Graft-versus-host disease

Graft-versus-host disease


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of pharmacology and clinical reasoning topics. Try it free today. 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. 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. 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. 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. 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. 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. 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.


11 thoughts on “Graft-versus-host disease

  1. Hey I don’t understand. The graft is suppose to reject the host tissue right.
    Here what you are saying basically is that the graft stimulates the host immune system and ultimately destroys the graft.
    But in GVHR the host tissue should be destroyed not the grafted tissue

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