Graft-versus-host disease (GvHD) is a syndrome
, characterized by inflammation in different organs. GvHD is commonly associated with bone marrow transplants
and stem cell transplant
White blood cell
s of the donor's immune system which remain within the donated tissue (the graft) recognize the recipient (the host) as foreign (non-self). The white blood cells present within the transplanted tissue then attack the recipient's body's cells, which leads to GvHD. This should not be confused with a transplant rejection
, which occurs when the immune system of the transplant recipient rejects the transplanted tissue; GvHD occurs when the donor's immune system's white blood cells reject the recipient. The underlying principle (alloimmunity
) is the same, but the details and course may differ. GvHD can also occur after a blood transfusion
if the blood product
s used have not been irradiated or treated with an approved pathogen reduction system.
In the clinical setting, graft-versus-host-disease is divided into acute
forms, and scored or graded on the basis of the tissue affected and the severity of the reaction.
In the classical sense, acute graft-versus-host-disease is characterized by selective damage to the liver
, and the gastrointestinal tract
. Newer research indicates that other graft-versus-host-disease target organs include the immune system (the hematopoietic system
, e.g., the bone marrow
and the thymus
) itself, and the lung
s in the form of immune-mediated pneumonitis
Biomarkers can be used to identify specific causes of GvHD, such as elafin
in the skin.
Chronic graft-versus-host-disease also attacks the above organs, but over its long-term course can also cause damage to the connective tissue
and exocrine glands
Mucosal damage to the vagina
can result in severe pain
, and appears in both acute and chronic GvHD. This can result in an inability to have sexual intercourse
The ''acute'' or ''fulminant'' form of the disease (aGvHD) is normally observed within the first 10 to 100 days post-transplant,
and is a major challenge to transplants owing to associated morbidity and mortality.
About one-third to one-half of allogeneic transplant
recipients will develop acute GVHD.
It’s less common in younger patients and in those with closer human leukocyte antigens
(HLA) matches between donor and the patient.
The first signs are usually a rash, burning, and redness of the skin on the palms and soles. This can spread over the entire body. Other symptoms can include Nausea, vomiting, stomach cramps, diarrhea (watery and sometimes bloody), loss of appetite, jaundice, abdominal pain, and weight loss.
Acute GvHD of the GI tract
can result in severe intestinal inflammation, sloughing of the mucosal membrane, severe diarrhea, abdominal pain, nausea, and vomiting. This is typically diagnosed via intestinal biopsy. Liver GvHD is measured by the bilirubin level in acute patients.
Skin GvHD results in a diffuse red maculopapular rash
sometimes in a lacy pattern.
Acute GvHD is staged as follows: overall grade (skin-liver-gut) with each organ staged individually from a low of 1 to a high of 4. Patients with grade IV GvHD usually have a poor prognosis. If the GvHD is severe and requires intense immunosuppression involving steroids and additional agents to get under control, the patient may develop severe infections as a result of the immunosuppression and may die of infection. However, a 2016 study found that the prognosis for patients with grade IV GvHD has improved in recent years.
The ''chronic'' form of graft-versus-host-disease (cGvHD) normally begins 90 to 600 days post-transplant.
The appearance of moderate to severe cases of cGVHD adversely influences long-term survival.
The first symptom of cGvHD is commonly a rash on the palms of the hands or the soles of the feet, and the rash can spread and is usually itchy and dry. In severe cases, the skin may blister and peel, like a bad sunburn. A fever may also develop. Other symptoms of chronic GVHD can include:
* Decreased appetite
* Abdominal (belly) cramps
* Weight loss
* Yellowing of the skin and eyes (jaundice)
* Enlarged liver
* Bloated abdomen (belly)
* Pain in the upper right part of the abdomen (belly)
* Increased levels of liver enzymes in the blood (seen on blood tests)
* Skin that feels tight
* Dry, burning eyes
* Dryness or painful sores in the mouth
* Burning sensations when eating acidic foods
* Bacterial infections
* Blockages in the smaller airways of the lungs
In the oral cavity
, chronic graft-versus-host-disease manifests as lichen planus
with a higher risk of malignant transformation
to oral squamous cell carcinoma
in comparison to the classical oral lichen planus. Graft-versus-host-disease-associated oral cancer
may have more aggressive behavior with poorer prognosis, when compared to oral cancer in non-hematopoietic stem cell transplantation patients.
Three criteria, known as the Billingham criteria, must be met in order for GvHD to occur.
* An immuno-competent
graft is administered, with viable and functional immune cells.
* The recipient is immunologically different from the donor – histo-incompatible
* The recipient is immunocompromised
and therefore cannot destroy or inactivate the transplanted cells.
After bone marrow transplantation, T cell
s present in the graft
, either as contaminants or intentionally introduced into the host, attack the tissues
of the transplant recipient after perceiving host tissues as antigenically foreign. The T cells produce an excess of cytokine
s, including TNF-α
(IFNγ). A wide range of host antigens
can initiate graft-versus-host-disease, among them the human leukocyte antigens
(HLA). However, graft-versus-host disease can occur even when HLA-identical siblings are the donors.
HLA-identical siblings or HLA-identical unrelated donors often have genetically different protein
s (called minor histocompatibility antigens
) that can be presented by major histocompatibility complex
(MHC) molecules to the donor's T-cells, which see these antigens as foreign and so mount an immune response.
Antigens most responsible for graft loss are HLA-DR
(first six months), HLA-B
(first two years), and HLA-A
While donor T-cells are undesirable as effector cells of graft-versus-host-disease, they are valuable for engraftment by preventing the recipient's residual immune system
from rejecting the bone marrow graft (host-versus-graft
). In addition, as bone marrow transplantation is frequently used to treat cancer
, mainly leukemia
s, donor T-cells have proven to have a valuable graft-versus-tumor
A great deal of current research on allogeneic bone marrow transplantation involves attempts to separate the undesirable graft-vs-host-disease aspects of T-cell physiology from the desirable graft-versus-tumor
This type of GvHD is associated with transfusion
of un-irradiated blood to immunocompromised recipients. It can also occur in situations in which the blood donor is homozygous
and the recipient is heterozygous
for an HLA haplotype
. It is associated with higher mortality (80–90%) due to involvement of bone marrow lymphoid tissue, however the clinical manifestations are similar to GVHD resulting from bone marrow transplantation. Transfusion-associated GvHD is rare in modern medicine. It is almost entirely preventable by controlled irradiation of blood products to inactivate the white blood cells (including lymphocytes) within.
may be said to be able to cause a special type of GvHD because the recipient's thymocyte
s would use the donor thymus cells as models when going through the negative selection
to recognize self-antigens, and could therefore still mistake own structures in the rest of the body for being non-self. This is a rather indirect GvHD because it is not directly cells in the graft itself that causes it but cells in the graft that make the recipient's T cells act like donor T cells. It can be seen as a multiple-organ autoimmunity in xenotransplantation
experiments of the thymus between different species. Autoimmune disease is a frequent complication after human allogeneic thymus transplantation, found in 42% of subjects over 1 year post transplantation. However, this is partially explained by the fact that the indication itself, that is, complete DiGeorge syndrome
, increases the risk of autoimmune disease.
Thymoma-associated multiorgan autoimmunity (TAMA)
A GvHD-like disease called thymoma-associated multiorgan autoimmunity
(TAMA) can occur in patients with thymoma. In these patients rather than a donor being a source of pathogenic T cells, the patient's own malignant thymus produces self-directed T cells. This is because the malignant thymus is incapable of appropriately educating developing thymocytes to eliminate self-reactive T cells. The end result is a disease virtually indistinguishable from GvHD.
The pathophysiology of GvHD includes three phases:
# The afferent phase: activation of APC (antigen presenting cells
# The efferent phase: activation, proliferation, differentiation and migration of effector cells
# The effector phase: target tissue destruction
Activation of APC occurs in the first stage of GvHD. Prior to haematopoietic stem cell transplantation, radiation or chemotherapy results in damage and activation of host tissues, especially intestinal mucosa. This allows the microbial products to enter and stimulate pro-inflammatory cytokines such as IL-1
. These proinflammatory cytokines increase the expression of MHC and adhesion molecules on APCs, thereby increasing the ability of APC to present antigen.
The second phase is characterized by the activation of effector cells. Activation of donor T-cells further enhances the expression of MHC and adhesion molecules, chemokines and the expansion of CD8 + and CD4 + T-cells and guest B-cells. In the final phase, these effector cells migrate to target organs and mediate tissue damage, resulting in multiorgan failure.
-based tissue typing allows for more precise HLA matching between donors and transplant patients, which has been proven to reduce the incidence and severity of GvHD and to increase long-term survival.
* The T-cells of umbilical cord blood (UCB) have an inherent immunological immaturity, and the use of UCB stem cells in unrelated donor transplants has a reduced incidence and severity of GvHD.
are common drugs used for GvHD prophylaxis.
Further research is necessary to evaluate whether mesenchymal stromal cells can also be used for the prophylaxis.
* Graft-versus-host-disease can largely be avoided by performing a T-cell-depleted bone marrow transplant. However, these types of transplants come at a cost of diminished graft-versus-tumor effect, greater risk of engraftment failure, or cancer relapse, and general immunodeficiency
, resulting in a patient more susceptible to viral
, and fungal infection
. In a multi-center study, disease-free survival at 3 years was not different between T cell-depleted and T cell-replete transplants.
Intravenously administered glucocorticoids
, such as prednisone
, are the standard of care in acute GvHD
and chronic GVHD. The use of these glucocorticoids is designed to suppress the T-cell-mediated immune onslaught on the host tissues; however, in high doses, this immune-suppression raises the risk of infections and cancer relapse. Therefore, it is desirable to taper off the post-transplant high-level steroid doses to lower levels, at which point the appearance of mild GVHD may be welcome, especially in HLA mis-matched patients, as it is typically associated with a graft-versus-tumor effect.. Cyclosporine
are calcineurin inhibitor
s. Both substances are structurally different but have the same mechanism of action. Cyclosporin binds to the cytosolic protein Peptidyl-prolyl cis-trans isomerase A (known as cyclophilin), while tacrolimus binds to the cytosolic protein Peptidyl-prolyl cis-trans isomerase FKBP12. These complexes inhibit calcineurin, block dephosphorylation of the transcription factor NFAT of activated T-cells and its translocation into the nucleus. Standard prophylaxis involves the use of cyclosporine for six months with methotrexate. Cyclosporin levels should be maintained above 200 ng/ml.
Other substances that have been studied for GvHD treatment include, for example: sirolimus
, and alemtuzumab
In August 2017 the US FDA
to treat chronic GvHD after failure of one or more other systemic treatments.
[FDA expands ibrutinib indications to chronic GVHD. Aug 2017]
There are a large number of clinical trials either ongoing or recently completed in the investigation of graft-versus-host disease treatment and prevention.
On May 17, 2012, Osiris Therapeutics announced that Canadian health regulators approved Prochymal, its drug for acute graft-versus-host disease in children who have failed to respond to steroid treatment. Prochymal is the first stem cell drug to be approved for a systemic disease.
In January 2016, Mesoblast released results of a Phase2 clinical trial on 241 children with acute Graft-versus-host disease, that was not responsive to steroids.
The trial was of a mesenchymal stem cell therapy known as remestemcel-L or MSC-100-IV. Survival rate was 82% (vs 39% of controls) for those who showed some improvement after 1 month, and in the long term 72% (vs 18% of controls) for those that showed little effect after 1 month. [
Graft versus host disease has been implicated in eliminating several cases of HIV, including The Berlin Patient and 6 others in Spain.
* Graft-versus-tumor effect
* Transplant rejection
* Ferrara JLM, Deeg HJ, Burakoff SJ. ''Graft-Vs.-Host Disease: Immunology, Pathophysiology, and Treatment.'' Marcel Dekker, 1990
* Polsdorfer, JR ''Gale Encyclopedia of Medicine: Graft-vs.-host disease''
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