The role of immunology and graft rejection in transplantation

 

The general acceptance and success of transplantation has, to a large extent, depended upon the discoveries made in many other scientific and medical fields. These include the introduction in the 1860s by Joseph Lister of antiseptic medical policies; the arrival in the early 1900s of blood transfusion and the first effective pharmaceutical products; and the development in the years after World War 2 of devices and intensive care techniques that enabled patients to be treated with a degree of comfort and sophistication that was previously thought unimaginable. However, if there is one area where medical advances have played a significant role in enabling transplants to be successfully performed, it is in the field of immunology. Here scientists have learned how the immune system of each person reacts to the presence of a foreign substance in the body, as well as how to control this reaction in order to ensure that rejection of a newly placed organ does not occur. This is of fundamental importance, for “control of rejection remains the central obstacle to organ transplantation, whether between individuals of one species or between species” [1].

 

One of the first discoveries in immunology, formally noted by Paul Bert in 1863, was that when tissue was transferred between two individuals, rejection in the host of the new graft could take place. While early researchers did recognise that something was amiss when a graft died in this way, it was only in 1903 that C.O. Jensen was to formally argue that this took place because the body was able to initiate a process of active immunity against foreign matter. Soon thereafter, in 1912, G. Schone was to coin the term “transplant immunity” to describe the fact that the body had some sort of natural resistance mechanism against foreign matter. In 1944, Peter Medewar was to prove that the body could learn to acquire immunity against foreign elements, by demonstrating through empirical testing that repeated acts of grafting could result in accelerated rejection of tissue [2]. Here, it appeared that the immune system, having been exposed once to a foreign entity, would recognise and react against it much sooner if it was to be exposed to again in a subsequent period. From these early discoveries, it was realised that if transplants were not to be rejected, then methods of fooling the immune system and of overcoming the reactions that were inevitably created needed to be developed.

 

Unfortunately for organ recipients, the defences that constitute the immune system are not able to discriminate between foreign matter that enters a body for a good reason, such as transplanted tissue, from objects that are out to harm the body, such as viral matter. Thus, to ensure that transplants are not rejected, two main factors need to be controlled. First, the recipient must be of the same blood group as the donor. If this does not happen, then the process of sensitisation is bound to take place soon after revascularisation occurs, when the blood vessels of the new graft are connected to those of the host. Second, efforts must be made to identify what are known as the histocompatibility locus-associated (HLA) antigens, which are proteins on the surface of cells responsible for controlling the immune response [3]. Two groups of HLA antigen, which are governed by genes on the sixth chromosome, exist: class I antigens, which are found in all cells, are the targets of the rejection response, while class II antigens, which appear on only some cells, are the initiators of this response. While each person has a variety of antigens, those antigens that are located at three particular positions, or loci, play an important role in determining the success of a transplant. At each of these positions, known as the –A, –B and – DR loci, a person will inherit one antigen from each parent, giving a total of 6 antigens, each of which have their own specific subtypes (which are identified by a particular number) [4].

 

Together, the presence or absence of these six antigens can have an important bearing on whether and how severely a recipient’s immune system will attack a transplanted organ. In general, “grafts sharing all six HLA antigens, even with mismatches in “minor” antigens, can be expected to function well with relatively low levels of immunosuppression” [5], but in cases where antigens are poorly matched, the likelihood of immune response and graft failure increases as the number of divergent antigens increases. To minimise the prospects of graft failure, tissue typing tests are performed to see how compatible foreign tissues are with the antigens of the likely recipient, with grafts that match well being more likely to be well received in a person than grafts with a poorer antigen match. Well matched grafts are most likely to be found amongst members of a person’s biological family. According to the Mendelian laws of inheritance, there will always be a 50% antigen match between a parent and child, since a child receives exactly half of his or her chromosomes from one parent, with the remaining 50% of antigens being matched to the other parent, who obviously provided the remaining chromosomes. From this, the probability of a complete antigen match between siblings will stand at 25%, the probability of a zero antigen match will also be 25%, and the probability that they will share only half of their antigens will stand at 50% [6]. The only exception to this general rule is when we have identical twins – as these individuals are derived from the same piece of genetic material, the probability that their antigens match will always be 100%. As we move out of the family tree, the probability of finding a full match becomes proportionately lower, with the organs of certain individuals being more suitable in antigen based terms to the recipient than the organs of other individuals, although in all cases, there will be minor differences in the structure of each individual’s particular antigen composition.

 

While ensuring that potential recipients have a good antigen match with new organs may be considered a passive way of responding to the activities of the immune system, an active response would be to engage in immunosuppression, where deliberate measures are implemented to ensure that a patient’s capability against foreign bodies is severely weakened. 

 

One way of controlling rejection is to simply eliminate all the white blood cells, or lymphocytes, that are involved in rejecting tissues grafted into the body. While this procedure can be accomplished by draining the thoracic duct, where these cells are highly concentrated, a more common approach is to use whole body irradiation, where a patient is constantly exposed to doses of radioactive pulses that destroy active lymphocytes as well as retard the development of new lymphocytes. This rarely used therapy, which was the first type of suppressive procedure to have any success in enabling an organ graft to take hold in a patient, is not desirable, since it leads to the destruction of many other cells that are vital for the maintenance of life at the same time.

 

A more popular and effective approach involves chemical immunosuppression, where “cocktails” of different pharmaceuticals are used to inhibit the complete functioning of the immune system. While the first known attempt at chemical immunosuppression involved the failed use of benzene in 1912, the earliest drugs to be used with any success on organ recipients were introduced in the 1960s [7]. Of these, the most important was azathioprine, which was introduced in 1962, when kidneys were first transplanted between unrelated individuals. This drug, which is also known as Immuran, operates by blocking the formation of nuclear proteins that are used by the immune system to attack foreign tissues [8]. Around this time, the use of steroids, such as prednisone, as a form of immunosuppression was also developed, with these products being able to inhibit inflammatory responses and having general immunosuppressive powers. Finally, in the late 1960s, following advances in blood processing, specially derived immunoglobulin products were introduced to counter the activities of the white blood cells and ease the effects on patients of receiving their new organ. 

 

While these early products did help in countering the function of the immune system, they were not always effective, with many organ recipients soon having zero or partial graft function due to a resurgence in immune system activity, especially if drug doses could not be maintained at high enough levels. Consequently, the transplantation of several organs, including hearts, was deemed to be of limited value due to the inability of these products to ensure that the immune system could be fully suppressed for long periods of time. This situation was only altered when, in the mid-1970s, Jean Borel, a researcher working for the Swiss firm Sandoz, was able to synthesis a compound that was based on a fungus with strong immunosuppressive properties. The resulting product, known as cyclosporine, was to become the key drug that enabled transplantation to be undertaken with a much greater degree of reliability than was previously possible. In essence, cyclosporine works by inhibiting the function of T-cells, which are the white blood cells that are involved in identifying transplanted tissues as being foreign to a host. If these cells are unable to work properly, then the immune reaction cannot commence, as the other white cells will not be mobilised into action.

 

In the late 1980s, the fight against the immune system was bolstered by the introduction of another fungus derived drug that is even better than cyclosporine. This drug, known as both RK-506 and tacrolimus, is substantially more effective than cyclosporine in countering rejection while imposing milder side-effects on patients, which has led to it gaining an increasing share of the market in immunosuppressive drugs. In addition, attempts are under way to introduce what are known as monoclonal antibodies into service, which are used to kill specific, pre-identified lymphocytes. While these antibodies can be used during routine organ grafts, they are likely to be most useful in the grafting of tissues, such as bone marrow and intestinal tissue, that have high concentrations of immune cells that are able to trigger severe immune system attacks in a patient. So far, one such product, known as OKT-3, has been deployed for major use, with further products being in the initial stages of use.

 

In future, these forms of immunosuppression may be completely superseded if efforts to introduce gene therapy as an alternate way of countering rejection prove to be successful. Here, the host’s T-cells are removed and “re-educated” to see the donor’s antigens as being a natural part of the body’s own system rather than as foreign elements, with the logic being that if the donor’s cells are tolerated by the host, then no immune attack is likely to occur at all [9].

 

While these aggressive forms of immunosuppression have succeeded in ensuring that organ and tissue grafts are not rejected, they do expose patients to certain hazards. Although each drug may have its own particular side effects (e.g. azathioprine is toxic to the bone marrow), they share the common flaw of weakening the ability of the immune system to protect the host against the predation of undesirable microorganisms. The result is that organ recipients are highly susceptible to infection by a range of common viruses, including the Epstein-Barr virus, cytomegalovirus, and various forms of hepatitis and herpes. Patients also risk greater exposure to bacterial and fungal infections, plus they are more likely to be affected by rare infections such as Kaposis sarcoma, which is a type of cancer known to strike people with poorly functioning immune systems, such as those with HIV. While people who have working immune systems are often able to react adequately against these infections, with organ recipients this is not always possible, as these infections appear suddenly (as the body’s warning systems do not notice them) and manifest themselves in an aggressive manner (since the depleted immune system is incapable of mounting a full response to them). While drugs can be used to fight these diseases, the body may be seriously damaged, with a possibility always existing that there may be an inflammation or complete failure of the organ graft, especially if the patient is forced to stop consuming anti-rejection drugs while suffering from these infections [10].

 

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