Transplant immunology

BACKGROUND

Allogeneic organ transplantation is the removal of a whole or partial organ from one person (the donor) to another (the recipient) in order to fix or replace a damaged or failing organ such as a liver, heart, lung, or pancreas.

Since the 1950s when organ transplants were first performed, the procedure has continually improved. The long-term success rates for organ transplants vary depending on the specific organ that is transplanted, the number of organs transplanted in a single surgery, and the underlying condition that caused organ failure. In general, researchers estimate that about 80% or more single-organ transplants are successful. Kidney and pancreas transplants are two of the most successful procedures, with five-year survival rates of about 80%. The five-year survival rate for liver transplants is about 73-78%, for heart transplants it is just over 70%, and for lung transplants it is about 45%. Many other organs may also be transplanted, including the cornea, skin, bone, intestines, and bone marrow.

The number of patients who need organ transplants far exceeds the number of donated organs that are available. Therefore, organ transplant centers have ranked lists of patients that are based on such factors as the patient's overall health and age. An estimated 3,700 patients are added to the wait list every month and about 18 people on the organ transplant wait list die each day.

An autologous transplant, also called an autograft, is when part of an organ or tissue is removed from the patient and then later returned to the same patient. This type of transplant is typically 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. Since the cells do not come from another person, there is no chance of rejection.

Some patients may experience serious complications after receiving an allogeneic organ transplant, such as graft-versus-host disease and transplant rejection (also called host-versus graft disease). In order to prevent complications, the donor and recipient must undergo tissue typing, blood typing and cross matching to ensure that the donated organ is a compatible match with the patient.

Patients who receive allogeneic organ transplants must take immunosuppressant drugs for the rest of their lives to help prevent their bodies from rejecting the organs. Without preventative immunosuppression, organ and tissue transplantation would almost always lead to transplant rejection and destruction of the transplanted organ. Since immunosuppressants inhibit the body's ability to fight off infections and diseases, antivirals, antifungals, or antibiotics may also be prescribed to prevent infections.

GENERAL TRANSPLANT REQUIREMENTS

The United Network for Organ Sharing (UNOS) maintains a computer network that links all of the organ procurement organizations and transplant centers throughout the country. This computer database is accessible 24 hours a day, seven days a week.

Transplant centers evaluate potential transplant candidates that have been referred by their healthcare providers. Members of the transplant center perform medical tests, consider the patient's mental and physical health, as well as his/her personal support system. Patients who meet the requirement of the transplant center are added to the national patient waiting list. This list is not ranked.

When a deceased organ donor is identified, a transplant coordinator accesses the UNOS database and ranked lists of patients for each organ are generated according to organ allocation policies.

Rank is determined by factors such as blood type, length of time on the waiting list, and immune status. Since organs are only viable for a short time, the geographical distance between the candidate and donor must also be considered. For organs such as the heart, liver, and intestines, the patient's degree of medical urgency is also taken into consideration.

The organ is then offered to the transplant team of the first person on the list. In most cases, the first patient on the list does not end up receiving the organ. This is because the patient must be healthy enough to undergo major surgery and able to receive the transplant immediately. In addition, before surgery can be performed, a test that measures the compatibility between the donor and recipient must be performed.

Once an organ recipient is selected, contacted, and testing is complete, surgery is scheduled.

The amount of time it takes to receive an organ varies. There is no way to know exactly how long it will take an individual to receive an organ. Some patients may wait several months while others may wait several years. It is estimated that 18 people on the organ transplant waiting list die each day.

MATCHING DONORS TO RECIPIENTS

General: Transplant recipients undergo tissue typing and blood typing tests before they are added to the national transplant list. Once donated organs are procured they also undergo these tests. Potential recipients may also undergo a test that measures their panel of reactive antibody (PRA) sensitivity. The higher the sensitivity, the more likely the patient will reject a transplanted organ from the general population. Once an organ and recipient have 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.

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, called agglutinogen, that is 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.

Antibody screening: Potential organ recipients may also undergo a test that measures their panel of reactive antibody (PRA) sensitivity. This test helps healthcare providers determine how likely it is that the patient will reject an organ from the general population. During the procedure, a sample of the patient's white blood cells are mixed with red blood cells from 60 random donors. The patient's sensitivity is measured by how many samples the cells react to. The higher the sensitivity, the more likely the patient will reject a transplanted organ from the general population.

Cross matching: A crossmatch is performed to determine whether the potential recipient will react to the donated organ. 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.

Final blood test: A final blood test is usually performed in the transplant recipient 48 hours after surgery. This test is another crossmatch of the recipient's white blood cells and the donor's red blood cells to ensure that the patient has not produced any antibodies that will attack the donated organ. If antibodies are present, this indicates that the organ is being rejected. High doses of immunosuppressants are administered and the patient is closely monitored in the hospital.

COMPLICATIONS

Graft-versus-host disease (GVHD): Graft-versus-host disease (GVHD) is a rare disorder that occurs in bone marrow transplant recipients who are immunocompromised. The disease occurs when transplanted organ attacks the recipient's cells. This is because before the transplant is performed, the recipient's bone marrow, which produces immune cells, is destroyed with chemotherapy or radiation therapy.

For some survivors, the symptoms of GVHD may be painful, while others may only experience minor symptoms. GVHD can be acute or chronic.

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 enteritis (inflammation of the intestine).

Chronic GVHD develops three months or longer after the transplantation. The chronic form causes dermatitis (skin rash), tightening or inflammation of the skin, sores in the mouth, dry eyes and mouth, hair loss, liver damage, and indigestion. Chronic GVHD can last for months or years.

Both the acute and the chronic disease are treated with corticosteroids like prednisone or immunosuppressants like cyclosporine. These drugs suppress both the patient's immune system and the immune response that occurs in the transplanted bone marrow.

Antithymocyte globulin (ATG), an immunosuppressant that selectively destroys T-cells (white blood cells involved in the immune response), has been administered before bone marrow transplants to reduce the risk of graft-versus-host disease (GVHD).

After about six to 12 months, the grafted cells usually develop a tolerance to the recipient's cells and the medications can be gradually withdrawn.

Transplant rejection: Transplant rejection, also known as host-versus-graft disease, occurs when the recipient's immune system attacks the donated organ. The recipient's immune cells do not recognize the new organ cells triggering an immune response. Eventually, transplant rejection leads to permanent damage to the donated organ. Patients who experience transplant rejection commonly experience dysfunction of the transplanted organ and malaise (general discomfort). In rare cases, fever and pain or swelling may develop near the organ.

To help prevent transplant rejection from occurring, the organ from the patient and donor are typed and crossmatched before surgery to identify their unique human leukocyte antigens (HLA). Recipients receive immunosuppressants for the rest of their lives to prevent organ rejection.

TREATMENT

General: Patients who receive allogeneic organ transplants (donated organs) must take immunosuppressants for the rest of their lives in order to prevent their bodies from rejecting the organ. Since immunosuppressants inhibit the body's ability to fight off infections and diseases, other medications may also be prescribed to prevent infections. Patients should tell their healthcare providers if they are taking any drugs (prescription or over-the-counter), herbs, or supplements because they may interact with treatment.

Immunosuppressants: The most common oral immunosuppressants prescribed include tacrolimus (Prograf©), mycophenolate mofetil (CellCept©), sirolimus (Rapamune©), prednisone (Deltasone©, Orasone©, or Meticorten©), cyclosporine (Neoral©, Sandimmune©, or Gengraf©), and azathioprine (Imuran©). Depending on the transplant, some patients may need to take different combinations and doses of the drugs. In general, patients typically take two to three immunosuppressant medications for the rest of their lives.

Preventing infections: Individuals taking immunosuppressants have a suppressed immune system that is vulnerable to infection. Antivirals like acyclovir (Zovirax©) or valganciclovir (Valcyte©) have been used to prevent viral infections. Antifungals like fluconazole (Diflucan©), nystatin (Mycostatin© or Nilstat©), or itraconazole (Sporano©x) have been used to prevent fungal infections. Antibiotics like trimethoprim/sulfamethoxazole (Bactrim© or Septra©) have been used to prevent bacterial infections.

INTEGRATIVE THERAPIES

Unclear or conflicting scientific evidence :

L-arginine : Dietary supplementation with L-arginine and canola oil has been associated with decreased rejection rates after the first month in renal transplant patients. Due to reductions in cardiac events, long-term benefits for patient survival may be particularly important. Further research is needed to confirm these results.

Avoid if allergic to arginine or with a history of stroke, liver, or kidney disease. Avoid if pregnant or breastfeeding. Use cautiously if taking blood-thinning drugs (warfarin), blood pressure drugs, or herbs or supplements with similar effects. Check blood potassium levels.

Art therapy : There is some evidence suggesting that art therapy may help bone marrow transplant patients to 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.

Fair negative scientific evidence :

Omega-3 fatty acids : There are multiple studies of heart transplant and kidney transplant patients taking cyclosporine (Neoral©) who were also administered fish oil supplements. The majority of trials report improvements in kidney function (glomerular filtration rate, serum creatinine) and lower blood pressure compared to patients not taking fish oil. However, several recent studies report no benefits on kidney function and no changes have been found in rates of rejection or graft survival.

Avoid if allergic or hypersensitive to fish, omega-3 fatty acid products that come from fish, nuts, or linolenic acid. Avoid during active bleeding. Use cautiously with bleeding disorders, diabetes, low blood pressure, or drugs, herbs, or supplements that treat any such conditions. Use cautiously before surgery. The Environmental Protection Agency (EPA) recommends that intake be limited in pregnant/breastfeeding women to a single six-ounce meal per week, and in young children to less than two ounces per week. For farm-raised, imported, or marine fish, the U.S. Food and Drug Administration (FDA) recommends that pregnant/breastfeeding women and young children avoid eating types with higher levels of methylmercury and less than 12 ounces per week of other fish types. Women who might become pregnant are advised to eat seven ounces or less per week of fish with higher levels of methylmercury or up to 14 ounces per week of fish types with about 0.5 parts per million (such as marlin, orange roughy, red snapper, or fresh tuna).

PREVENTION

Tissue typing, blood typing, and crossmatching should be conducted before surgery to help ensure that the donated organ will be compatible with the patient.

Antithymocyte globulin (ATG), an immunosuppressant that selectively destroys T-cells, has been administered before bone marrow transplantations to reduce the risk of graft-versus-host disease (GVHD). However, it does not increase the patient's chance of survival.

To help prevent complications of transplantations, such as transplant rejection and GVHD, patients typically receive immunosuppressants for the rest of their lives. Commonly prescribed immunosuppressants include tacrolimus (Prograf©), mycophenolate mofetil (CellCept©), sirolimus (Rapamune©), prednisone (Deltasone©, Orasone©, or Meticorten©), cyclosporine (Neoral©, Sandimmune©, or Gengraf©), and azathioprine (Imuran©).

Individuals taking immunosuppressants have a suppressed immune system that is vulnerable to infection. Antivirals like acyclovir (Zovirax©) or valganciclovir (Valcyte©) have been used to prevent viral infections. Antifungals like fluconazole (Diflucan©), nystatin (Mycostatin© or Nilstat©), or itraconazole (Sporano©x) have been used to prevent fungal infections. Antibiotics like sulfamethoxazole/trimethoprim (Bactrim© or Septra©) have been used to prevent bacterial infections.

AUTHOR INFORMATION

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

• Coalition on Donation. www.donatelife.net. Accessed April 17, 2007.
• National Marrow Donor Program. www.marrow.org. Accessed April 17, 2007.
• Natural Standard: The Authority on Integrative Medicine. www.naturalstandard.com. Copyright © 2007. Accessed April 17, 2007.
• St. Jude Children's Research Hospital. Graft-vs-Host Disease. www.stjude.org. Accessed April 17, 2007.
• Transplant Living. www.transplantliving.org. Accessed April 17, 2007.
• U.S. Department of Health and Human Services. www.hhs.gov. Accessed April 17, 2007.