a short history of hla

Tissue Antigens ISSN 0001-2815

REVIEW ARTICLE

A short history of HLAE. Thorsby

Institute of Immunology, Rikshospitalet University Hospital and University of Oslo, Oslo, Norway

Key words

human leucocyte antigens; histocompatibility

antigens; H-2 complex; human leucocyte

antigens complex; international

histocompatibility workshops (IHWSs); major

histocompatibility complex; major immune

response complex

Correspondence

Erik Thorsby MD

Institute of Immunology

Rikshospitalet University Hospital

N-0027 Oslo

Norway

Tel: 147 2307 3500

Fax: 147 2307 3510

e-mail: [email protected]

Received 23 April 2009; accepted 23

April 2009

doi: 10.1111/j.1399-0039.2009.01291.x

Abstract

In 1958, just a littlemore than 50 years ago, analloantigenpresent onhuman leucocytes

wasdetected,whichwas to become the first human leucocyte antigen (HLA);HLA-

A2. Since then, we have seen a tremendous development of theHLA field, which has

moved fromhistocompatibility to become one of themost central fields in basic and

clinical immunology. This development is briefly reviewed in this article, focusingon

some highlights of the history of HLA class I and II molecules and their role in

immune responses. It is emphasized that the quick and extensive development of the

HLA field is the result not only of excellent individual contributions by outstanding

pioneers in the field, but also of an extensive international collaboration, in

particular through the many international histocompatibility workshops. Admit-

ting that it is too late to change the name now, it is concluded that instead of calling

the HLA complex and similar complexes in other species the major histocompat-

ibility complex, these gene complexes should better have been named the major

immune response complex, theMIRC.

Last year was 50 years since a human leucocyte antigen

(HLA) was first described as MAC, later to become HLA-

A2 (1). In the following, a short account of the development

of the HLA field is given, focusing on some highlights of the

history of HLA class I and II antigens, or molecules as they

should be called now,which I consider to be among themost

important. The review is based on an invited lecture given at

the opening of the 15th International Histocompatibility

and Immunogenetics Workshop Conference in Rio de

Janeiro on 17 September 2008. It is impossible in this short

historical review to mention all who have participated in

unravelling the structure and function of the HLA

molecules. Thus, Imust apologize to those whose important

contributions could not be included due to lack of space.

For a more comprehensive treatment of the subject, the

reader is referred to earlier extensive reviews by others (24).

It started in the mouse: discovery ofhistocompatibility antigen II and the H-2complex

Allogeneic tumour transplantation was often used in early

experiments to study tumour biology. In the early 1900s,

two US geneticists, Ernest E. Tyzzer and Clarence C. Little,

performed some crucial tumour transplantations in the

offspring of crosses between mice that were susceptible or

resistant to an allogeneic tumour. Based on the results, they

arrived at the conclusion that susceptibility to the growth of

allogeneic tumours was genetically determined, possibly by

asmany as 15 genes [references in (2, 3)]. The nature of these

susceptibility (or rather resistance) genes and their products

was, however, unknown.

An antigen responsible for rejection was first discovered

by the British physician and pathologist Peter A. Gorer

(Figure 1) in 1936,workingat that time in theLister Institute

for Preventive Medicine in London. Following a suggestion

from the British geneticist J. B. S. Haldane, he studied

whether resistance factors to the growth of allogeneic

tumours might be associated with some blood group

antigens. First, he found that his own serum contained

natural antibodies that could distinguish between eryth-

rocytes of three inbred strains of mice (5). He next

immunized rabbits with erythrocytes from the same three

strains of mice and obtained antisera with which he could

distinguish three different blood group antigens in mice (6):

2009 John Wiley & Sons A/S Tissue Antigens 74, 101116 101

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 tumour 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 tumour, while it grew well in strain A and first-

and second-generation crosses between A and C57BL that

expressed antigen II. Furthermore, he made the important

observation that sera ofmice rejecting the tumour contained

antibodies against antigen II (7). Thus, antigen II, shared

between malignant and normal cells, apparently was an

important resistance factor to the growth of an allogeneic

tumour when present in the donor and absent in the

recipient. Note that these findings were made before Peter

Medawar first established in 19441945 that rejection of

allogeneic transplants was caused by an immune response

against the graft (8, 9), a discovery for which he received the

Nobel Prize in 1960 (sharedwith FrankMcFarlane Burnet).

After World War II, Gorer visited the mammalian

geneticist George D. Snell (Figure 2) at the Jackson

Laboratory, Bar Harbor, ME. Snell was studying tumour

resistance genes, which he called histocompatibility or H

genes. He had previously found that mice carrying the Fu

gene (causing mice to develop a deformed tail), were

resistant to the growth of tumours from strain A. 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 tumour 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 (10).

BecauseGorers 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 [references in (2)], established

that the H-2 locus encoded strong or major histocompat-

ibility antigens, inducing quick rejection, compared with

weaker histocompatibility antigens encoded by other loci.

The H-2 locus therefore became the major histocompatibil-

ity locus in mice. Other H loci became minor H loci.

Snell received the Nobel Prize in 1980 for his contribu-

tions.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 knownH-

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 et al.

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 immune-response-associated

(Ia) antigens. The H-2 locus became the H-2 complex, or the

major histocompatibility complex,MHC, in the mouse.

Discovery of the first HLA antigens

Three papers appeared in 1958 by Jean Dausset, Jon van

Rood and Rose Payne and their associates, respectively (1,

13, 14), which laid the foundation of what was later to

become the HLA complex. All three papers described

antibodies in human sera from multitransfused patients or

multiparous women, sera that reacted with leucocytes from

many but not all individuals who were tested. Thus,

antibodies in these sera detected a polymorphic system of

antigens on human leucocytes.

The credit for discovery of the first HLA antigen goes to

Dausset (Figure 3). Studying sera from patients who had

Figure 1 Peter A. Gorer (19071961).

Figure 2 George D. Snell (19031996).

A short history of HLA E. Thorsby

102 2009 John Wiley & Sons A/S Tissue Antigens 74, 101116

received multiple blood transfusions, he found seven sera

that behaved quite similarly, in that they agglutinated

leucocytes from 11 of 19 individuals tested (1). Because

leucocytes from the donor of the sera were also not

agglutinated, the antisera obviously detected an alloantigen

present on human leucocytes. He gave the name MAC to

this antigen to honour three individuals who had been

important volunteers for his experiments and whose names

began with the initials M, A and C, respectively [Dausset

in ref. 4]. Antigen MAC (later to become HLA-A2) was

present in approximately 60% of the French population. At

the end of the paper, Dausset wrote that Finally, in a more

long time perspective, the study of leucocyte antigens might

become of great importance in tissue transplantation, in

particular in bonemarrow transplantation (translated from

French). Thus, he was very foresighted! For his discovery,

Dausset received the Nobel Prize in 1980 (shared with Snell

and Baruch Benacerraf).

Both vanRood and Payne followed up their initial findings

of alloantigens on human leucocytes (13, 14). Using (at that

time) a sophisticated computer analysis of the reaction

patterns of 60 sera from multiparous women against

leucocytes from a panel of 100 donors, van Rood (Figure 4)

found some sera that apparently detected a diallelic system of

leucocyte antigens, which he called 4a and 4b (later to become

HLA-Bw4 and -Bw6, respectively). The results were reported

in his PhD thesis from 1962 (15) [see also (16)]. Two years

later, Payne (Figure 5), together with Julia and Walter

Bodmer (Figure 9), also using sera frommultiparous women,

not only detected two leucocyte antigens, LA1 (later HLA-

A1) andLA2 (laterHLA-A2), apparently controlledbyalleles

but also postulated at least one additional antigen, LA3,

determined by an additional allele at the same locus (17).

Several other investigators also made original or first

identifications of leucocyte antigens in these early days of

HLA. They included, among others, BernardAmos, United

States; Richard Batchelor, UK; Ruggero Ceppellini, Italy;

Paul Engelfriet, the Netherlands; Wolfgang Mayr, Austria;

Flemming Kissmeyer-Nielsen, Denmark; Ray Shulman,

United States; Paul Terasaki, United States; Roy Walford,

United States; and myself [references in (18)].

Solving the complexity through internationalcollaboration: role of the InternationalHistocompatibility Workshops (I)

The relationship between the different leucocyte (later

HLA) antigens that had been identified and their poly-

morphism and genetics were difficult subjects to solve. No

Figure 4 Jon J. van Rood (1926) in the centre,

with his long-time associate Aad van Leeuwen

(19292009) to the left and his statistician Joe

dAmaro (1928) to the right, at one of the earlier

International Histocompatibility Workshops.

Figure 3 JeanDausset (19162009) discussing the complexity of human

leucocyte antigens at one of the earlier International Histocompatibility

Workshops.


E. Thorsby A short history of HLA

single laboratory could have carried out 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 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

IHWSwas organized byAmos (Figure 6) as early as in June

1964 at Duke University, Durham, NC. Amos should be

considered the father of theworkshops.Hewas also able to

obtain funds from National Institutes of Health (NIH) to

organize the first workshops. The major aim of the first

IHWS was to compare different techniques to detect

leucocyte antigens because a variety were in use by different

investigators (leucoagglutination, the indirect antiglobulin

consumption test, mixed agglutination, complement fixa-

tion, microcytotoxicity, etc). Twenty-three investigators

attended the workshop testing the same sera and cells with

their own techniques. Much to their dismay, most of the

results were discordant (19).

These disappointing results, coupled with the fact that

van Rood at the first IHWS had also presented evidence for

other clusters of leucocyte antigens in addition to 4a and 4b,

prompted van Rood to organize the second IHWS which

was held in August, 1965 at the University of Leiden, the

Netherlands. Here, investigators from 14 different groups

tested their own antisera, using their own techniques, on cells

froma commonpanel of 45 individuals. Themain aimwas to

see if local specificities defined in one laboratory correlated

with those defined in other laboratories.Most encouragingly,

it was now found that several local specificities were indeed

identical or almost identical (20). 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. Furthermore, Dausset

et al. (21) and van Rood et al. (22) also presented work

suggesting that most of the antigens they could identify were

controlled by a single chromosomal complex.

The third IHWSwas organized by thewell-knownhuman

geneticistRuggeroCeppellini (Figure 7) at theUniversity of

Turin, Italy, in June 1967. The main aim was to study the

genetics of the hitherto identified leucocyte antigens. Thus,

the organizers included blood from 11 families, including

monozygotic twins, thatwere tested blindly by the different

investigators with their own typing antisera and techniques.

Several investigators were now using the quicker and more

reliable microcytotoxicity test, initially developed by Ter-

asaki (Figure 10) and McClelland (23), which later became

the standard serological typing technique forHLAantigens.

Figure 5 Rose Payne (19091999), together

with the author (1938) of this review just after

the fourth International Histocompatibility

Workshop in 1970.

Figure 6 Bernard Amos (19232003).



The results showed 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, that is

human leucocyte, locus A (24). This was later changed to

HLA (without the hyphen), where A is now interpreted to

mean antigen.

Just after the third IHWS, in 1968, anHLANomenclature

Committee was established (first sponsored byWorldHealth

Organization, (WHO)) consisting of leading investigators in

the field. This 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 that could be recognized by

several different investigators using their own serological

reagents. An account of the lively discussions at their first

meeting in NewYork in September 1968 is given byWalford

in ref. 4. By quickly establishing a common uniform nom-

enclature and thus avoiding a long list of various local

specificities, the committee has played a major role in

unravelling the complexity ofHLA 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 (25). 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 et al. also

proposed that there were two different mutational sites

within the HLA chromosomal region (26). It was, however,

the work of Kissmeyer-Nielsen (Figure 12) and associates,

which firmly established that there were two HLA loci (27).

In extensive studies of unrelated individuals and families,

they showed that the two loci,LA (later namedHLA-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 leucocyte antigen,

AJ, which in population and family studies behaved as if it

was encoded by anotherHLA locus separate fromLA and 4

(28). 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 showed

the existence of a third HLA locus (29). This was first called

the AJ locus (from its first antigen) but was later named

HLA-C.

In 1964, two groups, Bach and Hirschorn (30) and Bain

et al. (31), independently described morphological transfor-

mation and cell division if leucocytes from two different

individuals were mixed. This was to become the mixed

lymphocyte culture (MLC) reaction. Fritz Bach (Figure 8)

togetherwithAmos then showed that theMLCreactionwas

governed by the HLA chromosomal region. Cells from

siblingswhowere genotypicallyHLA identical generally did

not respond to each other in reciprocal MLC tests (32).

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 (33). This was fully confirmed by Yunis and Amos

(34) who showed that there was a separate MLC locus in

the HLA chromosomal region responsible for the determi-

nants inducing the MLC response. From their studies in

mice, Bach et al. (35) then proposed that there were two

Figure 7 Ruggero Ceppellini (19171988),

giving a talk at one of the earlier International

Histocompatibility Workshops.



different types of determinants encoded by genes in the H-2

complex, serologically defined (SD) and lymphocyte-

defined (LD) determinants, the latter being responsible for

stimulation in the MLC test, a concept that was also

adapted for man.

This started an extensive hunt for the LD determinants in

man. It was Mempel et al. (36) who first suggested that

MLC-stimulating cells that 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, andmultiple LDdeterminants

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

LDdeterminantswere clearly defined byMLC typing by the

different participating laboratories, of which six LD

determinantswereacceptedby theNomenclatureCommittee

and provisionally (by the prefix w workshop) namedHLA-Dw16 (37). The corresponding locus was named

HLA-D. Sheehy et al. (38) reported that LD (or Dw)

determinants could also be identified by priming lympho-

cytes against givenLDdeterminants,whichwas calledprimed

LD typing. Later studies showed that the provisionalHLA-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

containing HLA antibodies were able to inhibit the MLC

reaction [(39) and refs therein]. This was confirmed by van

Leeuwen et al. who also obtained suggestive evidence that

the responsible antibodies recognized antigens present on B

cells but not on T cells or platelets (40). 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 (Figure 9), in

Oxford, UK. Using 177 selected antisera recognizing

antigens on B cells, antisera that had been exchanged

between the participating laboratories, it was possible to

convincingly identify seven different B-cell antigens that

correlated closely to the HLA-Dw17 determinants and

that therefore were named HLA-DRw1-7 (DR DRelated) (41).

In the early 1980s, the overall picture was that the HLA

chromosomal region, found to be present on the short arm

of chromosome number 6, encoded six different very

polymorphic series of determinants, A, B and C that were

present on most nucleated cells and DR, DQ and DP that

weremainly present onB cells, monocytes anddendritic 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. Klein (42) 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

corresponding antigens in other species), a nomenclature that

has since been followed. Furthermore, after the discovery of

additional class I antigens, HLA-G, -E and -F, with a more

limited tissue distribution, the latterwere named non-classical

HLA class I antigens, while the HLA-A, -B and -C antigens

were named classicalHLA class I antigens.

Later, many additional loci were detected in the HLA

chromosomal region or theHLAcomplex 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

Figure 9 Julia (19342001) and Walter Bodmer (1936). Dancing has

been one of the highlights at the farewell dinner of all International

Histocompatibility Workshops.

Figure 8 Fritz H. Bach (1934).



expressed, of which approximately 28% may have immune

functions (43). A further treatment of this development of

the HLA complex, including the finding of some comple-

ment genes, cytokine genes, RING (really interesting new

genes), BING (bloody interesting new genes) and many

others, is outside the scope of this short review (see Horton

et al. (43) for a complete gene map of the extended HLA

complex).

The HLA class I and II antigens are stronghistocompatibility antigens

From skin grafting experiments in the early 1960s, 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 al. (44) and Amos

et al. (45). They showed that first-set skin grafts between

HLA-identical siblings (who had inherited the same HLA

haplotypes from both parents) had a significantly longer

survival time than skin grafts between siblings differing for

one or two HLA haplotypes. Because skin grafting resulted

in the production of antibodies against HLA antigens of the

donor, this was also an evidence that theHLAantigens were

important histocompatibility antigens [references in (46)].

The first data suggesting a correlation between HLA

matching and kidney allograft survival were presented by

Terasaki (Figure 10) and coworkers as early as in 1965 (47).

These early results are quite remarkable, given the broadly

reacting typing reagents available at that time and just

typing for a fewHLA-Aand -B antigens.Other references to

early work on the impact of HLA matching on clinical

kidney transplantation are found in Brent (3) and Kiss-

meyer-Nielsen andThorsby (46). Taken together, the results

from skin and clinical kidney grafting, together with other

evidence [references in (46)], showed that the HLA complex

indeed was the 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 with HLA-mismatched

kidneys from cadaveric donors [references in (46)], HLA

typing to obtain well-matched kidneys in such unrelated

combinations was also used in many centres. However, the

benefits of the latter application were hit hard by a pre-

sentation by Terasakis group at the Third Congress of the

International Transplantation Society in Hague, the Neth-

erlands, in 1970. While HLA matching was found to be of

great importance using living-related donors, they reported

no effects of HLAmatching 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 this journal (48), accompanied

by comments by its editor at that time, Kissmeyer-Nielsen

(49), discussing reasons for the discrepancy between the

disappointing results reported by Terasakis group com-

pared 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 fromHLA-

matched and HLA-mismatched cadaveric donors were

considered by many surgeons to be too small to matter.

Following the identification of the HLA-DR antigens,

the picture changed. Three independent studies, published

in 1978, one by Ting and Morris (50), the second from our

own group in Oslo (51) and the third from the group in

Leiden (52), all showed beneficial effects ofmatching for the

HLA-DRantigens in cadaveric kidney transplantation.Our

own studies (53) also showed that the HLA-DR matching

effectwas seen irrespective ofmatching for theHLA-Aand -

B antigens (Figure 11). 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 outside

the scopeof this shorthistorical review. It suffices to say that in

many centres the best possible match between donor and

recipient for HLA-A, -B and -DR antigens is an important

factor considered, when using both living and cadaveric

donorsofkidneys. In sensitizedpatientswithHLAantibodies,

it is generally accepted that the crossmatch between serum

from the recipient and lymphocytes from the organ donor

must be negative, as tested by the microcytotoxicity test.

While the role of HLA matching in clinical organ

transplantation, in particular using cadaveric donors, has

continued to be a much discussed issue, the role of optimalFigure 10 Paul I. Terasaki (1929).



HLA matching in bone marrow transplantation (BMT) is

universally accepted. Graft-vs-host disease is a major

barrier to successful BMT. Early successful BMTs to

children with inborn immunodeficiencies (54, 55) and

patients with aplastic anaemia (56) 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 (57), that is their class II

antigens had to be matched. Together, this has resulted in

the formation of large international registries ofHLA-typed

volunteer bone marrow donors and banks of HLA-typed

cord blood, which have made it possible to offer HLA-

matched BMTs to most patients in need of this treatment.

The more recent developments in this area, that is

intelligent mismatching to promote graft-vs-leukaemia

effects, is outside the scope of this short review.

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 Hodg-

kins disease (51%) than among healthy individuals (27%)

(58). 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 with

those lacking it) was just 2.8 and the observation has been

hard to reproduce by others. It led, however, to an extensive

hunt for other HLA-associated diseases.

In 1973, came the big bang. Brewerton et al. (59) and

Schlosstein et al. (60) independently reported a very strong

association betweenHLA-B27 and ankylosing spondylitis.

The studies found that 88%96% of the patients carried

HLA-B27 compared with 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

the authors of one of these papers (60) speculated that

because the association was so strong, either an immune

response (Ir) gene in strong linkage (disequilibrium) to

HLA-B27 was involved or there was a cross-reaction

between HLA-B27 and the aetiologic agent causing the

disease. Later, the same year, Jersild et al. (61) 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 byMLC typing,

LD-7a (later to becomeHLA-Dw2, nowHLA-DR2), than

HLA-B7.

Since then, many diseases have been found to be

associated to given HLA antigens, in particular autoim-

mune diseases (62). Autoimmune diseases are the combined

result of predisposing genes and precipitating environmen-

tal factors, and in almost all autoimmune diseases, the

strongest genetic predisposition is associated to one ormore

HLA antigens. Fine mapping of the HLA complex genes

involved in these diseases and the possible mechanisms

behind the associations are therefore now major research

fields [see a recent review in this journal (63)].

Figure 11 Influence of HLA-DR matching in 96

transplants from a cadaveric donor. Left part

shows the overall data, and the right part shows

the data for transplantsmismatched for one or two

HLA-A or -B antigens. Reprinted from Albrechtsen

et al. (53), copyright 1978, with permission from

Elsevier. HLA, human leucocyte antigen.



Role of the IHWSs (II)

Science is of course to a large extent driven by competition

between individual investigators. This has also been the case

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

scientific fields where international collaboration has played

such a major role for the progress, mainly through the many

IHWSs. They have had an extremely important unifying

influence on the HLA field. They laid the ground for

a continuous open and friendly collaboration between

involved investigators all over the world, which is an

importantmark distinguishing this research field frommany

others. As reported above, the first three IHWSs were wet

workshops where the investigators carried out their inves-

tigations in the laboratory of the workshop chairman. From

the fourth IHWS, however, the project studies have been

carried out locally in the laboratories of the investigators, to

a large extent using exchanged reagents, followed by a joint

workshop meeting to discuss the results (Figure 12). More

recently, a conference for a broader audience has also been

arranged in conjunction with the workshopmeetings, where

not only the workshop results have been summarized but

also individual scientists have presented their most recent

research on HLA, its applications and related topics.

The role of someof the earlierworkshops for identification

of the first HLA-A, -B and -D/DR antigens has been

mentioned above. However, all workshops have been

instrumental for the development of the HLA field and its

application in researchand clinicalmedicine.To justmention

a fewachievements, the fifth IHWS showed thatHLA typing

would become an important tool in anthropology; in the

eighth IHWS, the role of HLA matching in clinical renal

transplantation was an important aim; the ninth IHWS

introduced various new techniques for studies of the poly-

morphism of HLA; as a result of the 10th IHWS, a reference

panel of well-typed cell lines was established, which has been

of great help for many investigators; and as a result of the

13th IHWS, a publicly accessible database was established,

which now contains a huge amount of data for future

research.Andsoon, the list ofwhathasbeenaccomplished in

the 15 workshops so far organized is long, very long. The

work laid down by the workshop chairmen and their

associates in organizing these workshops has been extensive

and so has also been the work of the participants. It is,

however, impossible in this short review to give a compre-

hensive account of all projects that has been studied in these

workshops and the results obtained, for which I apologize to

all workshop organizers and participants. Table 1 just gives

a very short and incomplete summary of some important

aims and results. For more details, the reader should consult

the proceedings from the various workshops (listed in

Table 1), which not only contain the Joint reports that

summarize the results of the various workshop projects but

also containmany important results of research onHLAand

its applications by individual investigators, presented at the

workshop conferences. These proceedings are thus a rich

source of information and also show the extensive develop-

ment that 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 com-

plexity 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 in-

vestigations that need large international collaboration

Figure 12 Somemembers of the Scandinavian

group studying their data at the fourth Interna-

tional Histocompatibility Workshop meeting in

1970. The leader of the group, Flemming

Kissmeyer-Nielsen (19211991), is seen (with

glasses) in the centre.



Table 1 Some major aims and results from the IHWSsa

WS number Date Place Chairman Some important aims and results Reference

1 June 1964 Durham, NC, USA D. Bernard Amos Comparison of different typing techniques 64

Results: very little consistency!

2 August 1965 Leiden, Holland Jon J. van Rood Comparison of different local specificities 65

Results: strong correlations between several

3 June 1967 Turin, Italy Ruggero Ceppellini Establish the genetics of leucocyte antigens 66

Results: strong correlations between more

local specificities; most are encoded

by genes at one chromosomal region; HLA

4 January 1970 Los Angeles,

CA, USA

Paul I. Terasaki Further definition of HLA specificities 67

Eleven HLA specificities accepted

5 May 1972 Evian, France Jean Dausset Use of HLA in anthropology 68

Established HLA frequencies in different populations

6 June 1975 Aarhus, Denmark Flemming

Kissmeyer-Nielsen

Focus on HLA LD antigens by exchange of

homozygous typing cells. HLA-Dw1-6 accepted

69

More HLA-A and -B antigens and five -Cw

antigens accepted

7 September 1977 Oxford, UK Julia and Walter

F. Bodmer

Focus on antigens expressed on B cells 70

HLA-DRw1-7 accepted, strong correlations to

corresponding HLA-Dw antigens

8 February 1980 Los Angeles,

CA, USA

Paul I. Terasaki Focus on applications 71

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 and

Wolfgang R. Mayr

Further dissection of HLA polymorphism by

family studies, also using monoclonal

antibodies and biochemistry

72

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, USA Bo Dupont Theme: Molecular genetic basis of HLA polymorphism 73

Comparison of HLA specificities detected by

different assays

Established a IHWS reference cell line panel

11 November 1991 Yokohama, Japan Kimiyoshi Tsjui, Miki

Aizawa, and Takehiko

Sasazuki

Establishment of DNA typing of HLA (PCR SSO) 74

New data on the role of HLA in transplantation, disease

associations, anthropology, etc.

12 June 1996 Saint-Malo, France Dominique Charron Theme: Genetic diversity of HLA 75

Extensive DNA typing, many new HLA variants detected

More data on applications

13 May 2002 Victoria, BC, Canada John A. Hansen Theme: immunobiology of the human MHC 76

New data on applications

Establishment of different IHWGs

Establishment of a publicly accessible MHC database

14 November 2005 Melbourne, Australia Jim McCluskey New results of work by the different IHWGs and others 77

New data on KIRHLA and applications, in

particular in BMTs

15 September 2008 Buzios, Brazil Maria Elisa Moraes and

Maria Gerbase-DeLima

Further results of the work by the different

IHWGs and others

78

New data on applications in clinical medicine,

anthropology, etc.

BMT, bone marrow transplantation; HLA, human leucocyte antigen; IHWGs, International Histocompatibility Working Groups; IHWSs, International

Histocompatibility Workshops; MHC, major histocompatibility complex.a The first three IHWSswere wet workshops,where participants carried out their investigations together in the laboratory of theworkshop 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.



involving many different centres. 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.

3. They have been biobanks long before this term was

coined, that is for collection of reliable typing

reagents, important patient sera, reference cell line

panels, oligonucleotides and complementary DNA

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

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 today with respect to our

knowledge of the HLA complex and its applications in

research and clinical medicine.

Immunobiological function of the HLA class Iand II antigens

But what was 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 MHC

for theHLA 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.

First, Benacerraf and colleagues reported in 1963 that the

antibody response in guinea pigs to a particular synthetic

polypeptide antigen (PLL) was controlled by a single gene

(79).Genes controlling specific immune responseswere later

called 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 that would lead to

an understanding of the immunobiological function of the

MHC antigens. Hugh McDevitt (Figure 13) together with

Marvin 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 that was closely

linked to the H-2 complex (80). These results were

confirmed and extended in further experiments by McDe-

vitt and Chinitz the next year (81). Using 33 different inbred

strains of mice that were of eight different H-2 types but

where mice having the same H-2 type had different genetic

backgrounds, they showed that all strains being H-2b

responded strongly to the synthetic antigen (T,G)-AL,

while strains of other H-2 types did not respond or

responded much more weakly. In contrast, when they

instead used another synthetic antigen, (H,G)-AL, differ-

ent 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 eitherwithmultiple Ir gene loci

or with a single Ir gene locus withmultiple 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. Itwas speculated that theymight be identical to the

MHC genes themselves, that is the genes encoding theMHC

class I antigens, and that the MHC antigens on immuno-

competent 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 (82). 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 antigens [references in (83)]. These

antigens were later shown to be encoded by two different loci

in the H-2 complex, I-A and I-E, corresponding toHLA-DQ

and -DR, respectively, that is the 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 (84). The next year, it was shown that the

same was true for the interaction of macrophage-associated

antigen with T cells (85). 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 theydiscovered

Figure 13 Hugh McDevitt (1930).



this was given by Zinkernagel and Doherty (86). The results

of their initial experiments were reported in two short and

yet momentous letters in Nature (87, 88).

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 was true when

they instead used T cells from LCMV-infected H-2d mice,

which were only able to kill LCMV-infected target cells

from H-2d mice and not LCMV-infected target cells from

H-2k mice. Thus, T-cell recognition of antigen from the

virus 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 that have been modified by the virus or the

TCR recognizes a complex formed between virus andMHC

antigens. They later proposed a unifying hypothesis that

T-cell recognition by cytotoxic (CD8) T cells and by helper

(CD4) T cells involved similar mechanisms, involvingMHC

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 inter-

acting immune system cells. Furthermore, they proposed

that this may also explain how theMHCantigens are strong

histocompatibility antigens and may predispose to diseases

(89). Although the exactmechanism how theMHCantigens

were involved in T-cell recognition could not be shown by

their experiments, Zinkernagel andDoherty came very close

(see subsequently). They received theNobel Prize in 1996 for

their seminal observations (Figure 14).

In 1986, it was first shown that MHC restriction, not sur-

prisingly, was also the case for human T-cell-mediated im-

mune responses, as shown by Goulmy et al. for cytotoxic

T cells (90) andbyBergholtz andmyself for helperT cells (91).

Structure of HLA resolved; the pieces cometogether

During the 1960s and 1970s, many studies on the structure

ofMHC antigens, bothH-2 andHLA, appeared [references

in (2, 3)]. By the early 1980s, it had been established that the

class I antigens are composed of two chains, a glycoprotein

heavy chain anchored in the cell membrane of molecular

weight (mw) of approximately 45 000, varying in its

membrane distal part between different class I molecules,

which is non-covalently associated with b-2 microglobulin(mwabout 12 000), which is constant in all class Imolecules.

In contrast, the class II antigens consist of two glycoprotein

heavy chains (a and b) of mw of approximately 34 000 and29 000, respectively, both anchored in the cell membrane

and where the b chain varied between different HLA-DRantigens.

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

now on. It was shown by Ziegler andUnanue (92) that CD4

T cells recognize fragments of antigens in association with

MHC class II molecules in macrophages and by Townsend

et al. (93) that CD8 T cells recognize peptide fragments of

antigen in association with MHC class I molecules in target

cells. But what was 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 also in immunology in general. In an article to

the memory of Don Wiley (19442001), Strominger has

given a very interesting account on how the group arrived at

their results (94). In the first Nature paper, Bjorkman et al.

(95), 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 showed that the membrane distal domain is a platform

of antiparallel b-strands topped by two a-helices, whichtogether form a large grove that 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 (Figures 15 and 16, which for many

years were the most frequent shown pictures in any lecture

on HLA or immunology). Thus, HLA molecules were

peptide-presenting molecules!

In the accompanying paper, Bjorkman et al. (96)

discussed how some of the polymorphic amino acid residues

in the groove of HLA class I molecules, and by inference

Figure 14 Peter Doherty (1940-) left and Rolf Zinkernagel (1944-)

receiving the Nobel Prize in 1996.



also in the groove of class II molecules [which was, however,

first shown 6 years later (97)], would interact with a peptide,

while other polymorphic residues of HLA molecules would

interact with the TCR.

This explained the phenomenon of MHC or HLA

restriction, that is a given T cell recognizes a particular

peptideHLA complex, where both the peptide and the

presenting HLA molecule constitute the ligand. This would

also explain allorecognition, which might involve T-cell re-

cognition of complexes of allogeneic peptides bound by self

HLA-molecules but also of allo-HLA molecules and their

bound peptides. The data also suggested that there would be

limitations in the ability of a given HLAmolecule to bind all

types of peptides [which were amply confirmed in later

studies by others of peptide binding to HLAmolecules (98)].

The MHC or HLA class I and II molecules of an individual

will to a large extent determine which peptides will be bound

and displayed and therefore recognized by his or her CD8 or

CD4 T cells, respectively. This explained theMHC-linked Ir

gene effects caused by different peptide-binding repertoires

of various MHC molecules. It also provided a probable ex-

planation for many HLA-associated autoimmune diseases.

The strongHLAassociationsmight be causedbypreferential

binding by the disease-associated HLA molecules of parti-

cular immunogenic peptides, which would be able to trigger

an autoimmune response, given the necessary precipitating

environmental factors. The pieces had come together.

It is interesting to note that the first HLAmolecule whose

structurewas fully shownwas the same as the very firstHLA

molecule discovered in man, that is MAC or HLA-A2,

discovered by Dausset 29 years previously (1).

Concluding remarks

It is now just a little more than 50 years since Dausset first

discovered a leucocyte antigen in man, which became the

firstHLAantigen,HLA-A2. Since then, the field hasmoved

from histocompatibility to become one of the most central

fields in basic and clinical immunology in general. As

a matter of fact, the term MHC for the HLA complex and

similar genetic complexes in animals should rather be

considered a misnomer because the role of the HLA class I

and II molecules as histocompatibility antigens is more

Figure 15 Schematic representation of the four domains of human

leucocyte antigen HLA-A2. Reprinted with permission from Macmillan

Publishers Ltd, copyright 1987 (95).

Figure 16 Surface representation of the top of the human leucocyte

antigen HLA-A2 molecule, showing (a) the deep groove identified as the

antigen recognition site and (b) the electron density found in this site,

probably a peptide. Reprintedwith permission fromMacmillan Publishers

Ltd, copyright 1987 (95).



a side-effect of their immunobiological function. Given the

instrumental importance of class I and II molecules, and

adding the function of many other HLA complex gene

products, both in innate and in adaptive immune responses,

a better name for the complex would be the major immune

response complex; the MIRC. But, it is too late to change

this now!

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 that must not be underestimated is the

extensive international collaboration, which has taken

place since the early days of HLA, in particular the

IHWSs. Together, the pioneers and the extensive inter-

national collaboration are responsible for the giant

progress we have seen in this field during the past

50 years.

Acknowledgments

I am grateful to Walter Bodmer, Jon van Rood and Paul

Terasaki for helpful comments to 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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