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In View: Medawar Prize Acceptance Speech

The Medawar Prize Acceptance Speech 2016

Soulillou, Jean-Paul MD

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doi: 10.1097/TP.0000000000001527
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Prof. Jean Paul Soulillou, when he was the director of the Institute and the Iserm Unit. Picture from 1990.

Mister the President chairman, Ladies and Gentlemen, Dear Colleagues and Friends,

I first would like to thank Sir Peter Morris, Prof, as I use to call him since a visiting professor stay on Oxford, for having accepted to introduce me to the audience and for his kind words. Needless to say how proud and grateful I feel for receiving this award. But I feel also very humble; humble not only in front of the iconic portrait of Peter Medawar of course but also in front of the gallery of the past Medawar Prize recipients. But more, I feel in front of this distinction as a kind of representative—only one of the several ambassadors of my generation.

This generation came 2 decades after major milestones in transplantation which open new avenues in biological science, progress in medicine and hope for hundreds of thousands of severely sick patients left without treatments. As a nephrologist student, I was very impressed by one of these milestones, which actually opened the transplantation to the clinic: the transplantation of the Herrick twin brothers. You all know the old photograph of the 2 Herricks twins in the front, and Dr Murray, Dr Ferguson, and Dr Merrill behind. So I wrote a letter to John P. Merrill who, because he just retired, passed my letter to Bernhard Carpenter, who allowed me to join the group of the Peter Bent Brigham Hospital. I must confess that this invitation was not based on a very elaborated program, just a few words that changed my life.

The Peter Bent Brigham Hospital had an extraordinary aura of the mid-1970s. This hospital was known everywhere, and it was really a strong feeling to discover in the spring of 1974, it is a Greek-inspired “academic” old building front, and also a gentle and very friendly architecture at Huntington Circle in Boston. To understand this aura, read the book “The Puzzle People” by Thomas Starzl, where he relates the first seminal series of successful kidney transplantation using immunosuppression at the Washington Congress in 1973. He wrote that he felt as if he was “parachuted” without having being “exposed to Harvard,” and he added, “including the Peter Bent Brigham.”

I had almost no background and record in research, my only bag was optimism. I was very lucky to have a great man as a mentor, the head of the immunology laboratory at the Peter Bent, Professor Carpenter. “Bernie” Carpenter was a really a mentor. In science, very smart, very simple, he provided me with clear and open guidance, but he was also a good man. I had to confess more difficulty being a good man (at that time!) than for science and I spent a really great time. I had the opportunity to share a tiny box in the fellow room “facilities” with Dr Makinan Suthanthiran, and Dr Tony D’Apice, and it has been the beginning of an unfailing friendship. Terry Strom was also here, but was more senior and already established.

Sir Peter Medawar's study and Burnet elaboration on the possible mechanisms—and thus the possibility to interfere with central tolerance—were very present in Bernie Carpenter laboratory. In fact, the project of this laboratory was to work on “active enhancement,” that is, here the capacity to prolong a graft by priming the recipient by an infusion of donor blood. Active enhancement was perceived as a kind of clinically oriented avatar of what Medawar experimented in newborn mice. The idea—or the dream—was to achieve tolerance in adult animals. I am pleased to remember that Sir Peter Morris laboratory was also one of the leaders in this field. Of course, it was a great hope generating an incredible excitation, because the message carried by Medawar work was that one could efficiently manipulate the immune system, at a time of poorly active immunosuppressive drugs.

In this respect, it is interesting to realize that the scene was already set with the 2 major paradigms of the treatment of allograft recipients. John P. Merrill in the 1950s tried to inject donor bone marrow to recipients of a kidney graft in the context of a trial using whole body radiation where they had of course to supplement the recipients with bone marrow. However, they also used a mixture of several sources of bone marrow, including the donor one. However, all these patients died from sepsis.

To close the evocation of this time that forged my future career, I show an old picture I took of the stairways of the Harvard library which speaks to my heart because of so many hours I spent discussing science in this library, which I could enjoy to visit again when I was appointed by Jerome Kassirer to join the board of New England Journal of Medicine.

I came back in France, in Nantes, a middle-sized City on the West Coast of France in the fall of 1975. Nantes University was created in the 16th century but closed, as several others, during the French Revolution and reopened only in 1962. Despite this seism, a school of medicine was still active and generated some brilliant physicians and scientists, such as René Théophile Laennec, who invented the stethoscope in the early 19 century or, more recently, Nicole Le Douarin, who did seminal works on neonatal tolerance and thymic function in birds.

However, although the program of kidney transplantation had already started, the scene was almost empty in terms of transplantation science and, if I can say, my career actually started from scratch.

Transplantation was in its springtime, and it was also a time of great optimism, a time for ideas, new ideas, but also a time to draw plans and build new clinics and laboratories devoted to transplantation in France. This is the artist's representation of the second Institute of Transplantation, which is still working (Figure 1). This institute which comprised 3 layers (floors) of clinic and 3 others devoted to laboratories became a leader European hospital at the beginning of the 1990s for the number of kidney transplantation with also a large program on pancreas transplantation and, even more importantly, has become an internationally recognized spot in transplantation science, which still develops. My obsession at that time was to try to substitute to the current collaboration between departments, a new organization based on a single integrated project. I used several management tools to approach this goal, such as having teams codirected by a clinician and a fundamentalist for instance. Of course, we were not 100% successful, but I think it generated the most important advances achieved in this institute and actually still contribute to hold high institute ambition. I also actively pursue development, the only way to see my research to meet a clinical utility, through the founding of startups, such as TcLand, Effimune, or Xenothera.

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FIGURE 1:
Artist representation of the current building of the Nantes Institute of Transplantation. The building has 3 levels of clinic (including the Divat data bank) and 3 levels of research including a small animal laboratory (microsurgery and genetic engineering in the basement). The large animal laboratory (primates, genetically engineered pigs, and surgical facilities) is in a separate local, in the main Hospital building vicinity.

This institute raised and attracted many brilliant physicians and investigators. Although it not possible to mention by name all the people who contributed to this Institute of Transplantation (Figure 2 and Figure S1, SDC,https://links.lww.com/TP/B371), some faces are also, more particularly, the puzzle face of this Medawar Prize. First clinicians (low turn-over): Dr Gilles Blancho, who also developed the Large Animal Laboratory, a key tool of the Institute for proof of concept in allo and xenotransplantation that I considered as a high priority at my return in France. Dr Magali Giral, who developed the multicenter DIVAT clinical and biological samples databank (WWW divat.fr) with also dedicated statisticians, a second major assets for the Institute. Dr Maryvonne Hourmant, Dr Jacques Dantal, and Dr Diego Cantarovich (who launched the pancreas transplantation program), and Dr George Karam, our senior surgeon.

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FIGURE 2:
The major research thematic of my career: tolerance, graft infiltrating cells, xenotransplantation, and “miscellaneous.”

The turnover was much higher laboratory side. I started with 3 PhDs who are now recognized researchers Dr Jean-Francois Moreau, now head of a renowned laboratory in Bordeaux, Dr Marc Bonneville and Dr Henry Vié. The first experienced investigator who joined my group was Yannick Jacques, one of the best specialists in the world for fundamental exploration of ligand/receptor interactions. Then later, a couple of decades after, came Dr Bernard Vanhove doing now development and research as well, Ignacio Anegon, Beatrice Charreau, Cristina Cuturi, and last but not least, Sophie Brouard, who has been kind enough to accept me, now as an Emeritus Professor, in her team!

I have not been the man of a single-research obsession, but rather too curious about too many things, which I confess may not be the best profile for research. In fact, many of the few articles I am proud of could be classified in a “miscellaneous column”! They concern for instance immunosuppression and malignancies,1 nonimmune risk factors after transplantation,2 initial disease relapses,3,4 or new biologics.5 But, looking back to these old times and more recent data, I can find coherence which, let us say, has often been ruled by utopia as the driving force. The utopia of my time: transplantation tolerance and xenotransplantation. There is now new utopia that are going to keep you busy for some decades.

To travel in these decades of work, I present few diagrams (Table S2, SDC,https://links.lww.com/TP/B371 and Figure S1A, B and C, SDC,https://links.lww.com/TP/B371) where I used a kind of symbolic background to show that, as molecules, ideas connect together and can provide coherence from initially hidden patterns. I say symbolic because this background represents a network of molecules extracted from additional the analysis of transcripts profiling in the blood of operationally tolerant patients.6 I superimposed on this background the 3 major thematic to which I contributed during my career, with many collaborations.

The first thematic was immune tolerance, as already mentioned an “active enhancement” model. I studied a rat model (priming by donor strain transfusion) on almost every angle and finally conclude, that it was actually not a pertinent model of tolerance, but rather a complex picture of regulation and chronic rejection (Figure S1A, SDC,https://links.lww.com/TP/B371). I later thus turn to operational tolerance which I believe provides a more relevant model of immune tolerance of mismatched grafts in humans. Together, with Sophie Brouard, and Magali Giral, we were the first to show an elevated number of B cells in the blood of these patients,7 we then provided the first and more elaborated signatures of tolerance from blood transcript profiling,6 and even more importantly some first evidences of the function of these B cells in tolerant recipients.8 Composite biomarkers of immune risk in transplantation stemming from these studies are now developed under the direction of Dr Sophie Brouard.

Unexpectedly, because I wanted at that time to see whether the phenomenon observed with the anti-class II in rats9 was also observed in humans, I think I did the first observation of the strong link between anti-class II antibody and rejection.10 I showed these data to Prof. [Jon van Rood], in the coffee room, during the 7th Histocompatibility Workshop in Oxford organized by Walter Bodmer (the Workshop of the birthday of the DRw Clusters) and—you always need a little of help from a mentor—[Jon] said to me, “please present a few slides during the discussion of the plenary session”. Table S2, SDC,https://links.lww.com/TP/B371 (from the subsequent Lancet paper10) shows indeed an almost perfect fit between antibodies against donor class II (class I antibodies were absorbed on platelets), and steroid-resistant rejection. These contrasted profiles were probably due to the poorly efficient immunosuppressive treatment of the precyclosporine era.

The second thematic (Figure S1b, SDC,https://links.lww.com/TP/B371) that occupied me a decade was a study of graft infiltrating cells, which started in the 1980s. We derived a collection of T cell clones from acutely rejected kidneys grown against EBV transformed donor B cells. It was not that popular a thematic at that time, and it has been extremely scientifically rewarding. We identified in the supernatant of such a clone the Leukemia Inhibitory Factor,11 which contributes to maintain stem cells in their pluripotent condition. We could develop grams of CD4/CD8 clones,12 and had enough of these cells to make antilymphocyte serum for instance, but these clones were also instrumental to study the receptor/ligand and particularly the effect of monoclonal anti–Il2-R, from the test tube to the patient for the first time in humans,13 as already mentioned by Sir Peter. The same vein allowed us to propose, more recently, monovalent antagonist anti-CD28 antibody lacking of Fc fragment,14 further developed by Dr Bernard Vanhove. This new molecule which has recently achieved successfully a phase I study without evidence of cytokine release will likely become a drug, because a big pharmaceutical company has acquired the license.

This institute will have thus brought to the clinic 2 important new drugs for the patients.

The last thematic (Table SI, Fig S1c, SDC,https://links.lww.com/TP/B371) also belongs to what is still likely an utopia: Xenotransplantation. However, xenotransplantation has been an extremely structuring thematic, particularly for the second INSERM unit I headed, because it allows to build the primate facility mentioned earlier and to have access to genetically engineered animals. It also allowed us to build a platform developed by Dr Ignacio Anegon, for the genetic engineering of small animals. Xenotransplantation thematic also allowed us to obtain in collaboration with the group of Cesare Galli double knockout pigs for α1,3 Gal and Neu5Gc that may offer further clinical development. In this respect, collaborations with the group of Emanuele Cozzi allowed us to be awarded by 2 major Europeans Framework recent programs (Xenome and Translink).

Mr. Chairman, Sir Peter, ladies and gentlemen, my last slide (Figure 3) does not need comments. You already saw this lady in the introduction of Sir Peter. Without our love, her patience, support and optimism, I will not be in front of you today to receive this award. Unfortunately, she could not afford to come today.

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FIGURE 3:
This picture with my wife around 1980 acknowledges that without her strength and optimism and our love, I will not have been able to achieve what has resulted in this 2016 Medawar prize award.

I thank you very much for your kind attention.

REFERENCES

1. Dantal J, Hourmant M, Cantarovich D, et al. Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens. Lancet. 1998;351:623–8.
2. Giral M, Nguyen JM, Karam G, et al. Impact of graft mass on the clinical outcome of kidney transplants. J Am Soc Nephrol. 2005;16:261–8.
3. Dantal J, Bigot E, Bogers W, et al. Effect of plasma protein adsorption on protein excretion in kidney-transplant recipients with recurrent nephrotic syndrome. N Engl J Med. 1994;330:7–14.
4. Le Berre L, Godfrin Y, Günther E, et al. Extrarenal effects on the pathogenesis and relapse of idiopathic nephrotic syndrome in Buffalo/Mna rats. J Clin Invest. 2002;109:491–8.
5. Mai HL, Boeffard F, Longis J, et al. IL-7 receptor blockade following T cell depletion promotes long-term allograft survival. J Clin Invest. 2014;124:1723–33.
6. Brouard S, Mansfield E, Braud C, et al. Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance. Proc Natl Acad Sci U S A. 2007;104:15448–53.
7. Louis S, Braudeau C, Giral M, et al. Contrasting CD25hiCD4 + T cells/FOXP3 patterns in chronic rejection and operational drug-free tolerance. Transplantation. 2006;81:398–407.
8. Chesneau M, Michel L, Dugast E, et al. Tolerant kidney transplant patients produce B cells with regulatory properties. J Am Soc Nephrol. 2015;26:2588–98.
9. Soulillou JP, Carpenter CB, d’Apice AJ, et al. The role of nonclassical Fc receptor-associated, Ag-B antigens (Ia) in rat allograft enhancement. J Exp Med. 1976;143:405–21.
10. Soulillou JP, Peyrat MA, Guenel J. Association between treatment-resistant kidney-allograft rejection and post-transplant appearance of antibodies to donor B-lymphocyte alloantigens. Lancet. 1978;1:354–6.
11. Gascan H, Godard A, Ferenz C, et al. Characterization and NH2-terminal amino acid sequence of natural human interleukin for DA cells: leukemia inhibitory factor. Differentiation inhibitory activity secreted by a T lymphoma cell line. J Biol Chem. 1989;264:21509–15.
12. Moreau JF, Bonneville M, Peyrat MA, et al. T lymphocyte cloning from rejected human kidney allografts. Growth frequency and functional/phenotypic analysis. J Clin Invest. 1986;78:874–9.
13. Soulillou JP, Cantarovich D, Le Mauff B, et al. Randomized controlled trial of a monoclonal antibody against the interleukin-2 receptor (33B3.1) as compared with rabbit antithymocyte globulin for prophylaxis against rejection of renal allografts. N Engl J Med. 1990;322:1175–82.
14. Vanhove B, Laflamme G, Coulon F, et al. Selective blockade of CD28 and not CTLA-4 with a single-chain Fv-alpha1-antitrypsin fusion antibody. Blood. 2003;102:564–70.

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