Strains of M. tuberculosis during infection

Winning essays 2003

Noor Jawad of Henrietta Barnett School wrote the winning essay, 'Why organ grafts are rejected but a foetus is not', and received the first prize of £50. The two runners up, who each received £25 for essays on 'Mad cows and English men', were:

Every entrant received a certificate recording their participation in the competition, and a copy of the latest Mill Hill Essays. As part of their prize the three winners also spent a day at the Institute.

Read the winning essay

Why organ grafts are rejected but a foetus is not, by Noor Jawad of Henrietta Barnett School

A graft is described as 'a piece of living tissue, organ etc., transplanted surgically'. Subsequently, the graft must battle with the host's immune system, which strives to rid the body of this 'foreign' invader. A foetus, however, although also 'a piece of living tissue', does not provoke the same reactions as the graft. Although there are circumstances when a foetus is rejected, and when an organ graft is not, it is more likely that the foetus survives whereas the graft does not. The key to understanding why this is so lies in understanding the body's immune system and the interactions between both graft and foetus with their host.

Immunology - key concepts

When faced with a foreign body, leukocytes are responsible for removing it before it poses a major risk to the body's survival. B cells (a type of lymphocyte) recognise antigens on the surface of the foreign cells as 'non self', and manufacture antibodies against them. These antibodies bind with the antigens and aid their removal from the body. T cells (another type of lymphocyte) also play an important role via cell-mediated immunity.

Organ transplants

The concept of organ grafting is not a novel one. Early attempts began in 800BC when Susrata, an Indian surgeon, grafted new noses onto people using flaps of skin. One thousand years later in China, organ transplantation was being attempted, but unsuccessfully. The first human heart transplant was performed in 1967 by Christiaan Barnard in Cape Town. The patient survived for 18 days, but the operation was hailed a success.

The success of an organ graft depends upon the blood type and Human Leukocyte Antigen (HLA) or tissue match of both the donor and the recipient. The more the tissue resembles the patient's own, the less likely it is to be rejected. As soon as the organ is transplanted, B cells attack the foreign material, and the latter directly stimulates the killer T cells, which cause rejection. Thus the human body rarely accepts long-term transplanted organs. Research has shown that rodents born without a thymus (the place where the T cells must pass through during maturation) have no mature T cells and therefore cannot reject transplants.

How can we prevent rejection?

Doctors try to prevent rejection with a series of toxic anti-rejection drugs, the most common being cyclosporin:

Cyclosporin, produced from a poisonous Norwegian fungus, has significant immunosuppressant properties, suppressing the action of the T cells that initiate the attack on the transplanted organ. Since this 'wonder molecule' has been introduced, the graft acceptance rate has increased to about 85-90% for kidneys, hearts and livers after one year, but the life of a graft is reduced because there are other side effects due to the long-term use of drugs. The patient becomes more vulnerable to other infections because the immune system has been dampened down.

It is important to note that transplant patients never fully accept their grafted organ, and most spend the rest of their lives on drugs 'walking a tightrope between rejection and infectious diseases'.

How is organ rejection advancing?

Research has found that nitric oxide, a free radical, which is highly volatile and reactive, can improve transplant rates because it damages cells and can therefore be used after transplant surgery. Blood transfusions can also be performed using blood from the donor - donor-specific transfusions (DST). The success rate is very high, although there is the chance of accidental AIDS transmission. Scientists are also looking to alternative transplantation methods such as xenotransplantation (from one species to another, e.g. from pigs to humans), due to long transplantation waiting lists. However, many factors should be taken into consideration such as the shorter animal life span, the chance of animal diseases being transmitted and ethical considerations of using animals for this purpose.

Pregnancy

During pregnancy, the mother's immune system initially attacks the embryo as a foreign body, trying to reject it. The surrounding tissue looks inflamed when the embryo implants, similar to the response to infection. However research has shown that a stress hormone, corticotrophin-releasing hormone (CRH), plays a major role in preventing foetal rejection. CRH is produced by the trophoblast - the outer layer of cells in the early ball of cells that later forms the placenta and induces the trophoblast to secrete a protein called Fas ligand. This FasL protein fits into the Fas molecule on the surface of the T cells like a key fits into a lock. This causes the T cell to enter an apoptosis stage, which results in T cell suicide. In this way T cells can be destroyed before the embryo develops, thus preventing rejection. Research has also found that the cells lining the uterus also produce CRH. Overall, this CRH/FasL system halts the mother's immune response to the foreign foetus.

Another way in which foetal rejection is prevented is due to the fact that foetal blood and maternal blood never mix, unlike organ grafts. This means that T cells are unable to reach the foetus and attack it. Antibodies are produced by the other against the paternal genes that the foetus possesses, and these can pass from the mother to the foetus. Rejection is avoided by the production of immunosuppressive hormones such as HCG (human chorionic gonadotrophin) and progesterone, which inhibits T cells. The foetus can be regarded as an extension of the mother (thus 'self@) rather than an addition, as the graft is. This can be disputed however, and symptoms such as pregnancy sickness (and ultimately miscarriage) may be a rejection response by the mother. However, the precise details of immunology in pregnancy have yet to be understood.

In conclusion, the foetus is less likely to be rejected, because it is already 50% 'self' and evolution has devised many features that assist its survival. The reason for organ rejection has yet to be understood fully. We know that the more similar donor and recipient are, the more likely it is that the graft will be accepted as 'self', and drugs are used to prevent rejection. However there are many complex interacting factors which need to be uncovered before this interesting subject is fully appreciated.

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