History of Transplant Immunobiology
History of Transplant Immunobiology (Part 1 of 2).
Rene J Duquesnoy, Ph.D.,
Professor of Pathology and Surgery,
University of Pittsburgh Medical Center
Introduction
During the past quarter-century, transplant immunobiology has established
itself as a scientific discipline to study the mechanisms by which a
recipient rejects or accepts a transplant from a genetically different
donor. In the early history of transplantation, five separate disciplines of
investigators approached the problem of graft rejection. They are the
surgeons, the tumor specialists, the Mendelian geneticists, the biologists
and finally the immunologists. Each had their own agenda and a lack in
communication prevented the recognition and application of conceptional
advances in the other disciplines. Nevertheless, most laws of transplant
immunity had already been defined during the first two decades of the
twentieth century. During the late 1960s, largely because of the work of Sir
Peter Medawar, transplant immunobiology became established as a
multidisciplinary science. This historical overview deals with progress made
in the different disciplines before that time. Part 1 summarizes events
before World War II and Part 2 deals with milestones from the 1940s through
the 1960s. Much of the information have been extracted from seven historical
reviews by noted investigators who offer additional perspectives. These
references are listed at the end of this article.
The Transplant Surgeons
For several milennia, the replacement of diseased or injured organs with
healthy ones has stimulated the imagination of humankind. In the
mythological world, chimeric gods and heros have been transplanted with
heads and other organs mostly from different species (these are examples of
xenotransplants). In the early biblical times the prophet Ezekiel refers to
cardiac transplantation:
"A new heart also I will give you, and a new spirit will be put within you;
and I will take away the stony heart out of your flesh, and I will give you
a heart of flesh".
The New Testament mentions transplant cases like Jesus of Nazareth restoring
a high priest servant's ear cut off by Simon Peter's sword. Later on Saint
Peter replanted the breasts of Saint Agatha pulled off during torture and
Saint Mark replaced an a soldier's hand amputated during battle. These are
examples of autotransplants.
In the fifth century BC, the legendary Chinese physician Pien Ch'iao
exchanged the hearts between a man with a strong spirit but a weak will and
a many with the opposite personality to cure the unbalanced equilibrium of
the two men's energies.
A famous example of a cadaveric allograft is described in Jacopo da
Varagine's Leggenda Aura in 348 CE. In the "miracle of the black leg", the
twin brothers Saints Cosmas and Damian succesfully replaced the gangrenous
leg of the Roman deacon Justinian with a leg from a recently buried
Ethiopian Moor.
While it seems unlikely, that proper surgical techniques were available to
perform these transplants, the practice of skin grafting has been known for
many centuries. During the second century BC, the Indian surgeon Sushruta
pioneered the skin grafting procedure for rhinoplasty, i.e. plastic surgery
whereby the patient's own skin is used to do reconstruction of the nose. In
those days, the cutting noses was a common practice to punish criminal
offenders and of course, we should not discount the fights with knives and
swords.
During the Renaissance, the Gaspare Tagliacozzi, a famous surgeon and
anatomist from Bologna, Italy, used a flap from the upper arm to do
reconstructive surgery on a person who had lost his nose. While autografts
were generally successful, virtually all allografts failed. The practice of
donation consent did not exist, since slaves were used as skin donors, and
often they suffered serious (infectious) complications. Such cases of the
"sympathetic nose" were criticized by Voltaire and other writers. In his
play Hudibras , Samuel Butler states
"When the date of Nock was out, off dropt the sympathetic Snout".
Taglicozzi was well aware of the limitations of the allograft procedure. In
1596, in his treatise "De Curtorum Chirurgia per Insitionem", he concluded
that
"The singular character of the individual entirely dissuades us from
attempting this work on another person. For such is the force and power of
individuality, that if any one should believe that he could achieve even the
least part of the operation, we consider him plainly superstitious and badly
grounded in physical science".
He seemed to have recognized the concept that individual differences were
responsible for these allograft failures. Almost nothing was known about
genetics until Mendel did his pioneering studies 250 years later.
Other early transplant-related activities dealt with the grafting of teeth;
this was done on humans already in the 17th century. Around 1800, the
renowned English surgeon John Hunter, reported successful transplants of
human teeth into the highly vascularized comb of a cock (a xenograft). He
also grafted a cock's spur into its comb and also a cock testes into a hen
("without altering the disposition of the hen"). Hunter concluded that
"Transplantation is founded on a disposition in all living substances to
unite when brought into contact with each other".
This view seems compatible with the modern concept about the relation
between microchimerism and allograft acceptance.
In 1804, G. Baronio in Milan, reported successful skin transplants between
sheep and other animals of the same and from different species. Other
investigators were much less successful with such allografts and xenografts.
In Paris, Paul Bert, a pupil of Claude Bernard, described in his 1863 thesis
"De la Greffe Animale", many kinds of allogeneic and xenogeneic skin
transplants. He could not duplicate Baronio's results. In parabiosis
experiments, Bert established a cross circulation between rats by using
belladonna injections ("la greffe siamoise")
The techniques of Reverdin (1869) and Thiers (1874) for covering granulating
surfaces with small pieces of epidermis lead to therapeutically acceptable
skin grafting procedures. There were no indications of long-term graft
survival. Successful allogeneic skin transplants have been reported. One
case involves Sir Winston Churchill, who during the Sudanese war in 1898,
was asked to donate a piece of skin for an injured fellow officer. The
doctor, a 'great raw-boned' Irishman, spoke to Churchill:
"Oi'll have to take it of you, Ye've heeard of a man being flayed aloive?
Well this is it what it feels loike."
(This is quite a unique approach for obtaining informed donor consent!).
And Churchill wrote:
" A piece of skin and some flesh about the size of a shilling from the
inside of my arm. This precious fragment was grafted to my friend's wound.
It remains there to this day and did him lasting good in many ways. I for my
part keep the scar as a souvenir."
Evidently, an example of a long-term success of a skin allograft!
Corneal transplant procedures were developed during the 19th century. In
1837, the Irishman Samuel Bigger performed a successful transplant of a
full-thickness cornea into the blind eye of a pet gazelle. Continuing
improvement in the grafting procedure and increasing success rates in
experimental animals led to the first successful human corneal transplant in
1906. Corneal transplantation became a standard procedure in ophthalmology
practice, its success was in marked contrast to the high failure rate of
skin grafts.
Because of the advances in suturing techniques towards the end of the 19th
century, surgeons began to transplant organs, especially kidneys between
dogs. Several reports claimed success and long-term graft survival. In Lyon,
the French surgeon Jaboulay tested pig and goat kidney transplants in
humans. Alexis Carrell perfected the vascular anastomosis technique and this
led to all kinds of experimental transplants including the grafting of a
dog's head onto the neck of another dog. All these allogeneic and xenogeneic
transplants were invariably unsuccessful as was the first human cadaveric
kidney transplant performed in 1933 by the Ukranian surgeon Voronoy.
Although nobody understood the reasons for the high failure rate, the
contention was that the major problems had been solved and that little work
remained to perfect transplantation. C.C. Guthrie, who worked with Carrell,
noted that
"...The outlook is by no means hopeless and the principles of immunity,
which yield such brilliant results in many other fields, would seem to be
worthy of being tested in this case".
Indeed, the field of immunology had undergone a dramatic expansion during
the past few decades as illustrated by the following examples:
* Pasteur: vaccination against cholera, anthrax and rabies
* Ehrlich: antibodies and antigens
* Koch: tuberculin hypersensitivity
* Von Behring: therapeutic potential of antitoxins
* Bordet and Gengou: complement activity
* Pfeiffer: immune bacteriolysis
* Belfanti and Carbone: immune hemolysis
* Landsteiner: ABO blood groups
* Portier and Richet: systemic anaphylaxis
* Von Pirquet and Shick: serum sickness
* Arthus: local antibody-mediated reaction
* Donath and Landsteiner: autoimmune disease
* Metchnikoff: phagocytic theory of host resistance
It should be noted that most immunological concepts in those days pertained
to humoral immunity and nothing was known about cellular immunity and
lymphocyte function.
During the first quarter of the 20th century, a relatively few number of
studies were reported on the immune basis of skin graft failures. Underwood
(1914) suggested that an "anaphylactic hypersensitivity" was responsible for
allograft rejection. With repeat skin transplants on children, Holman (1924)
reported that a "second set" of transplants from the same donor "did not
take but disappeared simultaneously with the first group of isografts".
Davis (1917) and Shawan (1919) suggested that blood groups might play a
determining role in allograft success or failure.
The Tumor Specialists
Most of the information about the immune basis of allogeneic transplant
failures would come from the studies of the tumor specialists. Stimulated by
the rapid advances in vaccination against microbial agents, the tumor
researchers attempted similar approaches for the treatment of cancer.
However, preventive immunization or serum therapy of naturally occurring
tumors was generally unsuccessful. This led to the development of
transplantable tumor lines in experimental animals. In 1912, Georg Schöne's
book: "Heteroplastische und Homoplastische Transplantation" summarized the
experimental work reported in about 500 publications during the first
decade. He coined the term: "Transplantationsimmunität" and formulated the
following rules:
* Heteroplastic (xenogeneic) transplants invariably fail
* Homoplastic (allogeneic) transplants usually fail
* Autografts are almost always successful
* There is an initial take of a first allograft which is then followed by
rejection
* Second grafts undergo accelerated rejection if recipient has previously
rejected a graft from the same donor or, if recipient has been
preimmunized with material from tumor donor
* Graft success is more likely when donor and recipient have a closer
"blood relationship"
As Silverstein points out in his 1989 book "A History of Immunology", the
"laws of transplantation" were substantially defined already in 1912. On the
other hand, Leslie Brent concludes in his recent book "A History of
Transplantation Immunology" that this credit to Schöne is not wholly
justified. A subsequent review published in 1916 by Tyzzer on "Tumor
Immunity" confirmed Schöne's findings . Tyzzer further pointed out that
* Presensitization for second set rejection requires living cells
* Cytotoxic antibodies cannot be found
* The delayed reaction is difficult to explain except that an 'immune
body' has been produced
* Lymphocytes predominate at rejection site: the reaction is not merely
exudative but is proliferative as well
* There is no tissue specificity, but rather a racial specificity with
respect to the genetic origin of the antigens
In 1929, Woglom's book "Immunity to Transplantable Tumors" represents a
review of 600 reports published since Schöne's book. His additional
conclusions include
* All living tissues can immunize for accelerated rejection
* Whole blood but not washed erythrocytes can immunize, activity in
leukocytes
* Transplantation immunity is systemic, but certain sites (brain) are
exempt
* Newborns from sensitized mothers are not immune to tumors
* Passive transfer of tumor immunity cannot be done with serum
While considerable evidence had accumulated for an immune basis of tumor
allograft rejection, only humoral mechanisms were considered. However, serum
antibodies were never effective in controlling in vivo tumor growth. In
those days, the concept of cellular (i.e. lymphocyte-mediated) immunity was
not recognized although Da Fano (1910) reported that rejecting tumor
allografts contained large numbers of lymphocytes rather than
polymorphonuclear leukocytes. These findings are similar to those of Tyzzer
who also noted that the lymphoid response was infiltrative and
proliferative.
Murphy and Rous (1912) described the histological predominance of
lymphocytes in fowl sarcoma rejection model. Injection of sarcoma cells in
chicken (as well as duck and pigeon) embryos resulted in uninhibited growth
during the early days of gestation. Thereafter, the tumors were rejected and
this coincided with the appearance of lymphocytes. Tumor rejection occured
also after transfer of adult lymphocytes into the embryo. These data
indicated for the first time a relation between the ontogeny of the immune
response and transplant rejection. Further studies by Murphy have shown that
lymphopenia inhibits tumor rejection and that X-irradiation causes
lymphopenia and depresses antibody formation. Unfortunately, the functional
role of the lymphocyte remained a mystery until the late 1950s.
It should be noted that other investigators did not ascribe to the immune
basis of tumor allograft rejection. In his 1930 Book "Transplantation and
Individuality", the prominent biologist Leo Loeb recognized the genetic
basis of individual differences and transplantation incompatibility. Rather
than considering immune mechanisms, he argued that rejection resulted
because the graft could not make the connections necessary to the survival
in the new environment of the recipient. His concepts were based on
Ehrlich's "athrepsia" theory which considers nutritional needs of tissues
and cells
The Mendelian Geneticists
In 1903, the Danish geneticist Jensen first demonstrated with a breeding
stock of albino mice that genetic differences control rejection of
transplantable tumors. Loeb (1908) and Tyzzer (1909) reported similar
findings with inbred "Japanese waltzing mice". Clarence C Little (1916) used
inbred mouse strains by brother-sister mating and concluded in 1924 that
"...The genetics of tissue transplantation is likely to become in the not
distant future of far greater importance".
In 1929 he founded the Jackson Memorial Laboratory at Bar Harbor, Maine and
George D Snell was hired in 1935. As the editor of the book "The Biology of
the Laboratory Mouse" , Snell was inspired by Little's chapter "The Genetics
of Tumor Transplantation" to pursue a research carreer in mouse genetics
which lead him to the discovery of the H (or histocompatibility ) locus that
controls tumor graft rejection.
During the late thirties, the Englishman Peter A Gorer performed serological
studies with sera from rabbits immunized with mouse red blood cells which
led to the discovery of antigen II expressed by certain mouse strains.
Grafting of albino mouse sarcoma cells induced the development of
anti-antigen II antibodies by the tumor-resistant Auguti and Black mice. All
tumor-susceptible cross-bred mice expressed antigen II and specific
antibodies killed tumor cells in vitro. In 1946, Gorer visited Snell and H
and II were combined as H-2, " a Major Histocompatibility Gene" and nine
alleles were identified. These investigators developed a highly productive
research collaboration which established the major strains of inbred
laboratory mice and more than twenty so-called congenic-resistant mouse
lines that differ only at H-2, most of them are still being used in
immunology research.
Progress in Transplantation Immunology during the Nineteen-Thirties
The nineteen-thirties was a period of decline of transplantation
immunology-related research. The surgeons concluded that, except for corneal
grafting, all attempts at skin and organ transplants will fail due to
rejection. Immunosuppression by X-irradiation turned out not to be
practical, and the immunity hypothesis of rejection was largely discarded.
The tumor researchers had lost faith in the approach of treating cancer via
vaccination or transplantation. The geneticists shifted their interest
towards "pure" genetics by breeding inbred strains of mice and by studying
gene polymorphisms.
And then came World War II (article to be continued in part 2).
References.
* Arthur M Silverstein: A History of Immunology, Chapter 11,
"Transplantation and Immunogenetics" (Academic Press, New York, 1989).
* Paul E. Terasaki (Editor): A History of Transplantation: Thirty-five
Recollections" (UCLA Tissue Typing Laboratory Press, 1991).
* Barry D Kahan: "Transplantation Timeline. Mankind's Three Millennia -
One Maverick's Three Decades in the Struggle against Biochemical
Individuality". Transplantation 51: 1-21, 1991.
* JM Converse and PR Casson: "The Historical Background of
Transplantation" In FT Rapaport and J Dausset (Editors) Human
Transplantation (Grune Stratton, New York, 1968).
* WR Clark: The Experimental Foundation of Modern Immunology, Chapter 8:
"Historical Development of the Concept of the Major Histocompatibility
Complexes" (4th Edit, John Wiley, New York,1991).
* Paul E Terasaki (Editor): History of HLA: Ten Recollections (UCLA
Tissue Typing Laboratory Press, 1990).
* Leslie Brent: History of Transplantation Immunology (Academic Press,
San Diego, CA, 1997).
