Graft versus host disease

BACKGROUND

Graft versus host disease (GVHD) is a rare disorder that occurs when the immune cells from donated bone marrow stem cells or a blood transfusion attack the recipient. The only transplanted tissues that contain enough immune cells (specifically T-lymphocytes) to cause GVHD are the blood and the bone marrow. This condition typically occurs in patients who have extremely weakened immune systems.

Researchers estimate that about 90% of bone marrow recipients develop GVHD. This is because before the transplant is performed, the recipient's bone marrow, which produces immune cells, is destroyed with chemotherapy or radiation therapy.

Bone marrow transplantation, also called hematopoietic stem-cell transplantation (HSCT), is a curative treatment for bone marrow cancer and inherited blood disorders like sickle-cell anemia.

Blood transfusions, which are used to replace blood-forming cells and immune cells, rarely cause GVHD. This condition is most likely to occur in individuals who have weakened immune systems (like chemotherapy or HIV patients).

Symptoms of GVHD generally include skin rash, liver dysfunction, and intestinal problems such as diarrhea (ranging from mild to severe) and abdominal pain, which may lead to decreased appetite and weight loss.

When the donated blood or organ is from an individual other than the recipient, it is called an allogeneic transplant. GVHD is most likely to occur after an allogeneic transplant or transfusion than an autologous transplant or transfusion.

An autologous transplant or transfusion is when the blood product or organ is removed from the recipient and then later returned to the same patient. This type of transplant is often conducted with stem cells from the bone marrow. For instance, chemotherapy destroys both healthy cells and cancer cells. Therefore, patients may have some of their stem cells removed and stored before chemotherapy. After treatment, the patient receives an infusion with these stem cells to help boost the immune system. Mild episodes of GVHD may occur after an autologous transplant because high doses of chemotherapy may damage the patient's DNA. The transplanted bone marrow may not recognize the cells if the DNA is damaged.

GVHD is treated with corticosteroids like prednisone (Deltasone©, Orasone© or Meticorten©) or immunosuppressants like cyclosporine (Restasis©). These drugs weaken the immune responses of both the transplant recipient and the donated stem cells or blood. The donated cells usually develop a tolerance to the host cells after six to 12 months, and the medications can be gradually withdrawn.

MATCHING DONORS TO RECIPIENTS

General: Bone marrow transplant recipients undergo tissue typing and blood typing tests before they are added to the national transplant list. Donated bone marrow also undergoes these tests. Once a donor and recipient have been shown to be close tissue and blood matches, a procedure called crossmatching is performed before surgery to ensure that the organ will not be rejected.

Transfusion recipients must undergo tissue typing to ensure that the donor and recipient have the same type of blood.

Tissue typing: A histocompatibility antigen blood test analyzes inherited proteins on the surface of cells. The results can be used to match donated tissue to organ transplant recipients.

Proteins called human leukocyte antigens (HLA) are found in the membranes (outer coating) of nearly every cell in the body. These antigens are in especially high concentrations on the surface of white blood cells.

HLA molecules are the major determinants used by the body's immune system for recognition and differentiation of self from non-self (foreign substances). There are many different major histocompatibility (HLA) proteins, and each person has only a small, relatively unique set that is inherited from their parents. It is unlikely that two unrelated people will have the same HLA make-up.

To help to prevent serious complications, such as graft-versus-host disease or transplant rejection, the potential donor and recipient must be tested to determine whether their HLA molecules are closely matched, making them compatible. Each person has unique HLA molecules (except for twins, who have identical molecules). Therefore, this test cannot prevent 100% of complications. However, the test can significantly reduce the number of patients who develop complications after transplantations.

Blood typing: Blood typing is performed because the donor and recipient must have the same blood type. Blood typing is a laboratory test that determines a patient's blood type. A potential donor and recipient are both blood typed before they are crossmatched. There are four blood types in the ABO blood group: A, B, AB, and O. These blood types are determined by agglutinogens (type of protein) that are present on the outside of the patient's red blood cells. Patients who have type AB blood are considered universal recipients because they can receive blood or blood products from any other blood type. However, these patients may only donate their blood to patients who have AB blood. Patients who have O blood are considered the universal donors because they can give blood to patients of any other blood type. However, they can only receive blood from patients who have O blood.

In addition, patients have either positive or negative blood. Patients who also have a protein called D antigen on their red blood cells are considered Rh-positive. If the D antigen is absent, the patient is Rh-negative. For instance, if a patient has type A agglutinogens but no D antigen, he/she has type A-negative blood.

Cross matching: A crossmatch is performed to determine whether the potential recipient will react to the donated bone marrow. During the procedure, white blood cells from the recipient and red blood cells from the donor are mixed. Clumping of the cells indicates that the patient has developed antibodies to the donor's cells. This means the patient will reject the donated organ if it is transplanted. Therefore, if clumping occurs, the blood is not compatible. If clumping does not occur, the blood is compatible.

CAUSES

GVHD occurs because the donor's T-lymphocytes (type of immune cell) contained in the transplanted organ or blood attack cells in the recipient's body.

Normally, the immune system uses markers called human leukocyte antigens (HLA) to recognize which cells are "self" cells and which are "foreign" cells. This allows the immune system to identify foreign invaders like bacteria, viruses, and fungi that may harm the body.

In GVHD, the donor's immune cells do not recognize the HLA antigens on the recipient's cells, so they attack them. To help avoid the development of GVHD, the donor's HLA antigens need to match recipient's as closely as possible. Selecting a closely matched donor or cord blood unit (blood from the umbilical cord that is rich in stem cells) may help reduce the risk of developing GVHD.

SYMPTOMS

Acute: Acute GVHD develops within three months of the transplant and it is characterized by dermatitis (skin rash), hepatitis (liver inflammation), difficulty breathing (due to stiffening of lungs), diarrhea (sometimes containing blood), jaundice (yellowing of the skin and eyes), and inflammation of the intestine.

Chronic: Chronic GVHD typically develops longer than three months after the transplantation and it can last for months or years. Chronic GVHD can range from mild (skin rash) to life threatening (causing liver failure and severe infections). Symptoms may include dermatitis (skin rash), tightening or inflammation of the skin, lesions in the mouths, dry eyes and mouth, hair loss, liver damage, and indigestion.

Transfusion-associated: Transfusion-associated GVHD typically develops within four to 30 days after the blood transfusion. Symptoms are the same as acute GVHD.

COMPLICATIONS

Infection: Because patients with GVHD have weakened immune systems, which are further weakened by immunosupressants, they are vulnerable to infections. Infection with one particular virus, called cytomegalovirus (CMV), is so common among GVHD patients that some experts recommend preventative medications.

Marrow aplasia: Marrow aplasia occurs when the bone marrow is unable to produce immune system cells. This condition is a frequent complication of transfusion-associated GVHD. However, this complication can be prevented by irradiating blood products with at least 2500 centigray (unit of radiation equal to one rad). During this process, X-rays are used to destroy the T-lymphocytes in the blood before an immunocompromised patient (like an HIV or chemotherapy patient) receives a blood transfusion. These T-lymphocytes are responsible for launching the immune response that causes GVHD.

Long-term effects: Some GVHD patients may experience long-term effects even after the disease is treated. Patients may experience photosensitivity (skin sensitivity to the sun or ultraviolet light). These patients are encouraged to wear sunscreen and avoid extensive sun exposure.

Other patients may develop cavities and gum disease, which is a result of dry mouth that is associated with GVHD. This is because saliva is necessary to prevent infection and tooth decay by controlling fungi and bacteria. These patients are encouraged to visit their dentists regularly. A fluoride rinse may be recommended. Other patients may experience dry or irritated eyes, which may be alleviated with over-the-counter eye drops. In some cases, plugged tear ducts may cause dry eyes.

Some patients may suffer from long-term diarrhea or difficulty digesting food. These patients should talk with the dietitians at their transplant centers to determine what foods to eat and what to avoid. In general, acidic and spicy foods are often difficult to digest in patients who suffer from gastrointestinal symptoms.

DIAGNOSIS

General: In 1966, researcher R. Billingham described three criteria necessary to confirm a diagnosis of GVHD. These criteria are still used today: 1) the graft must contain healthy immune cells; 2) the host must have transplantation alloantigens (molecules that allow the body to recognize self cells) that are not present in the donor cells making the host appear foreign to the graft, which stimulates an immune response; 3) the host must not be able to launch an effective immune response against the graft.

Alloantigen assay: An alloantigen assay may be conducted to determine whether alloantigens are present in the patient's blood. Alloantigens are molecules on the body's cells that allow the body to identify them as self-cells. If the host contains alloantigens that are lacking in the donor, this indicates GVHD.

TREATMENT

General: Both acute and chronic forms of GVHD are treated with corticosteroids and immunosuppressants, which weaken the immune responses of both the transplant recipient and the donated stem cells or blood. Grafted cells usually develop a tolerance to the host cells after six to 12 months and the medications can be gradually withdrawn.

Corticosteroids: Corticosteroids like prednisone (Deltasone©, Orasone©, or Meticorten©) and methylprednisolone (Solu-Medrol©) are used to treat GVHD. Since these steroids suppress the body's immune system (and the GVHD itself also weakens the immune system), patients are extremely vulnerable to infections. Therefore, the lowest effective dose is used to control the condition. Doses are gradually reduced as the condition improves. Treatment duration depends on the severity of the disease.

Immunosuppressants: Immunosuppressants like cyclosporine (Restasis©) are used to treat GVHD. Since immunosuppressants further weaken the immune system making the body vulnerable to infections, the lowest effective dose should be taken. Treatment duration depends on the severity of the disease.

INTEGRATIVE THERAPIES

Unclear or conflicting scientific evidence :

Art therapy : There is some evidence suggesting that art therapy may help bone marrow transplant patients strengthen positive feelings, alleviate distress, and clarify their existential/spiritual issues. It may be beneficial for patients who need to deal with emotional conflicts and feelings about life and death.

An art therapist helps a patient use many different types of artistic expression during art therapy. Drawing, painting, sculpting, and murals are just a few examples of techniques that are used.

Art therapy may evoke distressing thoughts or feelings. Use under the guidance of a qualified art therapist or other mental health professional. Some forms of art therapy use potentially harmful materials. Only materials known to be safe should be used. Related clean-up materials (like turpentine or mineral spirits) that release potentially toxic fumes should only be used with good ventilation.

Massage : Limited evidence suggests that massage may offer modest benefits for psychological well-being in bone marrow transplant patients. More studies are needed.

Avoid with bleeding disorders, low platelet counts, or if on blood-thinning medications (such as heparin or warfarin/Coumadin©). Areas should not be massaged where there are fractures, weakened bones from osteoporosis or cancer, open/healing skin wounds, skin infections, recent surgery, or blood clots. Use cautiously with a history of physical abuse or if pregnant or breastfeeding. Massage should not be used as a substitute for more proven therapies for medical conditions. Massage should not cause pain to the client.

Traditional or theoretical uses, which lack sufficient evidence :

Astragalus : In early study, astragalus has been investigated for its potential effects on graft-versus-host disease and bone marrow suppression from cancer or HIV. Reliable studies evaluating its efficacy are lacking and high quality clinical trials are needed.

Avoid if allergic to astragalus, peas, or any related plants or with a history of Quillaja bark-induced asthma. Avoid with aspirin, aspirin products, or herbs or supplements with similar effects. Avoid with inflammation (swelling) or fever, stroke, transplant, or autoimmune diseases (like HIV/AIDS). Stop use two weeks before surgery/dental/diagnostic procedures with a risk of bleeding, and avoid use immediately after these procedures. Use cautiously with bleeding disorders, diabetes, high blood pressure, lipid disorders or kidney disorders. Use cautiously with blood-thinners, blood sugar drugs, diuretics, or herbs and supplements with similar effects. Avoid if pregnant or breastfeeding.

Beta-carotene : Beta-carotene has been used to treat bone marrow transplant patients in early study. However, scientific studies evaluating its efficacy for this indication are currently lacking. High quality clinical research is needed to make a conclusion.

Avoid if sensitive to beta-carotene, vitamin A, or any other ingredients in beta-carotene products.

Probiotics : Probiotics have been used to treat bone marrow transplant patients; however, scientific studies evaluating its efficacy for this indication are currently unavailable. High quality clinical research is needed to make a conclusion.

Probiotics are generally considered safe and well tolerated. Avoid if allergic or hypersensitive to probiotics. Use cautiously if lactose intolerant.

Reiki : Traditionally, reiki has been used for bone marrow transplant support. Scientific studies evaluating its efficacy are currently unavailable. More research is needed in this area.

Reiki is not recommended as the sole treatment approach for potentially serious medical conditions, and should not delay the time it takes to consult with a healthcare professional or receive established therapies. Use cautiously with psychiatric illnesses.

Spleen extract : Spleen extract has been studied as a possible therapy for graft-versus-host-disease prevention in bone marrow transplant recipients. Scientific studies evaluating its efficacy are lacking and high quality clinical trials are needed.

Avoid if allergic or hypersensitive to spleen extract or its components, including tuftsin. Use cautiously if taking analgesics, anticoagulants/antiplatelet agents, bestatin, chemotherapy drugs, or psychotropic drugs. Use cautiously with bleeding disorders, in immunocompromised patients, with Hodgkin's disease, leukemia, and systemic lupus erythematosus. Use cautiously in children. Avoid in patients taking immunosuppressive therapy. Avoid spleen extract from countries where bovine spongiform encephalitis (BSE or "mad cow disease") has been reported. Avoid if pregnant or breastfeeding.

PREVENTION

Bone marrow transplant recipients undergo tissue typing and blood typing tests before they are added to the national transplant list. Donated bone marrow also undergoes these tests. Once a donor and recipient have been shown to be close tissue and blood matches, a procedure called crossmatching is performed before surgery to ensure that the organ will not be rejected. Whenever possible, compatible family donors can further decrease the risk because family members have similar human leukocyte antigens (HLA).

Transfusion recipients must undergo blood typing to ensure that the donated blood is a match.

Blood products can be irradiated with at least 2,500 centigray (unit of radiation equal to one rad). During this process, x-rays are used to destroy the T-lymphocytes in the blood before an immunocompromised patient (like an HIV or chemotherapy patient) receives a blood transfusion. These T-lymphocytes are responsible for launching the immune response that causes GVHD.

Antithymocyte globulin (ATG), an immunosuppressant that selectively destroys T-cells, has been administered before transplantation to reduce the risk of GVHD. However, it does not increase the chance of survival.

After a bone marrow transplant, patients typically receive the immunosuppressant drug cyclosporine with or without methotrexate or steroids to prevent GVHD. This is because an estimated 90% of bone marrow transplant recipients develop GVHD. Other agents that have been used to prevent GVHD include mycophenolate mofetil, sirolimus, keratinocyte growth factor (KGF) campath-1H, and suberoylanilide hydroxamic acid (SAHA).

AUTHOR INFORMATION

This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

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