Introduction
The immune system of a healthy human can distinguish foreign cells and tissues from the body’s own, and will attempt to destroy them. This is necessary to fight infections caused by organisms such as bacteria and viruses, and also gives the body some natural lines of defence against cancerous tumours.
Unfortunately, this also means that transplanted organs and tissues may be recognised as foreign and attacked by the immune system - this is called "rejection". Therefore after organ transplantation, patients are prescribed medication called immunosuppression, which aims to prevent the immune system attacking transplanted organs but at the same time aiming not to over-suppress the immune system as this would cause an increased risk of infections and tumours.
There are different types of rejection, which tend to occur at different times after organ transplantation, so the immunosuppressant treatment is also different at the various stages after a transplant.
Types of rejection
Hyperacute rejection is a very rare and aggressive form of rejection which occurs in a patient who already has antibodies directed at the tissue type of the donor. This may happen, for example, if the donor comes from a different blood group to the transplant patient. Hyperacute rejection occurs within minutes and the transplant must be immediately removed to prevent a severe generalised inflammatory response. This is a particular risk in kidney transplants, and so a special test called a “cytotoxic crossmatch” is performed prior to kidney transplantation to ensure that antibodies to the donor are not present. For other organs, hyperacute rejection is prevented by not transplanting organs from incompatible blood groups.
Acute rejection generally first occurs around 5-10 days after a transplant, and is most commonly caused by the organ being attacked by a special type of white blood cell known as “T cells”, but can also be caused by the formation of antibodies against the donor. If recognised and treated promptly acute rejection can normally be stopped completely, although very rarely it can destroy the transplant. A single episode is not a cause for concern, but recurrent episodes are associated with chronic rejection and premature failure of the transplant.
Chronic rejection is a term used for the long term loss of function in organ transplants associated with scarring of the internal blood vessels or other similar structures within the transplant, and can occur for many reasons. Depending on the organ, this may go by other names, usually describing the structures damaged by the scarring; for example, in a kidney this may be called “chronic allograft nephropathy”, or in a lung “bronchiolitis obliterans”.
Prevention of rejection
Rejection is usually prevented with drugs which suppress particular parts of the immune system. These can include antibodies given at the time of the transplant, as well as long-term medication given afterwards and needed for the entire life of the transplanted organ.
Combinations of drugs are usually used to increase the immune-suppressant effect while minimising the side effects of each individual drug. In the longer term, the risk of acute rejection decreases, and so generally drug doses are reduced or the number of drugs is reduced.
At the time of the transplant, an infusion of antibodies may be given to destroy or disarm the T cells, which are the main cells which cause rejection. Patients are then given a combination of medications typically including one of ciclosporin or tacrolimus, as well as a medication to limit rapid growth of cells which may attack the organ (either azathioprine, mycophenolic acid or MMF) and often steroids are prescribed, especially in the early stages after a transplant. Sirolimus can be given as well as or instead of cyclosporine or tacrolimus.
Treatment of rejection
Acute rejection is normally treated initially with a short course of high-dose steroids, which is usually sufficient to treat successfully. If this is not enough to stop the rejection process, more complicated treatments can be used such as anti-T cell antibodies for rejection caused by T cells, or plasma exchanges to remove antibodies from patients with rejection caused by antibodies.
Chronic rejection is irreversible and cannot therefore be treated effectively. The main strategy is to prevent it by avoiding known causes. If it occurs and leads to loss of the transplant function, re-transplantation would be considered.
Side effects of immunosuppression
There are general side effects affecting all forms of immunosuppression treatment, as well as specific side effects discussed in the pages about the individual drugs. The general effects are an increased risk of infection and of certain types of tumours. With modern immunosuppression, these risks are still far less dangerous than the the certain risk of losing a transplanted organ due to rejection if the prescribed immunosuppression is not taken.
Infections
The increased risk of infection includes normal bacteria, viruses and fungi, as well as some which do not normally infect people with normal immune systems: this second group of infections is known as "opportunistic infections" and may need treatment with special antibiotics or antiviral drugs.
CMV
One of the most important opportunistic infections in transplant patients is cytomegalovirus, which is generally called "CMV". This is a common infection, which in people with normal immune systems causes a mild 'flu-like illness which may even go unnoticed. Most patients have already had this infection and formed antibodies against CMV before they have a transplant, and so are relatively safe from further infection; however the virus remains in the body permanently and can rarely cause an acute infection if the immune system has to be very heavily suppressed, for example when treating severe acute rejection with plasma exchanges.
CMV infection is much more of a risk when patients who have not previously been infected with CMV get an organ transplant, as they will not have protective antibodies, and the virus may spread to the patient from the donated organ if the donor had previously been infected. To prevent this, both donors and recipients of organs have blood tests to see if there is antibody present, and if a recipient without antibody gets a transplant from a previously infected donor, they are given treatment with an antiviral drug called valganciclovir to prevent CMV infection.
Pneumocystis carinii
Pneumocystitis carinii, which is also known as Pneumocysitis jirovecii, is a fungal infection which does not affect people with normal immunity, but can cause an unusual and severe form of pneumonia in patients with immunosuppression. It is prevented with co-trimoxazole (Septrin), an antibiotic.
BK Virus
This is a very common virus, which has infected most people before the transplant. The actual infection is very mild, and may cause a mild flu-like illness, or no symptoms at all. It remains dormant in the kidney and urinary tract after the initial infection, but may become active again with immunosuppression, leading to damage to a transplanted kidney called "BK nephropathy". Where damage is suspected, BK virus infection is confirmed by specialist testing and is treated initially by adjustment of the immunosuppressant medication; specific anti-viral drugs are also used if necessary.
Tumours
Immunosuppression reduces the ability of the immune system to destroy tumours, and so some cancers are more common in transplant recipients than in other people. Skin cancers are especially more common in transplant patients, and so medical advice should be sought if any new moles or lesions appear on the skin, or if older ones change their appearance. The risk of cancer is still less harmful than the risk associated with loss of a transplanted organ from rejection, and so it is still far safer to take prescribed immunosuppression.
