Graft versus Host Syndrome
Graft-versus-host disease (GvHD) is a medical complication following the receipt of transplanted tissue from a genetically different person. GvHD is commonly associated with stem cell or bone marrow transplant but the term also applies to other forms of tissue graft. Immune cells (white blood cells) in the donated tissue (the graft) recognize the recipient (the host) as "foreign." The transplanted immune cells then attack the host's body cells. GvHD can also occur after a blood transfusion if the blood products used have not been irradiated or treated with an approved pathogen reduction system.
In the classical sense, acute graft-versus-host-disease is characterized by selective damage to the liver, skin (rash), mucosa, 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 lungs 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.
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.
Mucosal damage to the vagina can result in severe pain and scarring, and appears in both acute and chronic GvHD. This can result in an inability to have sexual intercourse.
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.
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.
In the clinical setting, graft-versus-host-disease is divided into acute and chronic forms.
- The acute or fulminant form of the disease (aGvHD) is normally observed within the first 100 days post-transplant, and is a major challenge to transplants owing to associated morbidity and mortality.
- The chronic form of graft-versus-host-disease (cGvHD) normally occurs after 100 days. The appearance of moderate to severe cases of cGVHD adversely influences long-term survival.
Billingham Criteria: 3 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 immuno-compromised and therefore cannot destroy or inactivate the transplanted cells.
After bone marrow transplantation, T cells 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 cytokines, including TNF-α and interferon-gamma (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 proteins (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 (long-term survival).
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 leukemias, donor T-cells have proven to have a valuable graft-versus-tumor effect. 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 effect.
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.
Thymus transplantation may be said to be able to cause a special type of GvHD because the recipient's thymocytes 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.
- DNA-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.
- Methotrexate, ciclosporin and tacrolimus are common drugs used for GVHD 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, bacterial, 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.
Several lab and imaging tests can be done to diagnose and monitor problems caused by GVHD.
A biopsy of the skin, mucus membranes in the mouth, or other parts of the body may help confirm the diagnosis.
How well a person does depends on the severity of GVHD. The outlook is better for patients who receive closely matched bone marrow tissue and cells.
Some cases of GVHD can damage the liver, lungs, digestive tract, or other body organs. Patients may also be at risk for severe infections.
However many cases, acute or chronic, can be treated successfully.
Successful treatment of GVHD does not guarantee that the transplant itself will succeed in treating the original disease.
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.