3 History of HLA
Erik Thorsby
INTRODUCTION
The first HLA antigen was described by the French
immunogeneticist Jean Dausset in 1958, i.e. just over 50
years ago. It was initially detected as an alloantigen on
human leukocytes, called MAC,1 but later became HLA-
A2. Since then we have seen a tremendous development
in our knowledge of the HLA complex, both concerning
the structure and function of its many genes and gene-
products. It is impossible to give a full account of this
development in a short book chapter. Thus, I will focus
on some highlights in the history of HLA class I and II
antigens, or molecules as they should be called now,
which I consider to be among the most important.
Further, it is impossible to mention all who have
contributed to this development. I must therefore
apologize to those whose important contributions could
not be included for lack of space. The chapter is a revised
and extended version of a recent short review by the
author on the history of HLA.2 Only some selected key
references will be given in the text and are listed at the
end of the chapter. References to other work mentioned
in the text are found in the review mentioned above.2
For a more comprehensive treatment of the subject
the reader is referred to earlier extensive reviews by
others.3-5
EARLY EXPERIMENTAL
ALLOTRANSPLANTATIONS
Experimental allotransplantations started in the late
1800s, first by surgeons mainly using skin grafts, and later
by tumor biologists to study the mechanisms behind
tumor growth. It was the latter group of scientists who
noted that while transplanted allogeneic tumors usually
were rejected, sometimes a tumor would grow in the
recipient if it belonged to the same stock as the donor of
the tumor. In the early 1900s, two US geneticists, Ernest
E Tyzzer and Clarence C Little performed some crucial
tumor transplantation experiments in the offspring of
crosses between mice who were susceptible or resistant
to an allogeneic tumor. Based on the results they arrived
at the conclusion that susceptibility to the growth of
allogeneic tumors was genetically determined, possibly
by as many as 15 genes. The nature of these susceptibility
(or rather resistance) genes and their products was,
however, unknown. The same was the case of the
mechanisms responsible for the rejection.
REJECTION IS CAUSED BY AN IMMUNE
RESPONSE
The fact that rejection of allografts was caused by an
immune response was first demonstrated by the British
biologist, Peter B Medawar in 1944-45. By performing
allogeneic skin transplantation in rabbits he observed a
massive infiltration of lymphocytes and monocytes in
the rejecting grafts. Further, rejection led to sensitization
which caused a quicker rejection of a second graft from
the same donor, but often not of grafts from a third party
donor, i.e. the sensitization was specific for the donor. In
addition, he found that rejection was a systemic response
and not localized to the site of the graft.6,7 Based on these
observations, Medawar concluded that rejection of an
allograft is caused by a specific and systemic immune
response against the graft. He received the Nobel prize
in 1960 for his seminal observations (shared with another
pioneer immunologist, Frank McFarlane Burnet).
 Chapter 3
IT STARTED IN THE MOUSE: DISCOVERY OF
HISTOCOMPATIBILITY ANTIGEN II AND THE
H-2 COMPLEX
An antigen responsible for rejection was first discovered
by the British physician and pathologist, Peter A Gorer
(Fig. 3.1) in 1936, working at that time in the Lister
Institute for Preventive Medicine in London. Following
a suggestion from the British geneticist JBS Haldane, he
studied whether resistance factors to the growth of
allogeneic tumors might be
associated with some blood
group antigens. First he found
that his own serum contained
natural antibodies which
could distinguish between
erythrocytes of three inbred
strains of mice. He next
immunized rabbits with
erythrocytes from the same
three stains of mice and
obtained antisera with which
he could distinguish three Fig. 3.1: Peter A Gorer
different blood group (1907-1961)
antigens in mice: 8
Antigen I: Shared by strains A and CBA, weakly
expressed in C57BL
Antigen II: Expressed strongly in strain A, weakly in
CBA, but not in C57BL
Antigen III: Shared by strains A, CBA and C57BL.
The rabbit antiserum recognizing antigen II behaved
similar to his own serum.
He then grafted a tumor from a mouse of strain A
(carrying antigen II) into mice of strain C57BL (lacking
antigen II) and into offspring of crosses between these
strains. He found that mice lacking antigen II quickly
rejected the tumor, while it grew well in strain A and
first and second generation crosses between A and C57BL
which expressed antigen II. Further, he made the
important observation that sera of mice rejecting the
tumor contained antibodies against antigen II.9 Thus
antigen II, shared between malignant and normal cells,
apparently was an important resistance factor to the
growth of an allogeneic tumor, when present in the donor
and absent in the recipient. Note that these findings were
made before Peter Medawar first established that
rejection of allogeneic transplants was caused by an
immune response against the graft.
After World War II, Gorer visited the mammalian
geneticist George D Snell (Fig. 3.2) at the Jackson
History of HLA 43
Laboratory, Bar Harbor,
Maine, US. Snell was
studying tumor resistance
genes, which he called
Histocompatibility or H genes.
Chapter 3
He had previously found
that mice carrying the Fu
gene, causing mice to
develop a deformed tail,
were resistant to the growth Fig. 3.2: George D Snell
of tumors from strain A. (1903-1996)
Thus, he concluded that there was a strong linkage
between an H gene and the Fu gene. During his visit
Gorer tested various backcross strains segregating for the
Fu gene with his antiserum against antigen II, and found
that erythrocytes of almost all mice carrying the Fu gene
tested negative with his antiserum. In contrast, the
presence of antigen II on erythrocytes of the host was
strongly associated with growth of the tumor from strain
A.10 This was further strong evidence that antigen II was
encoded by a gene at an H locus in strain A, and that the
mice carrying the Fu gene probably carried another allele
at the same locus. Their combined results indicated three
alleles at this H locus. Since Gorers antiserum against
antigen II was the first to detect an allele at this H locus,
it became Histocompatibility locus 2, or H-2.
The work of Gorer and Snell, extended by Snell and
coworkers and others later,3 established that the H-2 locus
encoded strong or major histocompatibility antigens,
inducing quick rejection, compared to weaker histocom-
patibility antigens encoded by other loci. The H-2 locus
therefore became the major histocompatibility locus in
mice. Other H loci became minor H loci.
Snell received the Nobel prize in 1980 for his
contributions. At that time Gorer had passed away (he
died in 1961). If not, he would no doubt have shared the
prize with Snell.
Later the H-2 locus became more and more complex,
seemingly consisting of several different subdivisions,
and where each allele apparently determined many
different antigens. In 1970, I first suggested that the
hitherto known H-2 genes belonged to two segregant
series, encoded by two different loci, D and K
respectively, similar to the at that time two known loci
in the HLA complex.11 Snell and coworkers arrived at a
similar conclusion.12 The two locus model for the H-2
antigens known at that time turned out to be correct.
Subsequently, many additional H-2 loci were found,
including those encoding the Ia antigens (see later). The
H-2 locus became the H-2 complex, or the major
histocompatibility complex, MHC, in the mouse.
 44 Section 1 Introduction to Immune System

DISCOVERY OF THE FIRST HLA ANTIGENS Jon van Rood and Rose Payne both followed up their
initial findings of alloantigens on human leukocytes.
Three papers appeared in 1958, by Jean Dausset, Jon van
Using (at that time) a sophisticated computer analysis of
Rood and Rose Payne and their associates
the reaction patterns of 60 sera from multiparous women
respectively,1,13,14 which laid the foundation of what was
against leukocytes from a panel 100 donors, van Rood
Section 1

later to become the HLA complex. All three papers

(Fig. 3.4) found some sera which apparently detected a
described antibodies in human sera from multitransfused
diallelic system of leukocyte antigens, which he called
patients or multiparous women, sera which reacted with
4a and 4b (later to become HLA-Bw4 and -Bw6,
leukocytes from many but not all individuals who were
respectively). The results were reported in his PhD thesis
tested. Thus, antibodies in these sera detected
in 1962.15 Two years later Payne (Fig. 3.5), together with
alloantigens on human leukocytes.
Julia and Walter Bodmer (see Fig. 3.9, later), also using
The credit for discovery of the first HLA antigen
sera from multiparous women, detected two leukocyte
goes to Jean Dausset (Fig. 3.3). Studying sera from
antigens, LA1 (later HLA-A1) and LA2 (later HLA-A2),
patients who had received multiple blood transfusions,
apparently controlled by alleles, but also postulated at
he found seven sera which behaved quite similarly in
least one additional antigen, LA3, determined by an
that they agglutinated leukocytes from 11 out of 19
additional allele at the same locus.16
individuals tested.1 Since leukocytes from the donor of
the sera were also not agglutinated, the antisera
obviously detected an alloantigen present on human
leukocytes. He gave the name MAC to this antigen, to
honor three individuals who had been important
volunteers for his experiments, and whose names began
with the initials M, A and C respectively. Antigen MAC
(later to become HLA-A2) was present in approx. 60
percent of the French population. At the end of the paper
Dausset wrote: Finally, in a more long-time perspective,
the study of leukocyte antigens might become of great
importance in tissue transplantation, in particular in bone
marrow transplantation (translated from French). Thus,
he was very foresighted! For his discovery, Dausset
received the Nobel prize in 1980 (shared with Snell and Fig. 3.4: Jon J van Rood (1926- ) in the center, with his long-time
Baruch Benacerraf). associate Aad van Leeuwen (1929-2009) to the left, at one of the
earlier IHWSs

Fig. 3.3: Jean Dausset (1916-2009) discussing the complexity of

HLA at one of the earlier International Histocompatibility Workshops Fig. 3.5: Rose Payne (1909-1999), together with the author
(IHWSs) (1938- ) just after the fourth IHWS in 1970
 Chapter 3
Several other investigators also made original or
first identifications of leukocyte antigens in these early
days of HLA. They included, among others, Bernard
Amos, US; Richard Batchelor, UK; Ruggero Ceppellini,
Italy; Paul Engelfriet, The Netherlands; Wolfgang Mayr,
Austria; Flemming Kissmeyer-Nielsen, Denmark; Ray
Shulman, US; Paul Terasaki, US; Roy Walford, US; and
myself.17
SOLVING THE COMPLEXITY THROUGH
INTERNATIONAL COLLABORATION: THE FIRST
THREE INTERNATIONAL HISTOCOMPATIBILITY
WORKSHOPS
The relationship between the different leukocyte (later
HLA) antigens which had been identified, and their
polymorphism and genetics, were difficult subjects to
solve. No single laboratory could do this alone. Therefore,
very early, International Histocompatibility Workshops
(IHWSs) were established, where investigators in the field
met to compare their reagents, techniques and results,
and communicate new findings. The aims and results of
all 15 workshops hitherto organized are briefly
summarized in Table 3.1 (see later), and comprehensively
treated in the proceedings from the workshops.2
The first three IHWSs were wet workshops where
the investigators carried out their experiments together,
in the same laboratory, using the same panel of cells. The
first IHWS was organized by Bernard Amos (Fig. 3.6) as
early as in June 1964, at Duke University, Durham, North
Carolina, US. Amos should be considered the father
of the workshops. He was also able to obtain funds from
the National Institutes of Health, NIH, to organize the
first workshops. The major aim of the first IHWS was to
compare different techniques to detect leukocyte
Fig. 3.6: Bernard Amos (1923-2003)
History of HLA 45
antigens, since a variety were in use by different
investigators (leukoagglutination, the indirect
antiglobulin consumption test, mixed agglutination,
complement fixation, microcytotoxicity, etc.). Twenty-
three investigators attended the workshop, testing the
Chapter 3
same sera and cells with their own techniques. Much to
their dismay, most of the results were discordant.
These disappointing results, coupled with the fact that
van Rood at the first IHWS had presented evidence also
for other clusters of leukocyte antigens in addition to 4a
and 4b, prompted van Rood to organize the second
IHWS already in August the next year, at the University
of Leiden, The Netherlands. Here investigators from 14
different groups tested their own antisera, using their
own techniques, on cells from a common panel of 45
individuals. The main aim was to see if local
specificities defined in one laboratory correlated with
those defined in other laboratories. Most encouraging, it
was now found that several local specificities were indeed
identical or almost identical. These included the
specificities MAC (of Dausset), LA2 (of Payne and the
Bodmers), 8a (of van Rood), B1 (of Shulman) and Te2 (of
Terasaki), later to become HLA-A2. Further, Dausset et
al and van Rood et al also presented work suggesting
that most of the antigens they could identify were
controlled by a single chromosomal complex.
The third IHWS was organized by the well known
human geneticist Ruggero Ceppellini (Fig. 3.7) at the
University of Turin, Italy, in June 1967. The main aim
was to study the genetics of the hitherto identified
leukocyte antigens. Thus, the organizers included blood
from 11 families, including monozygotic twins, which
were tested blindly by the different investigators with
Fig. 3.7: Ruggero Ceppellini (1917-1988), giving a talk
at one of the earlier IHWSs
 46 Section 1 Introduction to Immune System
their own typing antisera and techniques. Several
investigators were now using the quicker and more
reliable microcytotoxicity test, initially developed by Paul
Terasaki (Fig. 3.11, later) and McClelland, which later
became the standard serological typing technique for
Section 1
HLA antigens. The results demonstrated strong
correlations between 13 local specificities. But more
importantly, it was now fully established that most of
these specificities were encoded by closely linked genes
at one chromosomal region. This led to the designation
HL-A for this chromosomal region, i.e. human leukocyte;
locus A. This was later changed to HLA (without the
hyphen), where A is now interpreted to mean antigen.
Just after the third IHWS, in 1968, an HLA
Nomenclature Committee was established (first sponsored
by the World Health Organization, WHO), consisting of
leading investigators in the field. The Committee, which
still exists, is responsible for giving official names to HLA
specificities and loci. In the early days, an officially
recognized or accepted HLA specificity was a
specificity which could be recognized by several different
investigators, using their own serological reagents. An
account of the lively discussions at the first meeting of
the Committee in New York in September 1968 is given
by Roy Walford in ref. 5. By quickly establishing a
common, uniform nomenclature and thus avoiding a
long list of various, local specificities, the Committee has
played a major role in unravelling the complexity of HLA
genes and their products.
SEVERAL LOCI IN THE HLA CHROMOSOMAL
REGION
The first to propose two HLA loci were Bodmer and
Payne and their associates in 1966. They called the two
loci LA (adapted from the LA antigens of Payne and
coworkers) and 4 or Four (adapted from the 4a and
4b antigens of van Rood). At the third workshop in Turin,
Ceppellini and coworkers also proposed that there were
two different mutational sites within the HLA
chromosomal region. It was, however, the work of
Flemming Kissmeyer-Nielsen (Fig. 3.13, later) and
associates in 1968 which firmly established that there
were two HLA loci.18 In extensive studies of unrelated
individuals and families they showed that the two loci,
LA (later named HLA-A) and 4 (later named HLA-B), were
closely linked and contained at least seven and eight
alleles, respectively.
There had been suggestions in 1969 from Dausset,
Terasaki and Walford and their associates also of a third
locus in the HLA chromosomal region. The strongest
evidence came, however, from the studies by a
Scandinavian group of an antiserum detecting a new
leukocyte antigen, AJ, which in population and family
studies behaved as if it was encoded by another HLA
locus separate from LA and 4.19 Later, we were able to
show in cell-membrane capping experiments that antigen
AJ indeed was independent of antigens encoded by the
LA and 4 loci, which firmly demonstrated the existence
of a third HLA locus. This was first called the AJ locus
(from its first antigen), but was later named HLA-C.
In 1964, two groups, Bach and Hirschorn, and Bain,
Vas and Lowenstein, independently described
morphological transformation and cell division if
leukocytes from two different individuals were mixed.
This was to become the mixed lymphocyte culture (MLC)
reaction. Fritz H Bach (Fig. 3.8) together with Amos then
demonstrated that the MLC reaction was governed by
genes in the HLA chromosomal region. Cells from
siblings who were genotypically HLA identical generally
did not respond to each other in reciprocal MLC tests.20
Later Amos and Bach also obtained results indicating that
the HLA determinants stimulating in the MLC test might
not be identical to the serologically defined HLA-A and
-B antigens. This was fully confirmed by Yunis and Amos
in 197121 who demonstrated that there was a separate
MLC locus in the HLA chromosomal region responsible
for the determinants inducing the MLC response. From
their studies in mice, Bach and co-workers then proposed
in 1972 that there were two different types of
determinants encoded by genes in the H-2 complex;
serologically defined (SD) and lymphocyte defined (LD)
Fig. 3.8: Fritz H Bach (1934- )
 Chapter 3
determinants, the latter being responsible for stimulation
in the MLC test, a concept which was also adapted
for man.
This started an extensive hunt for the LD
determinants in man. It was Mempel et al22 who first
suggested that MLC stimulating cells which were
homozygous at the LD locus could be used to type for
LD determinants in man, in that non-responsiveness of
the responding cells would indicate that the stimulating
and responding cells shared the same LD determinant(s).
Several investigators showed that this indeed was
possible, and multiple LD determinants were identified
by what was generally called MLC typing. This was also
a major topic at the sixth IHWS in 1975, organized by
Kissmeyer-Nielsen in Aarhus, Denmark. By exchange of
62 LD homozygous typing cells, eight different LD
determinants were clearly defined by MLC typing by the
different participating laboratories, of which six LD
determinants were accepted by the nomenclature
committee and provisionally (by the prefix w =
workshop) named HLA-Dw1-6. The corresponding
locus was named HLA-D. Sheehy et al reported23 that
LD (or Dw) determinants could also be identified by
priming lymphocytes against given LD determinants,
which was called primed LD typing; PLT. Later studies
showed that the provisional HLA-D locus consisted of
several different closely linked loci, which encoded three
different series of determinants; DR, DQ (previously
called DC) and DP (previously called SB).
In the early 1970s, several groups reported that some
sera which contained HLA antibodies were able to inhibit
the MLC reaction. This was confirmed by van Leeuwen
et al in 1973 who also obtained suggestive evidence that
the responsible antibodies recognized antigens present
on B cells, but not on T cells or platelets.24 Thus these
antisera might serologically detect HLA-D determinants.
This was therefore made a major topic at the seventh
IHWS in 1977, organized by Julia and Walter Bodmer
(Fig. 3.9), in Oxford, UK. Using 177 selected antisera
recognizing antigens on B cells, antisera which had been
exchanged between the participating laboratories, it was
possible to convincingly identify seven different B cell
antigens which were closely correlated to the HLA-Dw1-
7 determinants, and which therefore were named HLA-
DRw1-7 (DR = D Related).
In the early 1980s, the overall picture was that the
HLA chromosomal region, found to be present on the
short arm of chromosome no. 6, encoded six different
very polymorphic series of determinants; A, B and C
which were present on most nucleated cells, and DR, DQ
History of HLA 47
Chapter 3
Fig. 3.9: Julia (1934-2001) and Walter Bodmer (1936- ). Dancing
has been one of the highlights at the farewell dinner of all IHWSs
and DP which were mainly present on B cells, monocytes
and dendritic cells. In 1967, Ceppellini had introduced
the term HLA haplotype for the genetic information
carried by each of the two HLA chromosomal regions of
an individual. In 1977, Jan Klein introduced the terms
class I to describe the A, B and C antigens, and class II to
describe the DR, DQ and DP antigens (and the corres-
ponding antigens in other species), a nomenclature which
has since been followed. Further, after the discovery of
additional class I antigens, HLA- G, -E and -F, which have
a more limited tissue distribution, the latter were named
non-classical HLA class I antigens, while the HLA-A,
-B and -C antigens were named classical HLA class I
antigens.
Later, many additional loci were detected in the HLA
chromosomal region, or the HLA complex as it is called
now. As a matter of fact, in the extended HLA complex
covering a total of 7.6 Mb, as many as 252 genes have
been found expressed, of which approx. 28% may have
immune functions (Fig. 3.10). This is further treated in
other chapters in this book.
THE HLA CLASS I AND II ANTIGENS ARE STRONG
HISTOCOMPATIBILITY ANTIGENS
From skin grafting experiments in the early1960s, both
Dausset and coworkers and van Rood and coworkers
had obtained evidence that the HLA antigens are strong
histocompatibility antigens. This was confirmed and
extended in studies by Ceppellini et al25 and Amos et
al.26 They showed that first set skin grafts exchanged
 48 Section 1
Section 1
Fig. 3.10: A very simplified picture illustrating just some of the many loci in the extended HLA complex. Red squares: Classical HLA
class I and II genes. Blue squares: Non-classical HLA class I genes. Yellow squares: Some other HLA complex genes
between HLA identical siblings (who had inherited the
same HLA haplotypes from their parents) had a
significantly longer survival time than skin grafts
between siblings differing for one or two HLA
haplotypes. Since, skin grafting resulted in the
production of antibodies against HLA antigens of the
donor, this was also evidence that the HLA antigens were
important histocompatibility antigens.27
The first data suggesting a correlation between HLA
matching and kidney allograft survival were presented
by Terasaki (Fig. 3.11) and coworkers as early as in 1965.28
These early results are quite remarkable given the
broadly reacting serological typing reagents available at
that time, and just typing for a few HLA-A and -B
antigens. Other references to early work on the impact
of HLA matching on clinical kidney transplantation are
Fig. 3.11: Paul I Terasaki (1929- )
Introduction to Immune System
found in refs 4 and 27. Taken together, the results from
skin and clinical kidney grafting, together with other
evidence27 demonstrated that the HLA complex indeed
was the major histocompatibility complex, MHC, in man, as
it had been previously shown for H-2 in mice.
At the start of the 1970s, it had become accepted that
the survival of kidneys transplanted between HLA
identical siblings was superior to all other combinations.
HLA typing to obtain such or other well matched
combinations in kidney transplantations from living
related donors became of general use. Following several
reports of better survival also of HLA matched compared
to mismatched kidneys from cadaveric donors,27 HLA
typing to obtain well matched kidneys in such unrelated
combinations was also used in many centers. However,
the benefits of the latter application were hit hard by a
presentation by Terasakis group at the Third Congress
of the International Transplantation Society in Hague,
The Netherlands, in 1970. While HLA matching was
found to be of great importance using living related
donors, they reported no effects of HLA matching when
instead cadaveric donors were used. The results raised
such a storm at the Congress that their paper was not
included in its proceedings. Instead, it was published
separately in an article in Tissue Antigens in 1971,29
accompanied by comments by its editor at that time,
Kissmeyer-Nielsen, discussing reasons for the
discrepancy between the disappointing results reported
by Terasakis group compared with the beneficial effects
of HLA matching in cadaveric donor transplantation as
reported by several others. The result was, however, that
HLA matching in cadaveric donor transplantation went
into a state of limbo. The differences in survival found
between grafts from HLA matched and mismatched
cadaveric donors were considered by many surgeons to
be too small to matter.
 Chapter 3
Following the identification of the HLA-DR antigens,
the picture changed. Three independent studies
published in 1978; one from Oxford, another from Oslo
and a third from Leiden, all showed beneficial effects of
matching for the HLA-DR antigens in cadaveric kidney
transplantation. Our own studies30 also demonstrated
that the HLA-DR matching effect was seen irrespective
of matching for the HLA-A and -B antigens (Figs 3.12A
and B). The impact of HLA-DR matching was later also
confirmed in studies by many others. The further
developments in this area and the present use of HLA
matching in clinical organ transplantation are treated in
other chapters in this book.
While the role of HLA matching in clinical organ
transplantation has continued to be a much discussed
issue, the role of optimal HLA matching in bone marrow
transplantation (BMT) or hematopoietic stem cell
transplantation (HSCT) is universally accepted. Graft-
versus-host disease (GVHD) is a major barrier to
successful HSCT. Early successful HSCTs to children
with inborn immunodeficiencies and patients with
aplastic anemia were obtained by using HLA identical
siblings as donors. It was also shown that it was
particularly important that the MLC test between donor
and recipient was negative, i.e. their HLA class II antigens
had to be matched. Together this has resulted in the
formation of large international registries of HLA typed
Figs 3.12A and B: Influence of HLA-DR matching in 96 transplants
from a cadaveric donor. Left part shows the overall data, the right part
shows the data for transplants mismatched for one or two HLA-A orB
antigens. 0, 1 and 2: Transplants mismatched for 0, 1 or 2 HLA-DR
antigens respectively. Reprinted from The Lancet 312: 1126-7, copyright
1978, with permission from Elsevier
History of HLA 49
volunteer HSC donors and banks of HLA typed cord
blood, which have made it possible to offer HLA matched
HSCT to most patients in need of this treatment. The more
recent developments in this area are treated in other
chapters in this book.
Chapter 3
HLA ANTIGENS ARE ASSOCIATED WITH
DISEASES
Already at the third IHWS in 1967, Amiel reported that
an HLA antigen, 4C (later shown to be a broad antigen
including several different HLA-B locus antigens), was
found significantly more frequently in patients with
Hodgkins disease (51%) than among healthy individuals
(27%).31 The association was not strong, the relative risk,
RR, (i.e. how much more frequently the disease occurs
among individuals carrying the antigen under study
compared to those lacking it) was just 2.8, and the
observation has been hard to reproduce by others later.
It led, however, to an extensive hunt for other HLA
associated diseases.
In 1973 came the big bang. Brewerton et al32 and
Schlosstein et al33 independently reported a very strong
association between HLA-B27 and ankylosing
spondylitis. The studies found that 88-96% of the patients
carried HLA-B27, compared to 8-4% of healthy controls,
respectively. These data were later confirmed by many
other groups, giving an RR of >100 to develop ankylosing
spondylitis in individuals being positive for HLA-B27.
The reason for this very strong association was unknown,
but it was speculated that since the association was so
strong, either an immune response (Ir) gene in strong
linkage (disequilibrium) to the gene encoding HLA-B27
was involved, or there was a cross-reaction between
HLA-B27 and the etiologic agent causing the disease.
Later the same year Jersild and coworkers34 first reported
a strong disease association to an HLA class II antigen.
Multiple sclerosis was found to be more strongly
associated to a determinant as established by MLC
typing, LD-7a (later to become HLA-Dw2, now -DR2),
than HLA-B7.
Since, then many diseases have been found to be
associated to given HLA antigens, in particular
autoimmune diseases. Autoimmune diseases are the
combined result of predisposing genes and precipitating
environmental factors, and in almost all autoimmune
diseases the strongest genetic predisposition is associated
to one or more HLA antigens. Diseases associated to HLA
antigens and the possible mechanisms involved are
treated in detail in other chapters in this book.
 50 Section 1 Introduction to Immune System

ROLE OF THE INTERNATIONAL development of the HLA field and its application in
HISTOCOMPATIBILITY WORKSHOPS research and clinical medicine. To just mention a few
additional achievements, the fifth IHWS showed that
Science is of course to a large extent driven by competition
HLA typing would become an important tool in
between individual investigators. This has also been the
anthropology; in the eighth IHWS, the role of HLA
Section 1

case in the HLA field. However, there must be very few

matching in clinical renal transplantation was an
other scientific fields where international collaboration
important aim; the ninth IHWS introduced various new
has played such a major role for the progress, mainly
techniques for studies of the polymorphism of HLA, as
through the many International Histocompatibility
a result of the tenth IHWS a reference panel of well-typed
Workshops (IHWSs). They have had an extremely
cell lines was established which has been of great help
important unifying influence on the studies of HLA. The
for many investigators, and as a result of the thirteenth
IHWSs laid the ground for a continuous open and
IHWS a publicly accessible database was established,
friendly collaboration between involved investigators all
which now contains a huge amount of data for future
over the world, which is an important mark
research. And so on, the list of what has been
distinguishing this research field from many others. As
accomplished in the 15 workshops so far organized is
reported above, the first three IHWSs were wet
long, very long. The work laid down by the workshop
workshops where the investigators carried out their
chairmen and their associates in organizing these
investigations in the laboratory of the workshop
workshops has been extensive, and so has also been the
chairman. From the fourth IHWS, however, the project
work of the participants. It is, however, impossible in
studies have been carried out locally in the laboratories
this short review to give a comprehensive account of all
of the investigators, to a large extent using exchanged
projects that has been studied in these workshops, and
reagents, followed by a joint workshop meeting to discuss
the results obtained, for which I apologize to all workshop
the results (Fig. 3.13). More recently, a conference for a
organizers and participants. Table 3.1 just gives a very
broader audience has also been arranged in conjunction
short and incomplete summary of some important aims
with the workshop meetings, where not only the
and results. For more details, the reader should consult
workshop results have been summarized, but also where
the proceedings from the various workshops,2 which not
individual scientists have presented their most recent
only contain the Joint reports which summarize the
research on HLA, its applications and related topics.
results of the various workshop projects, but also contain
The important role of the first three wet workshops
a lot of important results of research on HLA and its
as well as some of the other early IHWSs for identification
applications by individual investigators, presented at the
of the first HLA antigens, has been treated above.
workshop conferences. These proceedings are thus a rich
However, all workshops have been instrumental for the
source of information, and also demonstrate the extensive
development which has taken place during the 45 years
since the very first workshop was organized.
If I should try to very briefly summarize some
important achievements of the workshops, I would list
the following:
1. They have been instrumental for solving the
complexity of HLA. This has been the case for all
workshops, but in particular the early ones.
2. They have been necessary in order to carry out
investigations which need large, international
collaboration, involving many different centers. These
projects include, among many others, the role of HLA
matching in renal transplantation and in BMTs, the
role of antibodies in chronic rejection, studies of HLA
associated diseases and use of HLA in anthropology.
Fig. 3.13: Some members of the Scandinavian group studying their
data at the fourth IHWS meeting in 1970. The leader of the group,
3. They have been biobanks long before this term was
Flemming Kissmeyer-Nielsen (1921-1991), is seen (with glasses) in coined, i.e. for collection of reliable typing reagents,
the center important patient sera, reference cell line panels,
 Chapter 3 History of HLA 51

Table 3.1: Some major aims and results from the International Histocompatibility Workshops (IHWSs)1
WS Dates Places Chairmen Some important aims and results
nos.
1 June 1964 Durham, NC, US D Bernard Amos Comparison of different typing techniques.

Chapter 3
Results: Very little consistency!
2 August 1965 Leiden, Holland Jon J van Rood Comparison of different local specificities.
Results: Strong correlations between several.
3 June 1967 Turin, Italy Ruggero Ceppellini Establish the genetics of leukocyte antigens.
Results: Strong correlations between more local specificities;
most are encoded by genes at one chromosomal region; HL-A.
4 January 1970 Los Angeles, US Paul I Terasaki Further definition of HL-A specificities.
Eleven HL-A specificities accepted.
5 May 1972 Evian, France Jean Dausset Use of HL-A in anthropology.
Established HL-A frequencies in different populations.
6 June 1975 Aarhus, Denmark Flemming Focus on HLA LD antigens by exchange of homozygous typing
Kissmeyer-Nielsen cells. HLA-Dw1-6 accepted.
More HLA-A and-B antigens, and five -Cw antigens accepted.
7 September 1977 Oxford, UK Julia and Walter Focus on antigens expressed on B cells.
F Bodmer HLA-DRw1-7 accepted, strong correlations to corresponding
HLA-Dw antigens.
8 February 1980 Los Angeles, US Paul I Terasaki Focus on applications. A possible beneficial effect of HLA
matching in renal transplantation from unrelated donors.
Strong HLA-DR associations to some diseases.
9 May 1984 Munich, Germany Ekkehard D Albert Further dissection of HLA polymorphism by family studies, also
Wolfgang R Mayr using monoclonal antibodies and biochemistry.
More HLA specificities accepted.
Beneficial effects of both HLA-A, -B and -DR matching in renal
transplantation from unrelated donors.
10 November 1987 Princeton, NY, US Bo Dupont Theme: Molecular genetic basis of HLA polymorphism.
Comparison of HLA specificities detected by different assays.
Established an IHWS reference cell line panel.
11 November 1991 Yokohama, Japan Kimiyoshi Tsjui Establishment of DNA typing of HLA (PCR SSO).
Miki Aizawa New data on the role of HLA in transplantation, disease
Takehiko Sasazuki associations, anthropology, etc.
12 June 1996 Saint-Malo, France Dominique Charron Theme: Genetic diversity of HLA. Extensive DNA typing, many
new HLA variants detected. More data on applications.
13 May 2002 Victoria, BC, John A Hansen Theme: Immunobiology of the human MHC.
Canada New data on applications. Establishment of different
International Histocompatibility Working Groups (IHWGs).
Establishment of a publicly accessible MHC database.
14 November 2005 Melbourne, Jim McCluskey New results of work by the different IHWGs and others.
Australia New data on KIR-HLA and applications, in particular in BMTs.
15 September 2008 Buzios, Brazil Maria Elisa Moraes Further results of the work by the different IHWGs and others.
Maria Gerbase- New data on applications in clinical medicine, anthropology, etc.
DeLima
1
The first-three IHWSs were wet workshops, were participants carried out their investigations together in the laboratory of the workshop
chairman. From the fourth IHWS the participants carried out their investigations locally in their own laboratories, often using exchanged
reagents. The investigators then met at the workshop meeting to discuss the results.
 52 Section 1 Introduction to Immune System
oligonucleotides and cDNA probes, and for
generation of publicly accessible HLA databases, all
of which have been instrumental for workers in the
field.
4. They have been platforms for further research and
Section 1
developments in individual laboratories. Many new
and original contributions by individual investigators
have been based on workshop results or reagents
provided by the workshops.
5. They have played an important educational role,
making quick technology transfer possible. Many less
experienced laboratories have by participation been
actively trained and learned new techniques.
The bottom line is that, without these workshops, we
would not have been where we are to day with respect
to our knowledge of the HLA complex and its
applications in research and clinical medicine.
IMMUNOBIOLOGICAL FUNCTION
OF THE HLA CLASS I AND II ANTIGENS
But what is the immunobiological function of the HLA
class I and II antigens? It was clear very early that they
were strong histocompatibility antigens, hence the name
major histocompatibility complex or MHC for the HLA and
analogous complexes in other species. But this could not
be their real immunobiological function! The first
answers mainly came from studies in the mouse.
Baruch Benacerraf and colleagues first reported in
1963, that the antibody response in guinea pigs to a
particular synthetic polypeptide antigen (PLL) was
controlled by a single gene.35 Genes controlling specific
immune responses were later called Immune response or
Ir genes. Benacerraf received the Nobel prize in 1980
(shared with Snell and Dausset) for his contributions on
Ir genes. Then, in 1968, came the first data which would
lead to an understanding of the immunobiological
function of the MHC antigens. Hugh McDevitt (Fig. 3.14)
together with Tyan then first showed that the ability of
mice to make an antibody response to a series of synthetic
polypeptide antigens was a genetic trait which was
closely linked to the H-2 complex. The next year McDevitt
and Chinitz confirmed and extended these results in
further experiments.36 Using 33 different inbred strains
of mice, which were of eight different H-2 types but
where strains having the same H-2 type had different
genetic backgrounds, they demonstrated that all strains
being H-2b responded strongly to the synthetic antigen
(T,G)-A--L, while strains of other H-2 types did not
respond or responded much more weakly. In contrast,
Fig. 3.14: Hugh McDevitt (1930- )
when they instead used another synthetic antigen (H,G)-
A--L, different mouse strains being H-2a or H-2k
responded strongly, strains being H-2b responded poorly
and strains having other H-2 types did not respond or
responded variably. Thus genes closely linked to the
H-2 complex controlled specific immune responses! The
authors concluded that their results were compatible
either with multiple Ir gene loci, or a single Ir gene locus
with multiple alleles, but in both cases closely linked to
the H-2 complex.
MHC linked Ir genes were later identified in several
species, and the mechanism of their function became
much discussed. It was speculated that they might be
identical to the MHC genes themselves, i.e. the genes
encoding the MHC class I antigens, and that the MHC
antigens on immunocompetent cells in one way or
another might modify the antigen receptors on these cells.
Alternatively, the Ir genes might be different from the
genes encoding the MHC class I antigens, and represent
a new set of antigen receptors on T cells. Later studies
showed that the murine Ir genes were separate from and
mapped to a position between H-2D and H-2K, and that
some antisera recognized the corresponding gene
products, called Ia (Immune-response associated)
antigens. The Ia antigens were later shown to be encoded
by two different loci in the H-2 complex, I-A and I-E,
corresponding to HLA-DQ and -DR in man respectively,
i.e. class II antigens of mice.
In 1972, it was first shown that cooperation between
T and B cells required MHC compatibility between the
interacting cells.37 The next year it was shown that the
same was true for the interaction of macrophage-
 Chapter 3 History of HLA 53

associated antigen with T cells.38 That the MHC antigens

were directly involved in T cell recognition of antigens
was, however, first shown in 1974 by Rolf Zinkernagel
and Peter Doherty, when they worked together in
Canberra, Australia. A very interesting account of how

Chapter 3
they discovered this is given by Zinkernagel and
Doherty.39 The results of their initial experiments are
reported in two short and yet momentous letters in
Nature.40,41
Very briefly, using mice infected with lymphocyte
choriomeningitis virus (LCMV), they observed that T
cells from the H-2k strain were only able to kill LCMV
infected target cells from the H-2k strain, and not LCMV
infected target cells from the H-2d strain. The reverse
Fig. 3.15: The two different explanations proposed by Zinkernagel
was true when they instead used T cells from LCMV and Doherty to explain the results of their experiments, very
infected H-2d mice, which were only able to kill LCMV schematically
infected target cells from H-2d and not LCMV infected
target cells from H-2k mice. Thus, T cell recognition of
virus antigens was restricted by the MHC antigens of
the T cell donor, which was called MHC restriction. They
proposed two explanations for their results, either the
antigen-specific receptor on T cells, the T cell receptor
(TCR), recognizes MHC antigens which have been
modified by the virus, or the TCR recognizes a complex
formed between virus and MHC antigens (Fig. 3.15).
They later proposed a unifying hypothesis that T cell
recognition by cytotoxic (CD8) T cells and by helper
(CD4) T cells involved similar mechanisms, involving
MHC class I and class II antigens respectively, and that
this may explain the experiments summarized above on
Ir gene effects and the need for histocompatibility
between interacting immune system cells. Further, they
proposed that this may also explain how the MHC
antigens are strong histocompatibility antigens and may
predispose to diseases.42 Although the exact mechanism
Fig. 3.16: Peter Doherty (left) and Rolf Zinkernagel
how the MHC antigens were involved in T cell receiving the Nobel prize in 1996
recognition could not be revealed by their experiments,
Zinkernagel and Doherty came very close (see later).
played an important role in their function. As will be
They received the Nobel prize in 1996 for their seminal
treated in detail in other chapters in this book, some self
observations (Fig. 3.16).
MHC class I antigens are important inhibitory ligands
In 1986, it was first shown that MHC restriction, not
for activation of NK cells. Thus, MHC or HLA antigens
surprisingly, was also the case for human T cell mediated
play an important immunobiological function both in
immune responses. Goulmy et al43 first demonstrated
adaptive and innate immune responses.
that human cytotoxic (CD8) T cells were restricted by the
HLA class I antigens of the T cell donor, while Bergholtz
STRUCTURE OF HLA RESOLVED:
and myself44 first showed that human helper (CD4) T
THE PIECES COME TOGETHER
cells were restricted by the HLA class II antigens of the T
cell donor. During 1960s and 1970s a lot of studies on the structure
When the natural killer (NK) cells were discovered, of MHC antigens, both H-2 and HLA, appeared.3,4 By
it was soon found that the MHC class I antigens also the early 1980s it had been established that the class I
 54 Section 1 Introduction to Immune System

antigens are composed of two chains. One was a

glycoprotein heavy chain anchored in the cell membrane
of molecular weight (mw) of approx. 45.000, varying in
its membrane distal part between different class I
molecules. This heavy chain was non-covalently
Section 1

associated with -2 microglobulin (2m; mw about

12.000) which was found to be constant in all class I
molecules. In contrast, the class II antigens consisted of
two glycoprotein heavy chains ( and ) of mw of approx.
34.000 and 29.000 respectively, both anchored in the cell
membrane, and where the chain varied between
different HLA-DR antigens.
The studies by Zinkernagel and Doherty summarized
above, and studies by many others later, had shown that
T cells recognize foreign antigens associated with MHC
antigens, or MHC molecules as we should call them from Fig. 3.17: Schematic representation of the four domains of HLA-A2.
now on. It was shown by Ziegler and Unanue45 that CD4 Reprinted by permission from Macmillan Publishers Ltd: Nature,
T cells recognize fragments of antigens in association with copyright 1987;329:506-12 48

MHC class II molecules in macrophages, and by

Townsend et al46 that CD8 T cells recognize peptide-
fragments of antigen in association with MHC class I
molecules in target cells. But what is the mechanism?
In 1987, two papers by the Strominger/Wiley group
were published back-to-back in Nature, which provided
the explanation and caused a paradigm shift not only in
the HLA field but in immunology in general. In an article
to the memory of Don Wiley (1944-2001), Jack Strominger
has given a very interesting account on how the group
arrived at their results.47 In the first Nature paper, Pam
Bjorkman and coworkers,48 using X-ray crystallography,
showed that the part of the HLA-A2 molecule proximal
to the cell-membrane contains two domains with
immunoglobulin-folds that are paired in a novel manner.
However, more importantly, they also demonstrated that
the membrane distal domain is a platform of antiparallel
-strands topped by two helices, which together form
a large groove which provides a binding site for
processed antigen, probably a peptide. They also showed
that an unknown peptide material was found in this site
in crystals of HLA-A2 (Figs 3.17 and 3.18, which for many
years were the most frequently shown pictures in any
talk on HLA or immunology).
In the accompanying paper, Bjorkman and
coworkers49 discussed how some of the polymorphic
amino acid residues in the groove of HLA class I
molecules, and by inference also in the groove of class II Figs 3.18A and B: Surface representation of the top of the HLA-A2
molecule, showing (A) the deep groove identified as the antigen
molecules (which was, however, first demonstrated six recognition site and (B) the electron density found in this site, probably
years later50) would interact with a peptide, while other a peptide. Reprinted by permission from Macmillan Publishers Ltd:
polymorphic residues of HLA molecules would interact Nature copyright 1987;329:506-1248
 Chapter 3
with the TCR. Thus a given T cell recognizes a particular
peptide-HLA complex, where both the peptide and the
presenting HLA molecule constitute the ligand. In other
words, the HLA molecules present peptide-fragments
of antigen to T cells (Fig. 3.19). The pieces had come
together.
It is interesting to note that the first HLA molecule
whose structure was fully revealed was the same as the
very first HLA molecule discovered in man, i.e. MAC or
HLA-A2, discovered by Dausset 29 years previously.1
Fig. 3.19: HLA molecules present peptide-fragments
of antigen to T cells
THE HLA COMPLEX IS THE HUMAN MAJOR
IMMUNE RESPONSE COMPLEX (THE MIRC)
The HLA class I and II antigens were first detected
because they induced alloantibody formation, and were
later shown to be major histocompatibility antigens in
man. Less than 30 years, later they were shown to be
peptide-presenting molecules for T cells (Fig. 3.19). As
will be fully described in later chapters in this book, the
HLA class I molecules A, B and C, which are found in
almost all nucleated cells, present peptides derived from
endogenous proteins to CD8 T cells. In contrast, the HLA
class II molecules DR, DQ and DP, which are mainly
found in specialized antigen-presenting cells (dendritic
cells, monocytes, B cells) present peptides derived from
exogenous proteins to CD4 T cells. The HLA molecules
do not distinguish between peptides from self proteins
or peptides from foreign proteins. Since, however, our T
cells by various mechanisms generally are tolerant to our
own, self peptide-HLA complexes, i.e. self-tolerance, a T
cell immune response will mainly be formed against
History of HLA 55
peptides from foreign proteins bound to self HLA
molecules.
The studies by Bjorkman et al cited above
demonstrated that a given T cell recognizes a particular
peptide-HLA complex, where both the peptide and the
Chapter 3
presenting HLA molecule constitute the ligand. Their
studies also suggested that there would be limitations in
the ability of a given HLA molecule to bind all types of
peptides. This was amply confirmed in later studies by
many others of peptide binding to HLA molecules.51 The
polymorphic residues in the peptide-binding groove or
cleft of HLA molecules determine which peptides will
be bound strongly and which will not be bound or bound
more weakly.
This explains the earlier findings of Zinkernagel and
Doherty referred to above, namely that T cell recognition
of antigen is restricted by the MHC of the T cell donor,
i.e. MHC restriction. The MHC molecules of the T cell
donor will not only determine which peptides may be
bound and presented to the T cell, they will also constitute
part of the ligand being recognized by the TCR of T cells.
This also explains the earlier findings of McDevitt and
coworkers referred to above of Ir genes in the MHC. The
MHC molecules of an individual will to a large extent
determine his or her immune response, i.e. which
antigenic peptides will be immunogenic and which will
not. Thus, the Ir gene effects are not caused by separate
genes in the MHC, they are a function of the MHC
molecules themselves. It should be noted, however, that
both class I and class II molecules have Ir effects. The
class I and II molecules of an individual will determine
the repertoire of peptides which will be presented to CD8
and CD4 T cells respectively, and thus be immunogenic
for the individual.
The Ir effects of HLA molecules also explain why
some HLA molecules are associated with protection
against diseases, as will be fully treated later in this book.
For example, HLA-B27 is associated with a relative
protection against HIV infection, which is most probably
caused by preferential binding and presentation by HLA-
B27 of some peptides from HIV to T cells. The protective
effects of HLA molecules also provide an explanation of
their extreme polymorphism. The more HLA molecules
to select from in a given population, the more likely it is
that some individuals will have optimal HLA molecules
for binding and displaying peptides from a foreign
intruder to induce an appropriate immune response, and
thus survive the infection.
The Ir effects of HLA molecules most probably also
explain why so many autoimmune diseases are
 56 Section 1 Introduction to Immune System

associated to given HLA molecules, as will also be treated

in detail in several other chapters later in this book. In
celiac disease, it has been shown that the strong
association to HLA-DQ2 and -DQ8 is caused by the
ability of these two class II molecules to preferentially
Section 1

bind gliadin peptides derived from ingested gluten, the

agent causing the disease.52 It has also been shown,
however, that what HLA-DQ2 and -DQ8 preferentially
bind are gliadin peptides which have been deamidated
by the enzyme tissue transglutaminase, i.e. modified
gliadin peptides. The autoantigens inducing an immune
response in autoimmune diseases are generally not
known. On the basis of the findings in celiac disease,
however, one may speculate that the autoimmune
response is not initially directed against native
autoantigens, but a self-protein which for one reason or
another has been post-translationally modified, i.e. a Fig. 3.20: Direct and indirect allorecognition, very schematically
modified self-protein. This would also explain the loss of (see text)
self-tolerance. The HLA associations in autoimmune
diseases may then be explained by preferential binding Indirect and direct allorecognition, leading to
of peptides from some modified self-proteins to the alloimmune responses against the graft, play important
disease-associated HLA molecules. parts in acute rejection. After donor DC in the graft are
To complete the picture, it should also be mentioned lost, alloimmune responses as a result of direct
that some diseases are (also) associated to HLA class I allorecognition become less important. In contrast,
molecules which are inhibitory ligands for NK cells. This indirect allorecognition becomes dominant, which may
is further treated in other chapters in this book. lead to chronic rejection where antibodies to foreign
But how can HLA molecules be major histocompatibility antigens in the graft, HLA and others, play a major role.
antigens? Briefly, since HLA molecules are present in very This is treated in other chapters in this book, as is also
high concentrations in cells, and thus also in cells of an the role of NK cells in alloimmune responses. For
allogeneic transplant, they will, when foreign to the example, after HSCT, NK cells among donor stem cells
recipient, constitute a major part of the antigenic challenge may be activated by recipient cells lacking donor NK cell
of the recipient. After processing, peptides derived from inhibitory HLA class I ligands.
the foreign HLA molecules will be a major source of It follows that the function of HLA molecules as major
foreign peptides presented to recipient CD4 T cells by self- histocompatibility antigens may be considered more as
HLA class II molecules of recipient dendritic cells (DC). a side effect of their function in general immune
Following activation these T cells will also help B cells to responses. Thus the term the major histocompatibility
produce antibodies against the foreign HLA molecules. complex, the MHC, for the HLA complex and similar
Together this is called indirect allorecognition (Fig. 3.20,
genetic complexes in animals is a misnomer, caused by
right part). T cells of the recipient are, however, also able
historical reasons before its true immunobiological
to directly recognize foreign peptide-HLA complexes on
functions were known. Given our current knowledge of
the grafted cells, in particular on donor DC. Recipient T
the instrumental importance of the MHC molecules both
cells will be tolerant to self peptide-HLA complexes, but
in innate and adaptive immune responses, and adding
not to allogeneic, foreign peptide-HLA complexes, i.e.
the function of many other products of the MHC in
complexes of peptides bound to foreign HLA molecules.
immune responses, a better name for the complex would
Even though the T cells of an individual during positive
be the major immune response complex, the MIRC. But it is
selection in the thymus become biased to recognize
too late to change this now!
peptides presented by self-HLA molecules, many of them
will because of cross-reactivity also be able to directly
CONCLUDING REMARKS
recognize complexes of peptides bound to foreign HLA
molecules. This is called direct allorecognition (Fig. 3.20, It is now just a little more than 50 years since Jean Dausset
left part). first discovered a leukocyte antigen in man, which
 Chapter 3
became the first HLA antigen; HLA-A2. Since, then
the field has moved from histocompatibility to become
one of the most central fields in basic and clinical
immunology in general.
There are several reasons for the quick and extensive
developments of the field. First and foremost are the
instrumental contributions by its many pioneers. Some
of them have received the Nobel prize (Snell, Dausset,
Benacerraf, Zinkernagel and Doherty), but several others
would also have been excellent candidates. That such a
relatively large number of Nobel prizes has gone to
pioneers in this field witnesses its importance. But
another factor which must not be underestimated is the
extensive international collaboration which has taken
place since the early days of HLA, in particular the
international histocompatibility workshops. Together the
pioneers and the extensive international collaboration are
responsible for the giant progress we have seen in this
field during the last 50 years.
ACKNOWLEDGMENTS
I am grateful to Walter Bodmer, Jon van Rood and Paul
Terasaki for helpful comments to the parts of this review
dealing with the early history of HLA, to Hugh McDevitt
for helpful comments concerning the part describing the
immunobiological function of HLA antigens, and to
Torstein Egeland, Ludvig Sollid and Frode Vartdal for
careful reading of the manuscript.
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