An Interview with Professor Manuel Varela: Graft Rejection and Immune Tolerance-The Work of Peter Medawar

Oct 22, 2018 by

Michael F. Shaughnessy –

Peter Medawar

1.Professor Varela, we have all heard about donors and donor transplant anda bit about “rejection” for various reasons. Also, people who have been burned in fires- often have skin grafts.  First, what is the current state of the art in terms of transplants – what CAN be transplanted and what cannot?

While the genomic DNA sequences of the human population are largely identical, just over 99% identical, individual human beings are just slightly dissimilar enough to constitute distinctive beings with slightly different cell and tissue antigens.  These slight antigenic dissimilarities make it quite difficult to transplant cells, tissues, organs, etc., collectively known as grafts, between any two distinct individual people. Dr. Peter Medawar discovered that the immune system that was largely responsible for this difficultly and making it ultimately possible to perform routine transplantations.

Patients with certain birth defects, burns, trauma, organ failure, or other infectious or cancerous maladies have a number of options available to them. One possibility is to remove the defective, burned, damaged, or cancerous tissue without performing a transplant. While it is certainly not an optimal situation for everyone, such patients, for example, may permanently lose their spleens, reproductive organs, parts of their gastrointestinal tract, gall bladder, appendix, some of their liver, most of their stomach, or one of their kidneys.

For patients who do require graft transplantation, however, the types of grafts can consist of a variety of living organs, tissues, and cells. With respect to the organs, transplantation grafts may include the heart, bladder, kidney, spleen, lung, intestinal tract, liver, pancreas, thyroid, testis, or the uterus. The most commonly grafted organs are kidneys, lungs, and hearts.

The types of tissue that may be used for graft transplantation include, for example, cornea, valves of the heart, nerve tissue, arteries, veins, bone, tendon, and skin. Recently included in this list of transplantable tissues are faces, hands (in one case two hands in one patient), feet, and muscle tissue, the latter type of which may also include bone tissue in the transplant. The most commonly grafted tissue is bone marrow. Face transplantation has gained popular attention, as faces are considered of importance for many personal, sociological, and psychological reasons.

The types of cells that may be transplanted include, for instance, red blood cells, bone marrow cells, which may include stem cells, immune cells, and other white blood cells. The most commonly transplanted cells are the red blood cells.

Interestingly, what cannot be transplanted presently includes the brain, head, and a total body. 

Unless the donor and recipient are genetically identical, such as in the case of identical twins, the grafts will be vigorously rejected by the recipient’s immune response as foreign. Dr. Medawar was the principle investigator who made this discovery. Perhaps the donor and recipient are highly related, as may be the case, for example, with a biological parent and child or between natural siblings.  In such cases, although the possibility of graft acceptance by the recipient may be somewhat enhanced, nevertheless, the chances are that even these types of highly related grafts will be summarily rejected by the recipient. Scientific advances in the development of immunosuppressive medicines have made it possible to conduct graft transplantation on a routine basis. 

Acceptance of a donor’s graft by a recipient, therefore, requires that the immune response of the graft recipient be sufficiently suppressed, and invariably the immunosuppression requires a lifelong administration of powerful anti-immune response chemotherapy for the recipient. Failure to take one’s immunosuppressive medication, even for a day or even missing one dose, may result in the graft recipient reacquiring an active immune response that could very well immediately reject the graft.

Furthermore, because the graft recipient has a largely immune-deficient status for the remainder of their lifetime, danger of infection by microbes and cancer may be a constant possibility.  In individuals with normally functioning immune systems, much of the microbes that one encounters on a minute-by-minute basis, and cancer, are regularly kept in check, neutralized, destroyed, or are purged from the body.  Furthermore, the immune system will enthusiastically remember the next encounter with the same microbes and cancers. The protection and memory afforded by the immune system are its primary purposes. In graft recipients, however, the immune system is subdued, and as a result, individuals with transplants may not be able to mount an effective immune response to infection and cancer. Thus, constant vigilance is required.

2) Now let’s talk skin—can skin be grafted from one part of the body to another (in the case of fire) and can say a husband receive skin from his wife?

When one considers skin, and graft transplantation in general, there are various types. In the first case you mentioned above, a graft from one part of the body to another part of that same body, it is usually referred to as an autograft. An example may include transplanting normal skin from the leg of an individual to another area of that same individual in which the graft recipient skin area is damaged by a burn, a microbial lesion, or some other form of physical trauma. Autografts are virtually always accepted, being rarely, if ever, rejected.

The other case you mentioned above, i.e., skin grafting from a donor husband to a recipient wife, or vice versa, the graft transplant would be referred to as an allograft.  In this case, as with most clinical transplantation cases, the donor and recipient are genetically distinct members of the same species. That is, the graft donor and recipient are unrelated—they will not be genetically identical to each other. Even grafts between biological siblings are considered allografts, as they are not genetically identical.

In cases where the graft donor and recipient are genetically identical, as in the case of identical biological twins, the graft would be referred to as an isograft. It is also sometimes referred to as a syngeneic graft. Consequently, since in these cases the donor and recipient quite frequently have the same sorts of immunegenetic capabilities, the recipient often accepts an isograft.

There are cases where the donor and recipient are not members of the same species, say from a lower animal to a human or between different lower animal species.  These types graft transplants are referred to as xenografts. An example of a xenograft may include a heart valve from a pig donor that is grafted onto the heart of a human being.

3) Why is it that there is a graft rejection, and what basically happens? 

The short answer to your inquiry is that the immune system is responsible for graft rejection by a recipient. Dr. Peter Medawar was a key investigator in making this determination that graft rejection was based on the immune response of the recipient. He found that skin allografts were rejected because of the immune system and that graft rejection followed the biological laws of immunity.  

The immune system of a graft recipient considers any foreign material to be a certified antigen, i.e., non-self-material, and from an immune system point of view, such antigenic matter must be destroyed or purged from the recipient. An immune system based graft rejection, while it may certainly be an otherwise well-meaning characteristic for many individuals who are fighting off an infection or cancer, clinical graft rejection is emphatically not good for patients who need the graft because of trauma or burn injuries.

The manner in which the immune system determines whether a graft is accepted or rejected is correlated with the genetic level of identity or similarity between donor and recipient.  In general, the more similar the graft donor and recipient are in terms of their antigenic characters, the better the chances are that recipient accepts the transplanted graft.

The primary component of the immune system that is devoted to graft rejection is called cellular mediated immunity. More specifically, it is the role of the so-called major histocompatibility complex (MHC) in lower animals and the human leukocyte antigen (HLA) of human beings to reject any graft that is considered non-self, or foreign. Additionally, the humoral immune response, making antibodies against the graft antigens, can play an important role in graft rejection.

If an allograft is to be accepted by a recipient, it often does so within 14 days after the graft transplantation therapy has been achieved. However, if an allograft is to be rejected by the recipient, it does so in a series of stages, depending on how many times an individual encounters a graft.

The first stage is called a first-set rejection, and it occurs between 7 and 10 days after the transplantation procedure has been performed in the recipient. The first set reaction mounts a so-called primary immune response, forming killer immune cells and memory cells that circulate in the body, patrolling for any second exposure to the rejected graft. The killer cells, called cytotoxic thymus-derived lymphocytes, or simply cytotoxic T-cells, serve to kill cells of the foreign graft.

If the recipient, who is now immune to the graft, encounters the same previously rejected graft a second time, then a more rapid second-set rejection transpires in the recipient who is again rejecting the graft. The second set reaction occurs usually under 4 days and is wholly complete in just under 6 days. The immune response that occurs during a repeated antigenic graft encounter is referred to as a secondary response. Typically, because of the memory cells that were produced during the first graft encounter, a secondary response during second graft encounter is more rapid than a primary response.

In both the first- and second-set reactions, rejection involves an infiltration of the graft with immune cells that harbor their incompatible MHC or HLA types on their surfaces. These cytotoxic T-cells can produce lytic enzymes that destroy graft cells, or the T-cells can produce pore proteins that allow programmed cell death factors to make entry into the cells of the graft to kill the graft cells. Both of these lytic and pore systems will potently kill the foreign antigenic graft cells. Additionally, antibodies directed against graft antigens will target the graft for destruction by the cell mediated immunity and components of innate immunity.

4) Now, on to Peter Medawar who seems to be a prolific scientist – he seemed to work also in immune tolerance.  We are all fairly familiar with the immune system- but give us your perspective on the immune system in the human body.

In addition to discovering that graft rejection was mediated by a recipient’s immune system, Dr. Medawar also provided the first experimental evidence to support the immune tolerance principle, a hypothesis of which was first formulated by co-Nobel Laureate Dr. Frank Macfarlane Burnet.  Dr. Burnet had proposed that if an individual were exposed to a foreign non-self antigen early on during embryonic development, that non-self antigen would be considered self, up to a point. It was Dr. Medawar who then performed the key experiments to directly test this immune tolerance theory.

In his Nobel Prize winning report, published in the journal Nature on October 3 of 1953, Dr. Medawar delineated his experimental work performed at University College, housed at the University of London, demonstrating that rejection of foreign tissue was mediated by the recipient’s immune system. His work in the same Nature paper showed also that if exposure to foreign antigens happened before a certain stage of development had occurred in graft recipient animals, then the immune system ignored (i.e., tolerated) the grafted foreign tissue. Dr. Medawar also showed that if an individual recipient was exposed to foreign antigens after the developmental stage had already passed, the immune tolerance was not observed.  Before this threshold in the developmental stage is reached, immunological tolerance predominates, but after the threshold, the immune system is intolerant and, thus, mounts a rejection response.

In his first experiment, Dr. Medawar grafted donor skin from mice of “strain A” onto the backs of “strain CBA” recipient mice.  The strain A grafts were summarily rejected by the CBA strain recipients. In his Nature article, Dr. Medawar recorded the rejection process.  He noted that the transplanted A mice skin on the CBA mice backs started to deteriorate after 2 to 3 days, showing discoloration and hardening, and ultimately being reduced to dried-up scabs after two weeks, completing the graft rejection process. The rejection reaction was even more vigorous if strain A skin was grafted again onto the backs of the same CBA mice that had already rejected the A skin the first time. 

Next, Dr. Medawar took out lymph node tissue from these CBA mice that had rejected A mice skin and used the excised tissue to inject brand new CBA mice that had never been exposed to A mice skin.  Then, Dr. Medawar challenged these CBA-lymph node inoculated mice with skin from A strain mice—the A skin was quickly rejected. It was as if the mice, immunologically speaking, had already seen the grafts before, but the mice had not. Thus, Dr. Medawar was successful in actually transferring the skin rejecting capability; that is, he transferred potent immunity against foreign grafts to new test animals without having to induce the immunity to do so. He had demonstrated a passive form of immunity transference against grafts.

Following up on these experiments, Dr. Medawar then prepared cells taken from A strain mice and grafted these A cells into pregnant CBA mice, letting these pregnant CBA mice produce their offspring.  After the CBA offspring were born, they were then challenged with skin from A strain mice, and the grafts were accepted! 

Dr. Medawar then used these CBA offspring mice, with their ability to tolerate A strain skin, for another experiment. 

In the new experiment, Dr. Medawar injected these so-called A strain-tolerant CBA offspring mice with lymph node tissue from brand new CBA mice that had rejected A strain mice skin. The previously A strain-tolerant CBA offspring mice now rejected the transplanted A strain skin!  It was an unprecedented finding.

The lymph node tissue that they had received presumably produced antibodies against the A strain skin. Now the previously tolerant CBA recipients rejected the A strain skin. Thus, Dr. Medawar had demonstrated that exposure of mice in utero (embryonic) to foreign antigenic grafts (from A strain mice) had made them (CBA mice) immunologically tolerant to that same foreign graft! 

Thus, Dr. Medawar had conducted the very first experimental demonstration of Dr. Burnet’s prediction that antigens would be immunologically tolerated in embryonic tissue. Dr. Burnet had hypothesized that the immune system was gradually acquired rather than developing abruptly at conception.

Dr. Medawar then confirmed that the same type of immune tolerance properties was in play when he performed another set of experiments in chickens. When Dr. Medawar took blood from young chicks of Rhode Island Red chicken variety and injected their blood into White Leghorn adult chickens, these White Leghorn birds vigorously rejected new grafts from Rhode Island Red chickens.  On the other hand, if Dr. Medawar took blood from the Rhode Island Red chickens and injected it into embryos of the White Leghorn, they then accepted the grafts from Rhode Island Red animals!  In so doing, Dr. Medawar had experimentally established the phenomenon of acquired immune tolerance. It was Nobel Prize worthy work.

5) What exactly is meant by immune tolerance?

In modern times, immune tolerance refers to a general lack of responsiveness to antigens. Fortunately, immune tolerance functions to protect us all from our own so-called self-antigens, biological matter that we need in order to live. Such immune tolerance occurs every day, in fact every minute, in virtually all living higher organisms.  For instance, immunologically speaking we humans tolerate our own self antigens all the time.

Immune tolerance is actually an active process that must constantly be maintained in order to produce the immune system unresponsiveness to our self-antigens. In other cases, we sequester our self-antigens by partitioning them away from any self-specific immune cells, resulting in a protective effect upon our own antigens.

We do not seem to mount immune responses to our own cells, tissues or organs, as such an immune intolerance situation would most certainly be detrimental to our own well-being, potentially destroying our own needed self-antigens. We obviously require our own cells, tissues and organs to live.

In certain cases, however, individuals may lack immune tolerance to self-antigens, thereby mounting an immune response to their own cells, tissues, or organs, destroying them and producing an autoimmune disorder. Autoimmunity can result in certain pathological circumstances, producing disease in such cases.  For instance, autoimmunity to one’s own adrenal glands results in Addison’s disease, and autoimmunity to one’s pancreas produces type 1 diabetes. Virtually any tissue or organ can succumb to a lack of immune tolerance, resulting in rare but serious ailments.  Autoimmunity may occur against the heart (producing a myocardial infarction), the kidneys (glomerulonephritis), acetylcholine receptors (myasthenia gravis), thyroid (Graves’ disease and Hashimoto’s thyroiditis) or DNA and red blood cells (lupus).

6) What were some of the other contributions of Peter Medawar? And where andwhen was he born, and what have I neglected to ask about this famous scientist?

Dr. Peter Brian Medawar was born Rio De Janeiro, Brazil, on the 28th day of February in the year 1915 to parents Nicholas Agnatius and Edith Dowling Medawar.  Medawar’s father was Lebanese, and his mother was British. The Medawar family actively pursued many intellectual interests, such as literature, music, the arts, and the sciences. Young Peter was recognized early on as being intellectually gifted.

In 1928, at the age of 13, Medawar attended a boarding school at Marlborough College in Wiltshire, England but suffering racism there, he transferred to Magdalen College, in Oxford, England, taking his undergraduate degree with highest honors in the field of Zoology, at the age of 20, in 1935.  He then took on a position as a demonstrator and then became a fellow, at Magdalen College. In 1947, he took his Ph.D. degree with honors.  He moved to Birmingham where he became professor of zoology until 1951, when he relocated to University College, London. In 1960, he was awarded the Nobel Prize in the areas of Medicine or Physiology for his work with immunological tolerance and tissue transplantation. In 1962, Dr. Medawar became the director of the prestigious National Institute for Medical Research and later chair of the transplantation division at the Medical Research Council, until 1986.  Dr. Medawar passed away on the 2nd day of October, in the year 1987, at the age of 72.

In his book titled “Memoir of a Thinking Radish: an Autobiography” Dr. Medawar recounted an incident that forever changed his life, and consequently the lives of future transplant patients.  While spending an afternoon with his wife, Jean Shinglewood Taylor, and his young daughter, a bomber aircraft crashed within a few hundred meters from where the family had been sitting. Rushing to the crash site, Dr. Medawar encountered a badly burned pilot who was still alive. The burn patient inspired Dr. Medawar to study skin grafting for the express purpose of providing a clinical option for treatment of burn victims.

After the Nobel, Dr. Medawar pursued studies of senescence in cellular systems. This work dealt mainly with the process of aging in living cells, tissue, and in the body. The area remains an actively studied field of study in modern times.

Later in life, Dr. Medawar became a productive author, writing numerous books devoted to science and philosophy.  One of my favorite books of Dr. Medawar’s is called “The Threat & the Glory.” He felt that it was both a glory and a threat that all in science, which in principle is possible, can be accomplished if the intention to do so is suitably resolute. He thought that scientists might bask in their glory while the non-scientific public may recoil at the perceived threats of new scientific discoveries.

In one particularly noteworthy book written by Dr. Medawar titled “Advice to a Young Scientist” he provided compelling guidance to aspiring scientific investigators, myself included amongst his many lifelong and devoted readers. As a result of this book and others, Dr. Medawar’s contributions will continue to remain an active influence in the world of science and literature.

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