Immunology Letters 162 (2014) 145–149

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

Review

Half a century of Dutch transplant immunology

Jon J. van Rood a , Frans H.J. Claas a , Anneke Brand a ,
Marcel G.J. Tilanus b , Cees van Kooten c,∗
a
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
b
Department of Transplantation Immunology, Tissue Typing Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands
c
Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands

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

Article history: The sixties have not only witnessed the start of the Dutch Society for Immunology (NvvI), but were
Available online 18 October 2014 also the flourishing beginning of the discipline of transplant immunology. The interest in immunology
in the Netherlands had its start in the context of blood transfusions and not for instance in the field of
Keywords: infectious disease, as in many other countries. It began in the 1950-ties thanks to Joghem van Loghem
Transplantation at that time director of the Central Laboratory of Blood Transfusion in Amsterdam. The discoveries of
Transfusion
these times have had major impact for transfusion medicine, hematopoietic stem cell transplantation
HLA
and organ transplantation. In this review we will look back at some early highlights of Dutch transplant
MHC
immunology and put them in the perspective of some recent developments.
© 2014 Elsevier B.V. All rights reserved.

1. The almost forgotten case history of the first patient
whose life was saved by HLA
In 1958 a non-haemolytic febrile transfusion reaction had made
clear to us that pregnancy could induce what later turned out to
be antibodies against HLA [1]. At that time access to a computer
which was able to perform a cluster analysis required to unravel
the complexity of the HLA system turned out to be next to impossi-
ble. However, one was located in the ministry of Inner Affairs which
was used to calculate and print our salary counterfoils. The analysis
resulted in the identification of what later would be called HLA-Bw4
and -Bw6 in 1962 and the thesis of Jon van Rood, entitled: “Leuco-
cyte Grouping; A Method and Its Application” [2]. After a sabbatical
in New York, he returned to the University Hospital in Leiden, which
was in the fortunate position to have one of the first hospital Blood
Banks in the Netherlands, and where he did most of the clinical
haematology rounds together with Freddie Loeliger, the coagula-
tion expert. There they were confronted with a woman who was
bleeding literally from all orifices, due to severe aplastic anaemia
after antibiotic treatment with chloramphenicol. Because the Blood
Bank had developed technologies to provide platelet transfusions,
this patient received the first platelet transfusions prepared from
donor blood by George Eernisse in 1964. The patient stopped
∗ Corresponding author at: Department of Nephrology, Leiden University Medical
Center, Albinusdreef 2, 2333ZA Leiden, The Netherlands.
E-mail address: kooten@lumc.nl (C. van Kooten).
bleeding and random platelet transfusions were given until the
patient, who had been pregnant, formed after a few weeks’ leuko-
cyte antibodies. Platelet recovery after the platelet transfusions
dropped to zero and she started bleeding again. As it was known
that the 9 “HLA” antigens that were recognised at that time in Lei-
den were genetically determined it was investigated whether some
of the eight brothers and sisters of the patient might turn out to have
a negative leucocyte agglutination cross match with her serum. This
turned out to be the case and every week one of these sibling donors
came to Leiden to donate platelets, which all had an excellent recov-
ery (Fig. 1). A splenectomy was done a few months later and the
patient recovered, and continued to visit the outpatient clinic [3].
2. Bone marrow transplantation and why the Dutch
registry is called Europdonor
Another major development during these early days was ther-
apeutic bone marrow transplantation. This was largely possible
because the University Leiden had managed to obtain a contract
with the Dutch government to establish an Institute for Radio
Pathology and Radiation Protection (IRPRP) in order to be prepared
to treat victims of a nuclear accident. For that purpose, an Isolation
Pavilion was built to treat such patients. Dick van Bekkum of the
Radio Biological Institute in Rijswijk provided data on a successful
stem cell transplant protocol after Total Body Irradiation and gut
decontamination in inbred mice, which they liked to upgrade for
patients. On our request he started to work with Rhesus monkeys to
confirm his findings in a larger outbred animal model and recruited

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0165-2478/© 2014 Elsevier B.V. All rights reserved.
146 J.J. van Rood et al. / Immunology Letters 162 (2014) 145–149
Fig. 1. The case history of the first patient whose life was saved by HLA knowledge.
Hans Balner to develop MHC typing in these animals. Their stem
cell transplant results were impressive and in 1968 Han de Kon-
ing and colleagues performed one of the three first successful stem
cell transplants in children suffering from congenital immune defi-
ciency. The other two were performed by Bob Good and colleagues
in Minneapolis, USA. All three patients survived more than 25 years
and the Dutch patient is still alive 45 years later [4].
In the Isolation Pavilion a bone marrow transplant program
was started and a first unrelated donor provided bone marrow
for a patient with aplastic anaemia and a first successful hap-
loidentical transplant to a patient with Severe Combined Immune
Deficiency [5–7]. The platelet support of patients with leukaemia
and transplantation turned out to be a heavy burden. Regular
platelet transfusions, containing many leukocytes, appeared strong
inducers of HLA antibodies developing in over 60% of patients and
not all of them possessed compatible family members. During the
annual meeting of the ‘Deutsche Transfusion’s Geselschaft’ in 1970
van Rood presented the Leiden results with HLA compatible platelet
transfusions and pointed out that international cooperation was
essential to support thrombocytopenic patients in need of HLA
matched platelet transfusions. The proposal was to start an orga-
nisation named Europdonor and for which the 20 HLA laboratories
in Europe were each offered sufficient anti-HLA reagents (at that
time regarded as research tools and not (yet) commercially avail-
able) to type 1000 blood transfusions donors [8]. At that time, circa
20,000 HLA typed donors in Europe were assumed sufficient to
help the majority of patients in need of HLA matched platelets or
unrelated bone marrow! In this plan, the Eurotransplant computer
facilities should collect, print and distribute these HLA typings.
However the proposal did not catch on and Europdonor became
a functioning reality only in the Netherlands [9]. By 1988, 20,000
donors had been HLA-typed and had provided thousands of life-
saving platelet transfusions. Meanwhile, by leukocyte-depletion of
blood products, HLA immunization reduced and preventive platelet
transfusions before a bleeding occurred became possible [10]. In
1988 the IRPRP organisation stopped, but Europdonor could con-
tinue functioning as a Foundation thanks to governmental funds.
In 1994 Anneke Brand and Fred Falkenburg established the Dutch
cord blood bank.
3. The start of renal transplantation and Eurotransplant
In 1954 it had become clear that organ transplantation between
monozygotic twins was feasible, which asked for the next step.
Major discoveries at the level of immunosuppressive therapy and
the understanding of histocompatibility led in 1966 in Leiden to
the first allogeneic renal transplantation from a mother to her son
with end stage renal failure. It could be shown that matching for
HLA made a difference in prognosis, and during the third Histocom-
patibility workshop in Torino in 1967 van Rood proposed to start
Eurotransplant [11]. The probability to find a donor and recipient
with a matching tissue type would strongly increase when there
would be a large database with the HLA typing of patients on the
waiting list. Initially 12 transplant centres in three countries par-
ticipated, but this rapidly expanded and nowadays over 70 centres
from 8 countries, including the Netherlands, Belgium, Luxemburg,
Germany, Austria, Slovenia, Croatia and Hungary, are actively par-
ticipating. Since its foundation, more than 140,000 donor organs
have been allocated by Eurotransplant.
In these early days of experimental medicine, a lot was learned
from erythrocyte and platelet transfusions in patients, but also
from several volunteers who received experimental skin grafts. The
protocol worked as follows: volunteer recipients received first an
intradermal injection of cells from a donor who was mismatched for
one HLA antigen with the volunteer (e.g.HLA-B7) and then experi-
mental skin grafts from two other volunteers: one who was HLA-B7
positive and the other HLA-B7 negative. One of these volunteer
was a married woman (mrs P.) who received a skin graft which
we expected to survive 10–12 days, but after 24 days the graft was
still doing fine. Only then it became clear she had been pregnant,
which was hypothesised to be an explanation for the unexpected
long survival: at that time called graft enhancement i.e. prolonged
survival caused by antibodies directed against the donor. Especially
the group of Rob Koene in Nijmegen performed at that time excel-
lent research on the basic aspects of enhancement in mouse models
[12]. Mrs P volunteered to cooperate to find out, rejected the skin
graft a day later and it could be shown that she had anti Class II HLA
antibodies. This enabled the development of a serological test for
HLA Class II typing, which made the selection of unrelated organ
and stem cell donors much easier [13,14].
4. From major to minor antigens
The concept of MHC restriction, as shown in the 70 by Zinker-
nagel and Doherty in murine models of viral infection, could also be
demonstrated in a patient (Mrs R.) suffering from aplastic anaemia
and treated by ATG and a haplo-identical stem cell transplant from
her brother. The donor’s stem cells caused a temporary chimerism
but then disappeared and the patient recovered. Using the Cell
Mediated Lympholysis test (CML) it was found that the blood of
 J.J. van Rood et al. / Immunology Letters 162 (2014) 145–149
Mrs R lysed about 50% of the HLA-A2 positive donor cells, while the
patient and her donor were both HLA-A2 positive. Upon discussing
these results, it was pointed out by Allen Munro, at that time on a
sabbatical in Leiden that a similar observation had been made by
Elisabeth Simpson in mice, which turned out to be caused by T cells
recognising HY peptides presented by Class I antigens. This recog-
nition of the male HY antigen by T cells could indeed be confirmed
in the clinical setting [15]. This field of Minor Histocompatibility
Antigens in man was expanded thanks to the work of Els Goulmy
and co-workers, identifying other minor antigens, and unravelling
their genetics, HLA-restriction, expression and tissue distribution
as well as their role in epithelial malignancies, graft versus host
disease and therapeutic graft versus leukaemia potentials [16,17].
The role of non-HLA antigens in transplantation is not restricted
to their role as target for T cell allorecognition. Studies by Leen Paul
and colleagues [18] showed that also antibodies against non-HLA
structures on kidney endothelium could lead to accelerated graft
rejection. Furthermore, antibodies against altered-self structures,
like basement membrane structures, are increasingly recognized
to play a role in chronic forms of rejection, including transplant
glomerulopathy [19].
5. Genes, alleles and extended polymorphism
Molecular analysis of the HLA complex revealed insight in the
gene organisation of individual loci [20–24]. The MHC sequenc-
ing consortium led, by the Sanger Centre Cambridge, identified
full chromosome sequences of 8 homozygous typing cells that are
of consanguineous offspring [25]. These homozygous typing cells
still are important as reference for many gene organisation and
gene polymorphism studies. A major transition in typing technolo-
gies became apparent upon the discovery of the polymerase chain
reaction (PCR), and its application for HLA typing by sequence spe-
cific priming (SSP) [26] and sequence specific oligo priming (SSOP)
[27]. The high polymorphic content of the numerous HLA alleles
however complicates the unambiguous identification of alleles. In
the 90-ties we and others introduced the Sequencing Based Typing
(SBT) approach for the identification of full exons sequences [28,29]
and is now available as full length gene unambiguous sequenc-
ing approach [30]. The next generation sequencing approaches,
although focussed on coverage of the exons, result also in full
length sequences. However the complexity of NGS approaches
[31] does not allow easy implementation of the identification of
single nucleotide polymorphism (SNP) in immune related genes
(e.g. minor antigens, cytokines, KIR polymorphism) or adjacent to
the classical HLA genes [32]. The new strategy for personalised
single molecule sequencing will allow the simultaneous identifica-
tion of HLA and immune related polymorphism of the individuals’
genome. However the functional relevance and significance of
the identified polymorphisms is not always clear, particularly in
matching algorithms the individual contribution of polymorphic
sites is difficult to predict in the context of other polymorphism.
The International Histocompatibility Working groups are essential
for reaching sufficient power for its analysis.
6. The importance of foetal maternal microchimerism
In the 80 , with the use of Homozygous Typing Cells obtained
from cousin marriages offspring, it had been possible to identify
so called acceptable mismatches in the sera from highly immu-
nised end stage renal patients waiting for an unrelated renal
allograft [33]. It was observed that the acceptable mismatches were
often an HLA-A and -B antigen known to be in high Linkage Dis-
equilibrium. This could potentially be explained by Non-Inherited
Maternal haplotype exposure during foetal life inducing tolerance
147
for adult immunization (grandmother theory) as first described for
Rhesus blood group antagonism by Ray Owen in 1954. Although
these Rhesus data have not been confirmed, the NIMA effect, as
it was baptised, has been clearly demonstrated in experimen-
tal models. Also in a retrospective analysis of renal transplant
recipients it could be demonstrated that NIMA mismatched haplo-
identical sibling renal allografts did as well as HLA identical sibling
grafts [34]. However this effect seems to be hampered by the
use of calcineurin inhibitors, like cyclosporine, a corner stone of
the standard immunosuppressive therapy in this population. This
clearly illustrates the complex situation that both allograft rejection
and immune regulation are active immunological processes and
that most of the current immunosuppression, which is essential to
prevent rejection, cannot distinguish between these two forms of
activation.
Furthermore in the large international registry of bone mar-
row transplantation, CIBMTR, it could be demonstrated that the
NIMA effect was also active in haploidentical sibling stem cell trans-
plantation, in the sense that GVHD was significantly reduced [35].
More recently it has been shown in two independent studies that in
Cord Blood (CB) Haematopoietic Stem Cell Transplantation (HSCT)
an HLA mismatched transplant has a prognosis similar to an HLA
matched one, as long as the mismatched HLA antigen with the
patient is identical to one of the NIMA antigens of the cord blood
donor [36]. Finally, a recent analysis indicated that the passive
transfer of maternal T cells with anti IPA (Inherited Paternal Anti-
gen) immunity in CB units, transplanted in patients with ALL and
AML, may play a significant role in the control of relapse [37].
7. Transplantation of (highly) sensitized patients
The presence of donor specific HLA antibodies before transplan-
tation is considered a contra-indication for transplantation. Highly
sensitized patients have HLA antibodies against the majority of
donors and tend to accumulate on the waiting list. However, not
every HLA mismatch has the same impact on graft survival and on
recognition by HLA antibodies. A spin off of these observation is the
acceptable mismatch program of Eurotransplant. Identification of
HLA antigens towards which the patients did not or cannot make
antibodies is used for a preferential allocation of donor kidneys to
highly sensitized patients with excellent results [38]. An alterna-
tive approach to transplant patients with HLA antibodies to their
potential living donor is the Dutch national paired donor-exchange
program initiated by Willem Weimar in Rotterdam [39].
8. The blood transfusion effect
After Gerhart Opelz and Peter Morris almost at the same time,
but independently, had observed that pretransplant blood trans-
fusions could improve renal allograft survival, an analysis of the
Eurotransplant data showed that a single Blood transfusion was
sufficient to cause this effect [40]. Subsequently it was shown
by Lagaaij and colleagues that in order to obtain the improved
graft survival it was necessary that the blood transfusion prod-
uct not only contained leukocytes, but also that donors should
share an HLA DR antigen with the recipient [41]. The group of
Leo de Waal in Amsterdam, showed that the presence or absence
of an immunomodulation effect of pretransplant blood transfu-
sions is associated with the establishment of cytotoxic T precursor
cells, dependent on the degree of HLA-DR sharing [42]. Moreover,
in bone marrow transplantation in the mouse, Rob Benner and
colleagues in Rotterdam showed that donor pre-treatment with
recipient derived blood transfusions can prevent the occurrence of
lethal graft versus host disease [43].
148 J.J. van Rood et al. / Immunology Letters 162 (2014) 145–149
Independently it was shown by Dean et al. that a maternal
pre-transplant blood transfusion diminished mixed lymphocyte
activity between the recipient and the maternal blood transfu-
sion donor, while a paternal one did not [44]. Rhesus monkeys,
who received three pretransplant blood transfusions before they
were transplanted, in some instances, if one or more of the pre-
transplant blood transfusions shared a class II antigen with the
recipient, did not reject the renal allograft for several years, even
when the immunosuppressive therapy consisting of cyclosporine
during the first 6–12 months was stopped [45]. Unfortunately a
prospective study to confirm these findings failed for logistic rea-
sons at a time that the management of the Primate Centre was
confronted with the thread of closure and left us with the frustrat-
ing conviction that we had seen the promised land of “tolerance in
organ transplantation” but were not allowed to enter it.
The subject of Blood transfusion and the reproducibility and
mechanistic understanding have remained a matter of strong
debate. The variation in composition and lack of standardization
of the transfusion product, combined with the increasing fear for
blood born infectious agents (like HIV) and the risk for sensitiza-
tion has almost completely eliminated the use of protocolized blood
transfusions. Still it should be considered as one of the first exam-
ples of personalized cellular therapy. Currently, both in the setting
of hematopoietic stem cell transplantation and organ transplanta-
tion, clinical trials are ongoing to investigate the potential beneficial
role of selected allogeneic cells like regulatory T cells, tolerogenic
dendritic cells and mesenchymal stromal cells [46].
9. Concluding remarks
In this overview we have given a biased view on the field
of transplant immunology, initiated by some early discoveries in
the area of HLA biology. However we realize that many impor-
tant aspects of this discipline have not been discussed, including
surgical and clinical management of these patients, immunosup-
pressive therapies, T cell biology and T cell regulation, involvement
of innate immunity and side effects like viral infections and we
apologize to all colleagues whose important work is not men-
tioned. Also we have been very restricted in the description of novel
developments in the high resolution typing and matching of HLA
and novel technologies to detect HLA antigen specific antibodies,
like Luminex-platform based developments. With the increasing
awareness that both early and late after transplantation antibody-
mediated forms of rejection seem to play an important role, for sure
the coming decade will see important novel discoveries. What this
historic overview hopefully learns us, is that (inter)national collab-
oration, as well as bench to bedside crosstalk and a spirit of freedom
and innovation will be essential to make such steps.
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