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A Biological Analysis of Individuality

1996; Lippincott Williams & Wilkins; Volume: 326; Linguagem: Inglês

10.1097/00003086-199605000-00002

1528-1132

P. B. Medawar,

Medical History and Innovations

It is appropriate to begin a symposium on immunology and its relationship to orthopaedics with an account of the life and work of Sir Peter Medawar who laid the foundation for our understanding of cell mediated immunity. The following classic article embodies his basic observations and ideas. The fact that his work was based on experiments with skin grafting does not diminish its importance to orthopaedics. Rather, it reemphasizes the value to our specialty of basic scientific work in related and, what may seem to be completely unrelated, areas. Peter Medawar (Fig 1) was born in Rio de Janeiro. He was educated in British boarding schools before attending Marlborough College and later, Magdalen College, Oxford, from which he graduated with a degree in zoology in 1935. As a lecturer in the Zoology Department at Oxford he was influenced by Howard W. Florey, 1 of the pioneers in the clinical use of penicillin. During World War II, Medawar began his studies of autografts and allografts of skin while working to improve the care of badly burned fliers. This work established the immunogenetic basis of allograft rejection and outlined its pathophysiology. In 1947, Medawar became professor of Zoology in Birmingham, moving to the University College, London in 1951. He became the director of the National Institute for Medical Research, London, in 1962 and remained in this position until 1971 when he was physically incapacitated by a stroke. During his entire academic career he concerned himself with the problems of the immunology of tissue transplantation. Medawar lectured and wrote extensively on the subject and trained an entire generation of investigators in his laboratory. The recipient of numerous honors and awards, including a Nobel Prize in 1960, this extraordinary man was the most distinguished British biologist of his generation. He laid the basis for our present practice of tissue and organ transplantation. Leonard F. Peltier, MD, PhD For ten years my colleagues and I have been studying a curious and clinically disturbing phenomenon which the following paragraphs will describe and make clear. Injuries such as burns may often have as their consequence the total destruction of a large area of skin. A defect of skin, like a gap in bone, will not heal satisfactorily of its own accord, and if the area of loss is greater than a few square inches, ugly scarring and disabling contracture are almost inevitable. Widespread loss of skin is therefore now made good by the operation known as skin grafting. The surgeon removes a thin sheet of skin from some uninjured part of his patient's body and causes it to heal into place over the area of loss. Skin so repaired (or so replaced) is very nearly as good as new, and the graft itself will have been cut so thin that the area from which it was removed will heal of its own accord within as little as two weeks. Were this not so, the operation would obviously be pointless. Such a procedure becomes less and less satisfactory as the area of skin loss increases, and a very severely burnt patient may well have lost more than can be wholly made good from his own resources. The surgeon cannot now cover the entire raw area with grafts, so what he does, in effect, is to “seed” it with small disks or squares of sound skin, relying upon outgrowth from these little grafts, combined with ingrowth from the edges of the wound, to complete the surface of new skin. This is admittedly a makeshift: the end result is neither elegant nor functionally very efficient: but it is designed to save life, and so it does. Now what the surgeon actually does is not nearly so interesting to the biologist as what he does not do; for if the patient cannot afford his own skin for grafting, the obvious alternative is to use skin removed from someone else. There is no surgical obstacle to such a procedure, and voluntary donors are not hard to come by; nor would there be any difficulty in setting up a “skin bank” to be drawn upon in just such an emergency, for skin may be stored alive and without deterioration for an indefinite period at the temperature of liquid air or solid carbon dioxide. The difficulty is that the surgeon's intended act of mercy is treated by the body as a genetical confidence trick. Skin taken from one human being will not form a permanent graft upon the body of another: the surgeon uses such a graft, if he uses it at all, only as a temporary dressing in cases of extreme emergency. Even grafts transplanted from mother to child or from brother to brother do not survive their transplantation for more than a matter of weeks. Each human being is so constituted as to be resolutely intolerant to skin transplanted to him from other members of his species. So is each rabbit, guinea-pig, and cow; nor will any mouse accept a skin graft from any other. The problem of how this comes about and why it should be so forms the subject matter of this article. INTOLERANCE TO GRAFTS Animals are not immediately intolerant of skin grafted upon them from other members of their own species. Such “homografts,” as they are called, behave at first just as if they had been transplanted from one part to another of the same individual. They heal on just as securely, they are as quickly and as richly infiltrated by new blood vessels, and they undergo just the same processes of reorganization and repair, perhaps even lasting long enough to grow new skin glands and hairs. Intolerance is provoked by the homografts themselves in the course of their residence: there is no readymade immunity against them as there is against the red blood corpuscles of an individual of blood group A which have been transfused into an individual of group B. The first outward sign that all is not well is a puffiness and inflammation of the grafted skin, leading to a weakening and then to ulceration of the skin surface, and finally to abject necrosis followed by a sloughing away. Just how soon this happens-perhaps after only ten days, or as long as two months-depends upon a number of variables, and in exceptional cases the homografts may last long enough to cause the surgeon to begin to hope that a natural law is about to be suspended in his favour. One of these variables is the quantity of foreign skin that is grafted: the more that is grafted, the shorter is expectation of life. Another is the genetical relationship between donor and recipient, for the more closely the two are related the longer may the graft be expected to survive. (The limiting case, when the donor and recipient are genetically identical, will be discussed later.) A third is the level of efficiency of the body's general defences, and it is a matter of some significance that homografts will last longer on a sickly animal than on a healthy one. However that may be, the homografts eventually succumb to the reaction they have provoked from their host, and the animal then becomes refractory over its whole body surface to any further grafts transplanted from the same donor. The grafts have elicited and succumbed to an “actively acquired immunity reaction.” A human being at first submits to and later recovers from an “attack” of foreign skin in much the same sort of way as he recovers from an attack of measles. Readymade immunity is absent or ineffective; resistance develops in the course of exposure, and recovery is followed by a refractory or “immune” state. There is much collateral evidence to support this analogy; for example, treatments which depress the activity of the cells that mediate immunological responses will also prolong the life of foreign skin; but the crucial evidence of the existence of specific “antibodies” directed against the cells of the foreign graft is still to be found. What is the material basis of the differences between individuals that are revealed by these incompatibilities? It would be a grave misrepresentation of the facts to say that the individuals of a species are chemically different from one another-at least in the sense that each human being (or mouse) contains at least one chemical compound which, being a unique property, distinguishes him from all others. For that is not the sort of way in which individuals differ. It is one of the fundamental theorems of modern genetics that the inborn differences between the individuals of a species are combinational in character. We differ not because we have unique endowments but because we have unique combinations of endowments, and it is a genetical truism to say that the number of possible combinations is larger than the number of actual individuals. The number of distinct combinations of blood groups, which cattle might have, runs it is thought, into 13 figures. It is the same with human beings. A man may be of any one of the blood groups A, B, AB, O; any one of these may be combined with any one of the blood groups M, MN, or N; any of these in turn with a dozen or so variants of the socalled Rh (rhesus) blood groups, and with other less familiar systems like Lutheran, Kell, and Duffy. Combine these with the multitude of other ways in which human beings may differ in their inborn endowments, and it becomes easy to admit that the number of possible genetic variants of human beings is virtually infinite. This, then, is the sort of way in which individuals differ. It is a fair guess that there are not less than twenty distinct immunity-provoking agents (hereafter “antigens”) which, present in the donor of a skin graft and lacking from its recipient, may cause the grafted skin to break down and be sloughed away. The number of possible combinations of twenty distinct antigens is very large indeed. The likelihood that human beings may be grouped for the compatibility of their skins as they may be grouped for compatibility of their blood is therefore very small. When blood from a person of group B is transfused into a person of group A, the grafted red cells (for such they are) become agglutinated and the recipient suffers a severe and sometimes fatal reaction. This incompatibility of blood is the consequence of what is, in a technical sense, an immunity reaction; and one is at first tempted to think it closely analogous to the reaction which leads to the casting off of foreign skin. Incompatibility of skin is indeed analogous to incompatibility of blood, but not to incompatibility of the type that has just been exemplified; for a person of group A is innately immune to the red blood corpuscles of a donor of group B-antibodies against B cells are already present in his blood and they agglutinate the grafted cells without delay. The immunity provoked by transfusions that are incompatible in terms of the Rh series of antigens is of quite a different sort. There is no ready-made incompatibility, and a first or even a second transfusion may have no perceptibly harmful consequence; but repeated transfusions cause a state of overt incompatibility or immunity to be “actively acquired.” This is closely analogous to the reaction elicited by the grafting of foreign skin, but the analogy must not be pressed too far, for there is no evidence at present that antigens present on red cells are the same as those on the cells of skin. Repeated blood transfusions are not the only means by which an immune state may be called into being by the antigens of the Rh system. A mother lacking the more powerful antigens of the Rh series may, in her second or subsequent pregnancies, develop an immunity against these antigens if they are present in her unborn child, and it has been shown that this is a principal cause of haemolytic disease of the newly-born. The foetus of a mammal is, in a sense, a graft of foreign tissue, and I shall discuss later the problem of why it does not invariably immunize its mother against itself. EXCEPTIONAL TISSUES The skin transplantations so far considered are of the type called “orthotopic”-they are grafts of skin into positions formerly occupied by skin. It is not to be assumed that all tissues of the body behave as skin does when grafted to someone other than its owner; or that foreign grafts are made equally unwelcome, in an immunological sense, in all the positions of the body to which they might be transplanted. There are immunologically privileged grafts and immunologically privileged positions. Corneal grafts, for example, are among those that may be transplanted from one person to another, and there has lately been some correspondence in The Times about the difficulties of ensuring their supply. There are half-a-dozen possible reasons why corneal homografts should succeed, but by a series of elegant and decisive experiments my colleagues, Dr. R. E. Billingham and Miss T. Boswell, have shown this one to be sufficient; corneal homografts survive because the position into which they are transplanted is such as to withhold from them any immunity reaction which they might provoke. The peculiarity of the cornea is its lack of any direct blood supply. The window of the eye is quite evidently free from blood vessels; the cornea derives its nourishment from the aqueus humour, a filtrate or perhaps an active secretory product ultimately derived from blood but lacking blood cells and proteins. Embryos, it should be said (and this is implicit in the foregoing argument), are not intolerant of foreign cells; “individuality,” in so far as intolerance measures it, is a property that comes into being during the course of development. Correspondingly, the embryo has no specific defences of its own against parasitization by viruses or bacteria. The very young mammal acquires its immunity at second hand from its mother's blood or milk, or both. Identical twins behave towards skin grafts as if they were still the single individual of their beginnings; but identical twinning is not the only way in which genetical similarity can be achieved. Prolonged and close inbreeding is an alternative, and if mice are propagated by brother-to-sister matings for upwards of 20 successive generations, they come to resemble each other as closely as if they were identical twins. Such mice are almost invariably tolerant of each other's cells. It would be a most disturbing anomaly if they were not. THE MEDICAL PROSPECT There is no reason to doubt that, by laboratory artifice, skin from one individual can be caused to live indefinitely on the body of another. For example, it should not be too difficult to reproduce experimentally the sort of “desensitization” or acquired indifference to foreign tissue that happens naturally in the lifetime of twin cattle. But will this be of any medical value? Almost certainly not, for the medical usefulness of any such procedure is bedevilled by the fact that every occasion on which skin homografts are wanted is an acute surgical emergency. There is no time to embark upon a course of desensitization, and it is folly to think that every human being should be desensitized by routine as an insurance against his being severely burnt. (It would be much easier, though not much less foolish, to deposit some of one's own skin in a “bank.”) What one hopes to be able to do is to prolong the life of foreign skin grafts for time enough to see the patient through the period of acute surgical distress, and to allow the surgeon to carry out his definitive operation of repair at a time chosen by himself, in his patient's interests, and not dictated by the exigencies of an immunity reaction over which he has no control. Now Dr. Krohn, Dr. Billingham, and I find that the injection or even the local application of cortisone will prolong threefold or fourfold the life of skin transplanted from one rabbit to another. Cortisone is (or is closely related to) one of the many steroid secretions of the cortex of the adrenal gland. It seems to control the proliferation and general physiological activity of the connective and blood-forming tissues of the body, a family to which the cells that mediate immunity reactions belong; and to this property it owes its spectacular powers of relieving the symptoms of rheumatoid arthritis. Unfortunately, the rabbit is particularly susceptible to the influence of cortisone; it has yet to be shown to prolong the life of skin homografts in human beings. Cortisone will prolong the life of skin homografts in guinea-pigs only, so Miss E. M. Sparrow finds, in daily dosages that would make a clinician shudder. For the time being, therefore, the less said about its possible benefactions the better. The problem will be solved, of course, this way or otherwise, provided the scientist continues to give his mind to it. The fact that the body rejects tissue that is genetically foreign to it is not really surprising. The parasitization of one organism by another is a phenomenon almost as old as evolutionary time, and the body has, so to speak, committed itself in general to the belief that any foreign living matter that gains access to it bodes no good. Physiologically speaking, we are hardly to know that the surgeon grafts skin from one person to another with the most praiseworthy and benevolent intentions. What is surprising, perhaps, is the extreme subtlety with which the body discriminates between what is foreign to it and what is not. BIOLOGICAL IMPLICATIONS The differences between individuals that reveal themselves in incompatibility of blood and tissue have, so far as we know, only harmful consequences. They are responsible for all the exacting routine of blood grouping, or, alternatively, for the accidents that will happen if grouping is not attended to; for haemolytic diseases and perhaps other abnormalities of the newly-born; and for the fact that badly burnt people cannot be permanently repaired by grafts of skin from their relatives or from voluntary donors. All this is a clinical misfortune, but it is not a biological mystery: it is part of the bill for having defence mechanisms of such marvelous powers of discrimination. The body will respond by specific defence mechanisms to chemical compounds (such as proteins conjugated with smaller molecules that alter their reactivity) which, being laboratory artifacts, no animal has ever experienced before. This is just as well, for it is a general truth that parasites evolve faster than their hosts, so that a defence mechanism that was not in this sense forward-looking would be outwitted time and time again-much as staphylococci outwit penicillin by the evolution of strains resistant to its action. A last problem may be raised. The mammalian embryo consists of tissue genetically foreign to its mother: why, then, does it not always provoke an immunity reaction against itself? The principal reason is that mother and foetus have strictly independent circulations. The foetus, as a graft, is in some ways comparable with a piece of foreign skin transplanted to the cornea of the eye: being unvascularized by its host, it is protected from the consequences of any immunity reaction it might elicit. It is certain that the possession of an independent circulation was a necessary condition for the evolution of mammals, and it is at least arguable that the sort of immunological quarantine it imposes on the foetus is the only reason why the possession of an independent circulation is absolutely obligatory. But there are likely to be ancillary devices to protect the foetus, and a good case can be made for the belief that the increased secretion of cortisone-like steroids during pregnancy is one of them. The problem discussed in this article was first formulated by clinical surgeons, and clinical surgery will get whatever material benefits are the outcome of its solution. But it must be clear that the problem is not a “medical” one at all; it is simply a bioligical problem with a rather obvious medical context. Genetics, immunology, embryology, and endocrinology have all been called in evidence of the uniqueness of individual mice and men. The fact that the evidence moves so freely to and fro across these frontiers is of no particular significance; it merely goes to show that, outside our pedagogic conventions, these frontiers simply do not exist.Fig 1: . Peter Brian Medawar (1915-1987).