Immunology Letters 167 (2015) 6366

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Immunology Letters
journal homepage: www.elsevier.com/locate/immlet

Peter Brian Medawar and the discovery of acquired immunological

tolerance
Domenico Ribatti
Department of Basic Medical Sciences, Neurosciences and Sensory Organs University of Bari Medical School Policlinico - Piazza G. Cesare, 11, 70124 Bari,
National Cancer Institute Giovanni Paolo II, Bari, Italy

a r t i c l e i n f o a b s t r a c t

Article history: The immunological tolerance was described for the rst time with the seminal observations made in
Received 10 June 2015 1945 by R.D. Owen, demonstrating that cattle dizygotic twins display red cell chimerism in adult life. F.M.
Received in revised form 4 July 2015 Burnet and F. Fenner highlighted the Owens discovery in their monograph The production of Antibodies
Accepted 10 July 2015
published in 1949. In 1953, P. Medawar and his co-workers showed that tolerance can be experimentally
Available online 17 July 2015
induced in fetal mice and in chick embryos. In 1960, Medawar in recognition of the signicance of his
1953 and 1956 papers was awarded the Nobel Prize in Physiology or Medicine with Burnet for their
Keywords:
discovery of acquired immunologic tolerance.
History of medicine
Innunology 2015 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.
Not-self
Self
Tolerance

1. Biographic prole
Peter Brian Medawar was born on February 28, 1915, Rio de
Janeiro Brazil, to businessperson Nicholas Medawar and the former
Edith Muriel Dowling. After the conclusion of the First World War
in 1918, the family moved to England. Medawar studied zoology
at Magdalen College, Oxford, completing his undergraduate stud-
ies with rst class honours in 1935. The same year he accepted
an appointment as Christopher Welch Scholar and Senior Demon-
strator at Magdalen College. He was named a fellow at Magdalen
in 1938 and remained at Oxford until 1947, when he accepted an
appointment as Mason professor of Zoology, at the University of
Birmingham.
When World War II broke out in Europe, the Medical Research
Council asked Medawar to concentrate his research on tissue trans-
plants, primarily skin grafts. In these years, Medawar together with
Rupert Billingham and Leslie Brent at the University College in Lon-
don investigated the use of skin grafts to determine whether cattle
twins were monozygotic or dizygotic. He observed that the rejec-
tion time for donor grafts was noticeably longer for initial grafts,
compared to those grafts that were transplanted for a second time.
Medawar formed the opinion that the bodys rejection of skin grafts
was immunological in nature.
From 1951 to 1962, Medawar served as professor of Zoology and
Comparative Anatomy at University College London. In 1962, he
became the Director of the National Institute for Medical Research
(NIMR), Mill Hill (Fig. 1), where he continued his study of trans-
plants and immunology.
In 1960, Medawar was awarded the Nobel Prize in Physiology
or Medicine with Sir Frank Macfarlane Burnet (Fig. 2) for their
discovery of acquired immunologic tolerance. Medawars Nobel
prize award was in recognition of the signicance of his 1953
and 1956 papers [1,2, the alphabetical order of their names was
Medawars convention and acknowledgement of their team work]
on induction of transplantation tolerance, experimentally provid-
ing supporting evidence for Burnets hypothesis of self/non-self
discrimination.
In 1969, Medawar suffered a stroke, the rst of several, that left
him partially paralyzed and forced him to step down as Director in
1972. On October 2, 1987, at the age of 72, Medawar died at the
Royal Free Hospital in London as a consequence of a last severe
stroke.
He was made a Fellow of the Royal Society in 1949 and received
many other honors throughout his career. Medawar was also a
philosopher and a gifted science communicator.

2. The inuence of Burnet

Fax: +39 80 5478310. In 1945, Raymond Owen (Fig. 3) discovered that chiamerism
E-mail address: domenico.ribatti@uniba.it in cattle twins protected red blood cells (RBCs) of both animals in

http://dx.doi.org/10.1016/j.imlet.2015.07.004
0165-2478/ 2015 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.
64 D. Ribatti / Immunology Letters 167 (2015) 6366

Fig. 1. Peter Medawar with colleagues at National Institute for Medical Research Fig. 3. A port trait of Raymond Owen.
(NIMR).

each of them. He made the observation that non-identical (dizy-

gotic) twin cattle, which shared the same placental circulation and
whose circulations were thereby linked, grew up with appreciable
numbers of RBCs from the other twin in their blood: if they had not
shared the same circulation at birth, red cells from the twin injected
in adult life would be rapidly eliminated by an immunological
response [3]. This paper was signicant with regards the hemopoi-
etic stem cell research as well. When Medawar was awarded the
Nobel Prize, he wrote a letter to Owen in which he declared that: I
think it is very wrong that you are not sharing in this prize; the only
consolation is that all your professional colleagues have a perfectly
clear understanding of the fact that you started it all. I have been
tortured by doubts as to whether or not that is a fact that I myself
have made clear enough in my own publications so I looked up
our big paper on tolerance in the Phyl. Trans. of 1956, and dont
think we can reproach ourselves. The fact of the matter is that luck
plays altogether too high a part in these awards they ought at
least consult the intended recipient before the award is made, for
he should know best where credit is due. [4].
From this nding Burnet and his colleague Frank Fenner con-
ceived the notion that potential antigens which reach the lymphoid
cells during their developing immunologically immature phase in
the perinatal period can specically suppress any future response
to that antigen when the animal reaches immunologically maturity.
As Burnet said: In the rst edition of Biological Aspects of Infec-
tious Disease (1940), I rst used the concept that once the simplest
animals evolved, the related requirements for mutation (by the
digestion of other organisms) and for protection from bacterial
infection, required a capacity to distinguish between the chemical
structure characteristic of self and any sufciently different chem-
ical structure which is recognized as not self. Self must remain
Fig. 2. A port trait of Sir Frank Macfarlane Burnet.
undamaged by the enzymes and other mechanisms that can digest
and destroy not self. This is the concept basic to modern immunol-
ogy but no one applied it seriously until 1949. [5].
 D. Ribatti / Immunology Letters 167 (2015) 6366
In 1949, Burnet and Fenner published the second edition of their
book entitled The Production of Antibodies. The core of this book
was the development of the concept of self/non-self discrimination:
If in embryonic life expandable cells from a genetically distinct
race are implanted and established, no antibody response should
develop against the foreign cell antigen when the animal takes an
independent existence. In other words, unresponsiveness to the
bodys own constituents (self) could be established and thereby
enable the lymphoid cells to make the distinction between self
and non-self.
In the Introduction to this monograph, Burnet identied the
problem of antibody synthesis as linked with two key biologi-
cal questions: the condition governing protein synthesis in the
living cells, and the capacity of an organism to remember its
rst encounter with a given antigen and to mount an acceler-
ated secondary immune response. In 1913, James B. Murphy had
demonstrated that the chick embryo was able to tolerate foreign
tissues [6]. Murphy predicted the absence of an immune response
in the chick chorioallantoic membrane at the time in which he
performed the experiments. He wrote that: Apart for the thin con-
tinuation of the chick membrane which covers the tumor and the
ingrowth of vessels with their scant accompanying stroma, there
is no histological evidence of reactions on the part of the embryo
to the invasion of foreign tissue [6]. This observation was con-
rmed after the 1950s by a number of researches concerning the
morpho-functional characterization of the immune system in the
chick embryo. Early lymphoid cells deriving from the yolk sac and
spleen are usually recognizable in the thymus on day 8 and in the
bursa of Fabricius on day 11 [7].Thymus cells are present by day
11 and cell-mediated immunity has been demonstrated day 1314
[8].
Burnet sustained that the rst requirement of an adequate
physiological theory of antibody production is to account for the
differentiation of function by which the natural entry of foreign
microorganisms or articial injection of foreign red cells provokes
an immunological reaction while the physiologically similar autol-
ogous material is inert. (. . .) The self-pattern is hereditary, while
the process by which the self pattern becomes recognizable is
acquired and takes place during embryonic or immediate past
embryonic stages [9].
As Burnet explained in his Nobel lecture: my part in the dis-
covery of acquired immunological tolerance was a very minor one,
it was the formulation of an hypothesis that called for experiment.
(. . .) I have introduced ideas about the evolution the process of
self-recognition because a biologist I believe we know less about
the process of differentiation and morphogenesis than about any
other major eld in biology. There is an insistent suggestion that
immunological self-recognition is derived from the process by
which morphological and functional intensity is maintained in
large and long-lived multicellular organisms [10].
Medawar applied the technique of skin transplantation rather
than by looking for the presence of absence of antibodies. If, to a
new-born mouse of strain A, Medawar gave an adequate number of
spleen cells from strain B mice, he found that a few weeks later the
treated A mouse would retain indenitely a skin graft of B which
would otherwise have been rapidly rejected. This demonstration
provided the proof for the validity of Burnets conjectures. The the-
ory postulates that for the successful transplantation of a healthy
organ into a body containing a defective one, the normal immune
mechanisms must be overcome so that the foreign organ will be
tolerated.
In a letter to Christopher Sexton, Medawar wrote that: As a
young research worker, trying with my colleague Rupert Billing-
ham to make sense of the remarkable phenomenon that skin grafts
exchanged between dizygotic twin cattle are accepted as readily as
they are between monzygotic twins, I came across The production
65
of antibodies by Mac Burnet and Frank Fenner. This propounded
the notion that later came to be called tolerance and made spe-
cial reference to the work on cattle twins of Dr. Ray Owen in the
Department of Agricultural Genetics in the University of Wisconsin.
Owens work enabled us to interpret our own ndings on skin grafts
in cattle and this in turn inspired us to provide the rst demonstra-
tion of acquired immunological tolerance that provided the proof
for the validity of Burnets conjectures. [11].
3. The discovery of acquired immunologic tolerance
Medawars earlier research had focused on the rejection of
skin grafts by burn patients [12,13], using outbreed rabbits to
investigate the process [1215]. This research identied immune
responses characterized by lymphocyte inltration of genetically
dissimilar grafts, but not of autografts, as being responsible for
rejection in both species.
In 1953, Medawar, Billingham and Brent published their rst
work [1] in which they demonstrated that some mice inoculated
in utero with a mixture of donor strain including splenocyte cells
failed to reject donor strain skin grafts when these were trans-
planted 68 weeks after birth. In other words, donor splenocytes
could be engrafted by their intravenous infusion into immunolog-
ically immature mice in utero or perinatally. When the inoculated
recipients mature, they could accept skin and other tissues from
the donor mouse strain.
Once the mice reached adulthood, Medawar performed skin
homografts from the original donor strain. The grafts were
accepted, but grafts from third, unrelated mouse strain were
rejected, indicating that self was dened during embryonic devel-
opment as Burnet had hypothesized [1]. Normally, mice reject skin
grafts from other mice, but the inoculated mice in their experiment
accepted the donor skin grafts. They did not develop an immuno-
logical reaction. The prenatal encounter had given the inoculated
mice an acquired immunological tolerance. A signicant proportion
of the recipient became tolerant indenitely. Medawar and his col-
laborators had proven Burnets hypothesis. The immune system is
not pre-programmed to distinguish between self and non-self but
learns to do so as a result of exposure to self-molecules during early
development. In their paper, Medawar and his collaborators com-
mented the previous ndings of Owen [3] as follows: An exactly
comparable phenomenon has been described by Owen, who found
that the majority of dizygotic cattle twins are born with, and long
retain, red blood cells belonging genetically to the zygote lineage of
its twin. . .There is reason to doubt that this is because cattle twins,
being synchorial, exchange blood in fetal life. . . [1].
In 1953, the same year of the paper of Medawars lab, a
Czech immunologist, Milan Hasek published a paper in which he
described the technique of embryonic parabiosis, involving the
anastomosis of two allogenic chick embryos through their chorioal-
lantoic membranes, resulting in free exchange of fetal blood from
about the 10th day of incubation [16]. Through this technique Hasek
demonstrated that, after hatching, the parabionts were less able to
form antibodies in response to each others serum proteins. Hasek
meet Medawar and Brent at an international morphology meeting
and thereafter interpreted his data in terms of acquired tolerance.
In 1956, Billingham and co-workers published a second semi-
nal paper including experiments showing that tolerance could be
abolished in adult animals by the adoptive transfer of normal or
presentisized lymphoid cells [2].
For the British immunologist N. Avrian Mitchison, the
work of Medawar on immunological tolerance: performed the
immensely important service of making transplantation scien-
tically respectable and gave the clinicians a well-dened goal
to attain. Moreover, antigen-specic suppression of the immune
66 D. Ribatti / Immunology Letters 167 (2015) 6366
response by something akin the acquired tolerance remains an aim
of research in transplantation and autoimmunity. [17].
In his autobiography entitled Memoir of a Thinking Radish,
Medawar explained: Thus the ultimate importance of the discov-
ery of tolerance turned out to be not practical, but moral. It put new
heart into the many biologists and surgeons who were working to
make it possible to graft, for example, kidneys from one person to
another [18].
In 1968, 15 years after the paper of Billingham, Brent, and
Medawar [2], Robert Good and Fritz Bach reported the rst
two successful human bone marrow transplants [19,20], and in
1980s, new immunosuppressive drugs were discovered, including
cyclosporine, tacrolimus, sirolimus, and mTor inhibitors.
As has outlined Park, the work of Medawar and Burnet: altered
the direction of immunologys development from chemical studies
of antigen-antibody reactions to biological investigations into liv-
ing organisms and their continuously shifting physiological states
[21].
References
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cells, Nature 172 (1953) 603606.
[2] R.E. Billingham, L. Brent, P.B. Medawar, Quantitative studies on tissue
transplantation immunity. III. Actively acquired tolerance, Phil. Trans. R. Soc.
London B. 239 (1956) 357414.
[3] R.D. Owen, Immunological consequence of vascular anastomoses between
cattle twins, Science 102 (1945) 400405.
[4] L. Brent, The discovery of immunologic tolerance, Hum. Immunol. 52 (1997)
7581.
[5] F.M. Burnet, Walter and Eliza Hall Institute 191565, Melbourne University
Press, Melbourne, 1971, p. 68.
[6] J.B. Murphy, Transplantability of tissues to the embryo of foreign species. Its
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[7] W. Leene, M.J.M. Duyzings, G. Von Steeg, Lymphoid stem cell identication in
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[15] P.B. Medawar, A second study of the behaviour and fate of skin homografts in
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[20] F.H. Bach, Bone marrow transplantation in a patient with the WiskottAldrich
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