune cells - giving the grafted immune cells enough time to mount an attack.
The final element is that the host must be immunologically different from the donor. In other words, the host’s histocompatibility antigens, mainly the HLA antigens, must appear as foreign to the grafted immune cells.
So, shortly after transplantation, the host’s dendritic cells which usually hang out in various host tissues, like the lining of the skin - might pick up antigens from that tissue and travel to the nearest lymph node, where a lot of the immune cells coming from the donor live.
So, that’s where they meet with helper T-cells and present those antigens upon their MHC class II molecules. If the donor helper T-cells recognize these antigens as foreign, they differentiate into type 1 helper T-cells, or Th1 cells.
Th1 cells then start releasing the cytokines interleukin-2 and interferon-gamma, which help both them and other T cells in the area proliferate.
At the same time, these cytokines induce the expression of more MHC class II molecules on the surface of the host’s cells, which makes it easier for the donor’s helper T-cells and host’s antigen-presenting cells to interact with each other.
Interferon-gamma also activates phagocytes, like macrophages which release pro-inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1, and interleukin-6 which recruits more immune cells to the area.
Activated macrophages also secrete lysosomal enzymes, which directly damage tissue. In addition to helper T-cells, there are also grafted cytotoxic T-cells circulating in the area.
These cytotoxic T-cells recognize antigens presented upon MHC class I molecules, which are on the surface of all nucleated cells in the host’s body.
As before, if these antigens are seen as foreign, the cytotoxic T-cells get activated and start secreting perforin and granzymes.
Perforin will perforate the target cell by forming pores and these pores will allow the granzymes to enter the cell. Once inside, the granzymes induce apoptosis, or programmed cell death.
Apoptosis is also induced by the interaction between a Fas molecule expressed on the surface of the target cell and a protein, called Fas ligand, expressed on the surface of cytotoxic T-cells.
This interaction triggers a cascade of signaling events inside the target cell, eventually causing apoptosis. Overall, the combined actions of helper and cytotoxic T-cells results in extensive injury of one or more tissues throughout the body.

Symptoms6:02–7:48

Now, the symptoms of graft-versus-host disease vary widely, depending on the type of tissue affected. And it’s not known why some types of tissues- usually the skin, liver, and digestive tract, are affected more frequently and more severely than others - and why there is a correlation with time after the transplant.
In the first three months following transplantation, there’s the acute form of the disease, which typically involves the skin.
It causes a painful or itchy rash on the palms of the hands or soles of the feet that can peel or blister and progress to covering the whole body.
After the skin, the next most common target is the liver, where the disease is usually asymptomatic, but leads to an elevation in bilirubin, alkaline phosphatase, and aminotransferases- like ALT and AST.
Acute graft versus host disease can also involve other parts of the digestive system, particularly the distal small intestine and colon, causing diarrhea, intestinal bleeding, and abdominal pain.
If graft-versus-host disease persists for more than 3 months following transplantation it’s considered chronic. Once again, the skin is most commonly affected chronically, and it can cause the skin to thicken.
It can also affect the eyes and lacrimal glands, causing a burning sensation and photophobia, or difficulty tolerating bright light.
Chronically, the proximal digestive tract can also be involved, particularly the mouth and salivary glands, causing dry mouth, sensitivity to acidic or spicy foods, and odynophagia or pain when swallowing.
Less frequently, chronic graft versus host disease can affect the lungs, causing shortness of breath and cough, and the muscles, causing muscle cramps and weakness.

Diagnosis7:48–8:09

Diagnosis of graft versus host disease is primarily based on signs and symptoms - like a skin rash. Lab tests, such as liver function tests, and imaging studies, like liver ultrasound, are often useful to assess the damage caused to specific organs.
Finally, a tissue biopsy of the affected organ can help confirm the diagnosis. Treatment for both acute and chronic graft-versus-host disease is intravenous glucocorticoids, to suppress the T-cell-mediated immune response.

Treatment8:09–8:23

However, these should be given in moderation in order to avoid raising the risk of infections. All right, as a quick recap, graft-versus-host disease occurs when T- cells of a graft react against tissues of the graft recipient, causing a variety of symptoms according to the affected tissue, which most commonly is the skin, the liver, or the gastrointestinal tract.

Review8:23–8:46

There’s an acute form, which happens in the first three months, and a chronic form, which happens later than three months after the transplantation.