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 b c
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands Department of Transplantation Immunology, Tissue Typing Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
a r t i c l e
i n f o
Article history: Available online 18 October 2014 Keywords: Transplantation Transfusion HLA MHC
a b s t r a c t The sixties have not only witnessed the start of the Dutch Society for Immunology (NvvI), but were 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 infectious disease, as in many other countries. It began in the 1950-ties thanks to Joghem van Loghem at that time director of the Central Laboratory of Blood Transfusion in Amsterdam. The discoveries of these times have had major impact for transfusion medicine, hematopoietic stem cell transplantation and organ transplantation. In this review we will look back at some early highlights of Dutch transplant 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 impossible. 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: “Leucocyte 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 coagulation 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: [email protected] (C. van Kooten). http://dx.doi.org/10.1016/j.imlet.2014.10.017 0165-2478/© 2014 Elsevier B.V. All rights reserved.
bleeding and random platelet transfusions were given until the patient, who had been pregnant, formed after a few weeks’ leukocyte 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 Leiden 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 recovery (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 therapeutic 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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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 Koning and colleagues performed one of the three first successful stem cell transplants in children suffering from congenital immune deficiency. 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 haploidentical 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 organisation 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 available) 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 lifesaving 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 continue 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 Histocompatibility 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 participated, 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 participating. 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 experimental 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 excellent 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 Zinkernagel 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 recognition 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 sequencing 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 technologies became apparent upon the discovery of the polymerase chain reaction (PCR), and its application for HLA typing by sequence specific 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 sequencing 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 identification 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 immunised 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 Disequilibrium. This could potentially be explained by Non-Inherited Maternal haplotype exposure during foetal life inducing tolerance
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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 experimental models. Also in a retrospective analysis of renal transplant recipients it could be demonstrated that NIMA mismatched haploidentical 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 marrow transplantation, CIBMTR, it could be demonstrated that the NIMA effect was also active in haploidentical sibling stem cell transplantation, 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 Antigen) 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 transplantation 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 alternative 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 transfusions 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 product 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 transfusions 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].
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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 transfusion 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 pretransplant 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 reasons at a time that the management of the Primate Centre was confronted with the thread of closure and left us with the frustrating 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 sensitization has almost completely eliminated the use of protocolized blood transfusions. Still it should be considered as one of the first examples of personalized cellular therapy. Currently, both in the setting of hematopoietic stem cell transplantation and organ transplantation, 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 important aspects of this discipline have not been discussed, including surgical and clinical management of these patients, immunosuppressive 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 mentioned. 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 antibodymediated 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 collaboration, 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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Tetrameric HLA class I-minor histocompatibility antigen peptide complexes demonstrate minor histocompatibility antigen-specific cytotoxic T lymphocytes in patients with graft-versus-host disease. Nat Med 1999;5(July (7)):839–42. [17] den Haan JM, Meadows LM, Wang W, Pool J, Blokland E, Bishop TL, et al. The minor histocompatibility antigen HA-1: a diallelic gene with a single amino acid polymorphism. Science 1998;279(February (5353)):1054–7. [18] Paul LC, Claas FH, van Es LA, Kalff MW, de Graeff J. Accelerated rejection of a renal allograft associated with pretransplantation antibodies directed against donor antigens on endothelium and monocytes. N Engl J Med 1979;300(May (22)):1258–60. [19] Joosten SA, Sijpkens YW, van Ham V, Trouw LA, van der Vlag J, van den Heuvel B, et al. Antibody response against the glomerular basement membrane protein agrin in patients with transplant glomerulopathy. Am J Transplant 2005;5(February (2)):383–93. [20] Larhammar D, Hylgen-Nielsen JJ, Servenius B, Andersson G, Rask L, Peterson PA. Exon-intron organization and complete nucleotide sequence of a major histocompatibility antigen DC beta gene. Proc Natl Acad Sci USA 1983;80:7313–7. [21] Rollini P, Mach B, Gorski J. Linkage map of three HLA-DR beta chain genes: evidence for a recent duplication event. Proc Natl Acad Sci USA 1985;82:7197–201. [22] Spies T, Sorrentino R, Boss JM, Okada K, Strominger JL. Structural organization of the DR subregion of the human major histocompatibility complex. Proc Natl Acad Sci USA 1985;82:5165–9. [23] Trowsdale J, Ragoussis J, Campbell RD. Map of the human MHC. Immunol Today 1991;12:443–6. [24] Shiina T, Tamiya G, Oka A, Takishima N, Yamagata T, Kikkawa E, et al. Molecular dynamics of MHC genesis unraveled by sequence analysis of the 1,796,938-bp HLA class I region. Proc Natl Acad Sci USA 1999;96(November (23)):13282–7. [25] Beck, et al. Complete sequence and gene map of a human major histocompatibility complex. Nature 1999;401:921–3. [26] Olerup O, Zetterquist H. HLA-DR typing by PCR amplification with sequence specific primers (PCR-SSP) in 2 hours: an alternative to serological DR typing in clinical practice including donor-recipient matching in cadaveric transplantation. Tissue Antigens 1992;39:225–35. [27] Angelini G, de Preval C, Gorski J, Mach B. High resolution analysis of HLA-DR polymorphism by hybridization with sequence specific oligonucleotide probes. Proc Natl Acad Sci USA 1986;83:4489–93. [28] Santamaria P, Lindstrom AL, Boyce-Jacino MT, Myster SH, Barbosa JJ, Faras AJ, et al. HLA class I sequence-based typing. Hum Immunol 1993;37(May (1)):39–50. [29] Scheltinga SA, Williams F, Van der Zwan AW, Rozemuller EH, Middleton D, Tilanus MGJ. HLA-A towards a high resolution DNA typing. Tissue Antigens 1998;51:549–52. [30] Voorter CE, Palusci F, Tilanus MGJ. Sequence-based typing of HLA: an improved group-specific full-length gene sequencing approach. In: Beksac¸ M, editor. Methods in molecular biology. 2nd edn. New York: Humana Press; 2014. p. 101–14. [31] Erlich H. HLA-DNA typing: past, present and future. Tissue Antigens 2012;80:1–11. [32] Petersdorf EW, Malkki M, Gooley TA, Spellman SR, Haagenson MD, Horowitz MM, et al. MHC-resident variation affect risks after unrelated donor hematopoietic cell transplantation. Sci Transl Med 2012;4:144ra101. [33] Claas FH, Gijbels Y, van der Velden-de Munck J, van Rood JJ. Induction of B cell unresponsiveness to noninherited maternal HLA antigens during fetal life. Science 1988;241(September (4874)):1815–7. [34] Burlingham WJ, Grailer AP, Heisey DM, Claas FH, Norman D, Mohanakumar T, et al. The effect of tolerance to noninherited maternal HLA antigens on the survival of renal transplants from sibling donors. N Engl J Med 1998;339(December (23)):1657–64.
J.J. van Rood et al. / Immunology Letters 162 (2014) 145–149 [35] van Rood JJ, Loberiza Jr FR, Zhang MJ, Oudshoorn M, Claas F, Cairo MS, et al. Effect of tolerance to noninherited maternal antigens on the occurrence of graft-versus-host disease after bone marrow transplantation from a parent or an HLA-haploidentical sibling. Blood 2002;99(March (5)):1572–7. [36] van Rood JJ, Stevens CE, Smits J, Carrier C, Carpenter C, Scaradavou A. Reexposure of cord blood to noninherited maternal HLA antigens improves transplant outcome in hematological malignancies. Proc Natl Acad Sci USA 2009;106(November (47)):19952–7. [37] van Rood JJ, Scaradavou A, Stevens CE. Indirect evidence that maternal microchimerism in cord blood mediates a graft-versus-leukemia effect in cord blood transplantation. Proc Natl Acad Sci USA 2012;109(February (7)):2509–14. [38] Claas FH, Rahmel A, Doxiadis II. Enhanced kidney allocation to highly sensitized patients by the acceptable mismatch program. Transplantation 2009;88(August (4)):447–52. [39] de Klerk M, Witvliet MD, Haase-Kromwijk BJ, Claas FH, Weimar W. Hurdles, barriers, and successes of a national living donor kidney exchange program. Transplantation 2008;86(December (12)):1749–53. [40] Persijn GG, Cohen B, Lansbergen Q, van Rood JJ. Retrospective and prospective studies on the effect of blood transfusions in renal transplantation in The Netherlands. Transplantation 1979;28(November (5)): 396–401.
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[41] Lagaaij EL, Hennemann IP, Ruigrok M, de Haan MW, Persijn GG, Termijtelen A, et al. Effect of one-HLA-DR-antigen-matched and completely HLA-DRmismatched blood transfusions on survival of heart and kidney allografts. N Engl J Med 1989;321(September (11)):701–5. [42] van Twuyver E, Mooijaart RJ, ten Berge IJ, van der Horst AR, Wilmink JM, Kast WM, et al. Pretransplantation blood transfusion revisited. N Engl J Med 1991;325(October (17)):1210–3. [43] Knulst AC, Bril-Bazuin C, Tibbe GJ, Benner R. Improved survival from potentially lethal graft-vs.-host disease by donor pretreatment with a recipient-specific blood transfusion. I. Requirements for induction and specificity of the effect. Eur J Immunol 1992;22(October (10)):2481–6. [44] Bean MA, Mickelson E, Yanagida J, Ishioka S, Brannen GE, Hansen JA. Suppressed antidonor MLC responses in renal transplant candidates conditioned with donor-specific transfusions that carry the recipient’s noninherited maternal HLA haplotype. Transplantation 1990;49(February (2)):382–6. [45] Leonard AA, Jonker M, Lagaaij EL. Complete withdrawal of immunosuppression in allograft recipients. A study in rhesus monkeys. Transplantation 1996;61(June (11)):1648–51. [46] Reinders ME, de Fijter JW, Roelofs H, Bajema IM, de Vries DK, Schaapherder AF, et al. Autologous bone marrow-derived mesenchymal stromal cells for the treatment of allograft rejection after renal transplantation: results of a phase I study. Stem Cells Transl Med 2013;2(February (2)):107–11.
Contents lists available at ScienceDirect
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 b c
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands Department of Transplantation Immunology, Tissue Typing Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
a r t i c l e
i n f o
Article history: Available online 18 October 2014 Keywords: Transplantation Transfusion HLA MHC
a b s t r a c t The sixties have not only witnessed the start of the Dutch Society for Immunology (NvvI), but were 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 infectious disease, as in many other countries. It began in the 1950-ties thanks to Joghem van Loghem at that time director of the Central Laboratory of Blood Transfusion in Amsterdam. The discoveries of these times have had major impact for transfusion medicine, hematopoietic stem cell transplantation and organ transplantation. In this review we will look back at some early highlights of Dutch transplant 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 impossible. 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: “Leucocyte 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 coagulation 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: [email protected] (C. van Kooten). http://dx.doi.org/10.1016/j.imlet.2014.10.017 0165-2478/© 2014 Elsevier B.V. All rights reserved.
bleeding and random platelet transfusions were given until the patient, who had been pregnant, formed after a few weeks’ leukocyte 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 Leiden 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 recovery (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 therapeutic 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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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 Koning and colleagues performed one of the three first successful stem cell transplants in children suffering from congenital immune deficiency. 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 haploidentical 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 organisation 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 available) 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 lifesaving 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 continue 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 Histocompatibility 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 participated, 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 participating. 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 experimental 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 excellent 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 Zinkernagel 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
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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 recognition 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 sequencing 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 technologies became apparent upon the discovery of the polymerase chain reaction (PCR), and its application for HLA typing by sequence specific 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 sequencing 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 identification 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 immunised 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 Disequilibrium. This could potentially be explained by Non-Inherited Maternal haplotype exposure during foetal life inducing tolerance
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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 experimental models. Also in a retrospective analysis of renal transplant recipients it could be demonstrated that NIMA mismatched haploidentical 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 marrow transplantation, CIBMTR, it could be demonstrated that the NIMA effect was also active in haploidentical sibling stem cell transplantation, 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 Antigen) 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 transplantation 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 alternative 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 transfusions 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 product 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 transfusions 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].
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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 transfusion 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 pretransplant 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 reasons at a time that the management of the Primate Centre was confronted with the thread of closure and left us with the frustrating 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 sensitization has almost completely eliminated the use of protocolized blood transfusions. Still it should be considered as one of the first examples of personalized cellular therapy. Currently, both in the setting of hematopoietic stem cell transplantation and organ transplantation, 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 important aspects of this discipline have not been discussed, including surgical and clinical management of these patients, immunosuppressive 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 mentioned. 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 antibodymediated 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 collaboration, 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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