1. Types of Transplant:

     The transplantation of human organs has been possible since the 1950s. The first successful kidney transplant between identical twins was performed in 1954, and the first heart transplant in man was performed in late 1967. Liver, lung, and pancreas transplants have also been done.

     The results in kidney transplants are generally fairly good. At the present time, heart transplants do badly, and they also raise very difficult ethical and legal problems as well as som, as yet unsolved biological questions.

     Transplants are of four types. In an auto transplant, the organ is moved from one location to another in the same animal. In an iso transplant the organ is moved from one member of a pair of identical twins to the other. In a homo transplant or allotransplant, the organ is moved from one person to another, not an identical twin. In a heterotransplant, the organ is moved from one species to another.

     Homo transplants present difficult immunological problems, but apparently not insuperable ones. Heterotransplants are, as yet, not feasible, except in some very rare cases.

     Auto transplants are often carried out in persons who have had severe skin burns. Skin grafts from other parts of the body "take" in the burned area. Each such graft has the ability to grow to form a circle about 5 cm in diameter By strategic placement of a number of small skin grafts, rather large areas can be covered with new skin, and the areas from which the grafts are taken heal from the adjacent skin.

     Isotransplants of skin may be performed when so much skin has been burned that there is not enough left to make grafts. Interestingly, homotransplants can also be made in such cases. They are rejected in a few days, but in the time before rejection, the subjects's own skin may have grown enough to make autografting possible. Isotransplantation of vital paired organs, such as the kidney presents more ethical and surgical problems than immunological.

2. The Recognition of Self:

     It was noted in the last chapter that the newborn animal has no mechanisms of chemical immunity; it probably lacks cellular immunity as well. Its defenses consist of its fairly thick skin and some antibodies from the mother that crossed the placental barrier before birth.

     In the process of becoming equipped with the mechanisms of adult immunity, the newborn learns the ability to reject foreign substances by cellular and chemical mechanisms. This requires two types of recognition, the recognition of self and the recognition of non-self. It is as important to the young animal to avoid rejecting its own organs as it is to learn to reject foreign materials.

     In the first few days of life, the young animal's defense systems appear to "study" its own organs. Somehow, these systems "learn" to accept what is there as "self", and at the same time they acquire the ability to reject what is not already there as non-self. Thus, white mice reject black mouse skin as "not self", but if, for example, a newborn white mouse is given some cells from an unrelated black mouse, these cells are accepted as "self" by the white mouse. Later in life, a skin graft from the black mouse to the white may be made. This skin is not recognized as foreign, the immunity mechanism of the white mouse having already accepted the cells of the black mouse as self. Yet the ability of the immunity mechanisms of the white mouse against skin grafts from gray mice or bacteria is quite normal.

     Seemingly, the inoculated animal has gained from the procedure in that it has increased its prospective donors. It has, in fact, been seriously suggested that human babies be injected early in life with a mixed human cell inoculum so that they will be able to accept any type of transplant at maturity. This idea is, to say the best of it, premature. There is evidence that the recipient pays a price for his increased tolerance. Immunologically competent cells inoculated into the young animal may be accepted by it, but they do not quite accept their host, producing antibodies against its cells which may bring about its death or failure of its development.

     The manner in which the young animal learns not to reject what it has been given is quite obscure. It may be postulated that in the presence of foreign cells which have taken root, the defense systems particularly competent to deal with that type of cell cannot grow fast enough to mount an effective attack against it or other cells of its type.

3. Tissue Typing:

     Once a homotransplant has been made, both physician and patient are caught on the horns of a fearful dilemma. In order to prevent rejection of the transplanted organ, the immune mechanisms must be suppressed. But this suppression opens the gates to any number of diseases which are ordinarily prevented only by adequate immunity mechanisms. Over-suppression of these mechanisms results in bacterial and virus diseases. Under-suppression results in rejection of the transplant.

     There is, of course, no problem when the transplanted organ is recognized as "self", and tissue typing, analogous to blood typing, has made great strides. In many cases, the tissue types of donor and recipient are so nearly the same that suppression of the immune response is not really needed. Small differences may exist, but the transplanted organ once it has "taken root" fights off, as it were, the rejection mechanisms.

     In the case of kidney transplants, where the recipient can be maintained for a long time by use of the artificial kidney until a suitable donor is available, "tissue typing" is possible. Though different in details, the principle is similar to that used in blood typing. Perfect matches are almost never achieved, but they can come very close. In the case of heart transplants, the circumstances do not permit leisurely assessment of the tissue type of the donor, who has usually died suddenly. The difference is shown in the success rate for "matched" and "unmatched" kidney transplants. The matched group in a recently reported series had a success rate of almost 80%, while successes in the unmatched group were 50%. Heart transplants, to date, have been about 50% successful, and the figure is not improving with time.

4. Immunosuppression:

     There are many methods of suppressing the immunity mechanisms. The rejection mechanism is usually similar to delayed anaphylaxis, which is to say it is cellular in nature, the predominant cells being lymphocytes and macrophages. A serum has been developed which is antilymphocytic called lymphocytoxic serum. This serum has been fairly useful in controlling the rejection of some transplant organs. A number of synthetic agents which appear to suppress protein formation have also been employed. Unfortunately, these drugs, of which 6-mercaptoporine and azothioprine (Imuran) are typical, prevent the formation of new cells everywhere. Lymphocytes, which have a short life, disappear, but the intestinal epithelium and bone marrow are also lost. It is virtually impossible to find a dose effective against lymphocyte formation which does not affect the other organs adversely.

     The glucocorticoids of the adrenal cortex reduce lymphocyte formation impressively and destroy some of the lymphocytes already present. It is not clear how these hormones act, but it is known that persons treated with them are quite susceptible to infection.

     X-ray irradiation kills cells, particularly those in a high oxygen environment and those which are dividing quickly. Leukocytes are quite susceptible. One of the first immunosuppressive treatments was total body radiation. This was thought necessary because as long as any of the leukocytes or macrophages or the cells which gave rise to them remained, it seemed probable that they would "seed" throughout the body. On the other hand, the destruction of all these cells destroyed immunity altogether. The clotting mechanism was also destroyed as the cells from which the platelets are derived were lost. A number of ingenious attempts to transplant bone marrow as well as the organ, in this case the kidney, from the donor to the recipient failed. Still another approach, employing x-rays has been used. The transplanted organ, during rejection, is surrounded by leukocytes and macrophages from the host. It seemed reasonable to irradiate the transplant organ itself. The host cells mobilized to reject it would, by this means, be destroyed before they could accomplish the rejection. For some reason, this approach has not been very successful.

     An interesting observation concerning transplants has not yet been fully evaluated, but it seems to offer much promise. It has been suggested that rejection of a transplant organ occurs in episodes, rather than being a continuous process. If these episodes could be identified, immunosuppressive treatment could be given at the time of rejection and not at other times. The recipient would be deprived of his immune mechanisms only occasionally; and during the rejection phases he could be protected from infection, in a hospital environment, with precautions against infection and antibiotic drugs. After suppressing a few rejection episodes, the body would, hopefully, came to regard the transplant organ more and more as "self", the time between rejections would become longer and longer, and eventually, rejections might stop.

5. The Future of Transplantation:

     The idea of homotransplantation is so dramatic and appealing that one often loses perspective. For example, at the time of this writing, about 60 human hearts have been transplanted, some of them in circumstances which are ethically and legally questionable. Of these, 29 are alive, a fairly unimpressive score, when it is recalled that the power to predict the fate of a person with a damaged heart is not available to any physician. One recalls the medical bulletins surrounding the numerous heart attacks suffered by Dwight Eisenhower in 1968; each was as gloomy as the worst predicted for those who have died after heart transplantation, yet Eisenhower is alive at this writing without transplantation, though a frightening number of otherwise healthy persons offered to contribute their hearts to him, suggesting that they may have been slightly deranged.

     As has been noted, kidney transplants do reasonably well if they are tissue typed. Presumably, the donors do well, since one kidney is quite adequate to maintain function. Yet, in all the world, there are probably less than 3,000 persons surviving with kidney transplants, and their life expectancy, at present, is 2-3 years. Values for the total number of deaths in kidney failure are not easy to obtain, though a total of 20-30,000 / year seems reasonable. This indicates that rather less than 10% of those with kidney disease have been benefited by the transplantation procedure. Presumably, this value could be raised by better case finding. It is doubtful if perfect case finding and perfect transplantation will ever save as many lives as are lost each year by, for example, avoidable birth injuries. In the case of the heart, the thirty surviving transplant patients represent one twenty-thousandth of the yearly deaths from coronary occlusion. Assuming that more and more surgeons will become willing to undertake the operation, we must raise the question: Where will the donors come from?

     A possible answer is from heterotransplants. Unfortunately, at this time, there has not been a single successful heterotransplant of any major organ.

     The routine answer to the implied question is that these procedures should be regarded as experimental, and, like any other research, they may have unexpected dividends. This is very often the case in pure research and is used to justify it. The argument founders, however, when it is recalled that this is not pure research. It is applied research in the strictest sense, and not one important previously unknown biological or medical generalization has resulted from all these efforts.

     The cost of this research is unknown, but it may be suspected that an equal expenditure might eradicate typhoid fever in South Viet Nam or find 100,000 cases of unsuspected and treatable cases of hypertension in the United States.

     This writer does not believe that the future of transplantation and its consequences is precisely predictable. It is, however, his feeling that the same is true of any type of research. If past experience is a guide, uncontrolled experiments yield little if anything in the way of new insights. Perhaps it is time to reconsider whether these experiments should be performed, at least in the case of the heart.