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In View: People in Transplantation

Jerzy Kupiec-Weglinski, MD, PhD

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doi: 10.1097/TP.0000000000003409
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You have received your MD from the Warsaw Medical Academy in 1974 and a PhD from the Polish Academy of Sciences in 1979. You started out with a clinical residency in Gastroenterology and Metabolic Diseases. What motivated you to focus your career on transplantation sciences?

JK-W: As a medical student, I volunteered in the Surgical Research Laboratory adjacent to the hospital where the first successful clinical kidney transplant in Poland had been performed in 1966. It was the place where Polish transplant pioneers, including Prof Nielubowicz, Rowinski, and Orlowski, were performing experiments on dogs. Interacting with them daily and participating first as a technician and then leading my own project was instrumental in shaping my interest in organ transplantation. My PhD thesis on “lymphocyte recirculation” was a “hot” topic in those days and with new molecular insights and technology, it still is. It was the work of James Gowans from Oxford, who discovered that immune surveillance requires lymphocytes to move continuously in dual circuits between blood and lymphoid organs via the lymphatic system. These were times of “small” lymphocytes, “large” lymphoblasts, and no interleukins. I am pleased that the conclusion from my first article published in 19781 stating that “immunoblasts behave like effector cells and localize preferentially in the small gut, lungs, and skin, ie, tissues with direct contact with the external environment” still holds valid over 40 years later.

You grew up in Poland behind the iron curtain. How challenging have been international academic exchanges and traveling at the time?

JK-W: My first mentor, Professor Waldemar Olszewski, who was “well connected” both in Poland (ie, politically) and abroad (ie, scientifically), spent a couple of years at Harvard in the late 1960s. As a PhD student in his laboratory, I had access to foreign scientific literature and was able to present my work abroad. Traveling from Warsaw to Barcelona, for instance, in the mid-1970s, was quite a treat…Not surprisingly, our laboratory was referred to by our (jealous) peers as “a window to the world.” In May 1977, we organized the annual congress of the European Society for Surgical Research in Warsaw. As May is the best time to visit Poland, this meeting attracted many prominent academic transplant surgeons, including Nicholas L. Tilney, MD, from Harvard—and the rest is history.

You moved to Boston as a research fellow in 1979. Can you share details of your move? Who were mentors helping you to be successful?

JK-W: I arrived in Boston around Halloween, 1979. I will never forget my first Thanksgiving spent with Mary and Nick Tilney in their Beacon Hill home or the many trips to their New Castle house in New Hampshire. Soon, we became good friends, and many years later, Nick became the godfather of my daughter, Sophie. The Peter Bent Brigham always was and still is the transplantation mecca. Looking back, I was blessed to have Nick as my mentor in many ways, including helping me think logically and writing scientific reports. I was also lucky to work in one of the very few labs in the United States with access to a new “magic powder,” cyclosporine. As I firmly believe that collaboration is the way to success, close interactions with Terry Strom of Beth Israel, and Bernie Carpenter of the Brigham, were instrumental throughout my 18 years at Harvard. The PubMed listed publications during that time speak by themselves. Out of 96 papers published with Nick, 32 were coauthored with Terry and 9 with Bernie. The legendary Brigham Surgery Chairman, Francis D. Moore, communicated my 3 PNAS reports. Stimulating discussions in the Countway Library with Carl Walter, the surgeon emeritus who developed an early kidney dialysis machine, and blood transfusion equipment often continued at his clambake gatherings on Cape Cod.

In 1987, you were promoted to Associate Professor at Harvard Medical School. Academic promotions from research fellow to faculty positions are frequently perceived as challenging. What made you successful?

JK-W: I guess hard work, thinking “out of the box,” and my publication record. There were no impact factors these days, however, Transplantation was the principal venue for our research reports.2,3 So far, I contributed over 80 papers in Transplantation. Two significant milestones guided my future transplant research career. First, was a year-long sabbatical in Sir Peter Morris’ Laboratory in Oxford in 1986, where I expanded my recirculation studies into dendritic cells, with 2 original papers published in The Journal of Experimental Medicine.4,5 The second was my first NIH R01 funding as a Principal Investigator in 1987, which I was able to renew many times.

You moved to UCLA as Professor of Surgery in 1997. Here, you changed your research focus slightly to Ischemia/reperfusion Injury in liver transplantation. Can you briefly discuss your 2 favorite publications during your time in Boston and then at UCLA?

JK-W: An ideal immunosuppressive agent should selectively target lymphocytes participating in transplant rejection without affecting host defense mechanisms. In joint studies with Terry Strom at Harvard and Tibor Diamantstein at Free University, Berlin, Germany, we introduced a new concept of IL-2 receptor (IL-2R) targeted therapy. Our findings from rat models were published between 1986 and 1990 in PNAS6,7 and JEM.8 Not knowing that anti-IL-2R (p55 chain) Abs were also targeting Treg (or T suppressor cells as referred to at that time), we were somewhat puzzled by not as expected in vivo efficacy of the approach. These studies, accompanied by clinical trials,9 headed by Jean-Paul Soulillou in Nantes, France, and followed by tremendous progress in molecular immunology, have paved the way for the successful inclusion of anti-CD25 mAb therapy in the clinical immunosuppressive armamentarium a decade later (Basiliximab, Daclizumab).

After moving to UCLA in 1997, my team has discovered striking cytoprotective functions of heme oxygenase-1, a heat-shock protein-32. Indeed, overexpression of this stress-responsive enzyme has proven central to reestablish homeostasis in tissues exposed to peritransplant preservation injury. This has led us to propose a novel idea of heme oxygenase-1-dependent donor liver “rejuvenation” by advancing the concepts of targeting proinflammatory responses while enhancing intrinsic cytoprotective mechanisms of hepatocyte regeneration. These findings, published in JCI,10 J. Hepatol,11 in addition to other publications have linked innate and metabolic signaling pathways into a common mechanistic framework of cell communication between liver nonparenchymal (macrophages) and parenchyma (hepatocyte) compartments. These ongoing investigations aim to improve the quality and size of the current organ supply, an imperative for the full therapeutic realization of solid organ transplantation.

The clinical/research team that you have built with Ron Busuttil at UCLA has been extremely productive coming across as working in a very synergistic way. What made this team so successful?

JK-W: Ron Busuttil has built one of the most accomplished clinical liver transplant programs in the world (over 7000 cases since 1984). In the past 20 years or so, we established a very successful bench-to-bedside translational research platform, encompassing innovative ideas and technologies relevant to molecular mechanisms in animal settings and liver transplant patients. A 2-way collaborative effort between the clinical enterprise and basic research is the approach to introduce novel therapeutic concepts to improve transplant outcomes, as well as diagnostic biomarkers to improve the quality of donor organs. These have been accomplished through collaboration between UCLA surgeons (Drs. Busuttil, Kaldas, Farmer), pathologists (Drs. Reed, Gjertson), computational bioscientists (Drs. Hoffmann, Ahn), and surgical basic researchers (Drs. Zhai, Ke, Ji). I take pride in leading our NIH Program Project (P01), as well as mentoring my younger colleagues and their own research supported by R01 and R21 mechanisms.

Most recently, you expanded your work into the area of metabolism. Can you speculate on how impactful this line of research (from a general perspective) will be on our understanding of alloimmunity and the potential to improve transplant outcomes?

JK-W: Commensal bacteria are increasingly recognized as an important factor in human metabolic health and disease. Recent evidence that microbiome modifications alter allograft success indicates the potential to leverage the microbiota to improve clinical outcomes. We have recently reported12 that mice and humans preconditioned with prolonged antibiotic regimen show decreased liver transplant injury and improved outcomes by reducing hepatic inflammation and ER-stress while increasing autophagy due to enhanced prostaglandin E2 signaling in the gut. To our surprise, liver transplant function improved significantly in patients who were of the highest acuity and required massive antibiotic therapy before surgery. In parallel, mice that received fecal transplants suffered liver damage, although they were pretreated with antibiotics. Thus, antibiotic-mediated transplant benefits relate to modulation of host microbiota. This study opens the door to further research that could determine which microorganisms protect liver transplant and which need to be “turned down” to limit their negative effects. This could be accomplished by resurrecting an over 100-year-old approach of phage therapy, which in contrast to antibiotics, may allow for a personalized manipulation of the microbiome and is virtually free of side-effects. Phages could also replace antibiotics and serve as selective antimicrobial agents reducing the risks of infections as well as acting as a low-risk adjunct immunosuppression.

Mentoring has been greatly important for you. In your own career, you have become a very successful mentor with many of your own mentees having moved forward with their own very successful careers. What is the ‘secret’ of your mentorship?

JK-W: I was flattered to receive the 2020 TTS Award for Mentorship or Education and Training in Transplantation. Indeed, I served as a preceptor to over 20 predoctoral trainees and over 40 research fellows. Most of them have reached high academic ranks in immunology, surgery, and even as CEOs of biocompanies. I also mentored over 30 clinicians when they were at the beginning of their academic careers. This eventually resulted in them achieving significant academic positions at universities in the United States and overseas, for example, in Japan (8), Germany (6), Switzerland (2), or Poland (2). There is no “secret” in my mentoring style, but I think my fellows sensed that I cared about them as a person and wanted each of them to succeed. These were hard-working, bright, and enthusiastic young physicians and scientists. My contribution was to provide them with an exciting and potentially important project and have guts (or vision) to terminate it in time (when it was going to fail). The scientific environments at Harvard and UCLA have always been outstanding for transplant-focused basic and translational research.

You have received an Honorary Doctorate at the Warsaw Medical Academy, are a member of the Polish Academy of Arts and Sciences, and have received several of the most relevant scientific awards in Poland. Can you share how you continue to cooperate and advise The Scientific/Medical Community in Poland?

JK-W: I am proud of being the first and the youngest Honorary Doctorate recipient of my Alma Mater, which was bestowed on me in 2002. This was particularly sweet as I was banned from my country for almost 10 years because of political reasons. I share the Warsaw Medical Academy honoris-causa title with other transplant luminaries, including Nicholas Tilney, Mark Hardy, Barry Kahan, E. Donnall Thomas, John Hansen, and Henri Bismuth. Being the elected Foreign Member of the Polish Academy of Sciences (PAN) since 2005, together with Paul S. Russell, after whom the Harvard Museum of Medical History and Innovations was named, is quite a distinction as well. I have been collaborating with my Polish peers in bad times (during the Solidarity era and martial law) and good times by hosting them at UCLA, serving at the Board of Curators evaluating the performance of PAN institutions, or reviewing grant applications. Certainly, I never refuse the invitation to give a lecture and visit the country of my birth!

You are looking back to a very productive academic career in Transplantation. What do you consider a key accomplishment during that time and where to you expect the most relevant progress moving forward?

JK-W: Indeed, time flies… In the past 40 years or so, 1-year survival of the majority of human transplants increased from about 50% to well over 90%. This could never be accomplished without enormous progress in our appreciation of the complex cellular and molecular immune mechanisms in the rejection cascade. Although tolerance still remains the “holy grail” in solid organ transplantation after all these years, studying vascularized composite allografts, may help to push the field forward. I tend to believe that xenotransplantation has a great future, and always will. The success of transplantation has become its primary obstacle as the donor pool fails to keep pace with a growing number of patients awaiting the life-saving organ. While living longer years, the quality of potential donor organs does not improve at all, but opposite. The exciting early findings on normothermic liver perfusion to alleviate peritransplant tissue damage and improve outcomes provides a unique opportunity to translate our experience from animal models into the real-life clinical scenario, with an immediate benefit to our patients.

As a member of the Polish Academy of Art and Science, you have not only had a focus on science but also an interest in art being married to an artist’s wife. How is art influencing Science and Life?

JK-W: I met my wife Kasia, a painter, printmaker, and art educator, originally also from Poland, during her painting exhibition, entitled “The Art for XXI Century” in Connecticut, back in 1991. Six months later, we tied the knot at the Harvard-owned Thomas Paine House, Sutton Island, Maine. As I have always been into the fine arts, albeit in somewhat different styles, this was and still is a perfect match. We do inspire each other, as some of Kasia’s paintings and installations address transplant-oriented dilemmas, such as “how many body parts can you exchange and still think of yourself as yourself?” A very timely question, indeed, when our community is starting to discuss (seriously?) the idea of human head transplantation, not only from the ethical but also immunological standpoints.

REFERENCES

1. Olszewski WL, Kupiec-Weglinski J. Whole body localization of intravenously injected lymphoblasts in normal rats. Lymphology. 1978; 11:222–230
2. Kupiec-Weglinski JW, Tilney NL. Migration patterns of lymphocytes from recipients of organ allografts. I. The unmodified host. Transplantation. 1981; 32:121–127. doi:10.1097/00007890-198108000-00008
3. Kupiec-Weglinski JW, Bordes-Aznar J, Clason AE, et al. Migration patterns of lymphocytes in untreated and immunologically manipulated recipients of organ allografts. Transplantation. 1982; 33:593–598. doi:10.1097/00007890-198206000-00005
4. Kupiec-Weglinski JW, Austyn JM, Morris PJ. Migration patterns of dendritic cells in the mouse. Traffic from the blood, and T cell-dependent and -independent entry to lymphoid tissues. J Exp Med. 1988; 167:632–645. doi:10.1084/jem.167.2.632
5. Austyn JM, Kupiec-Weglinski JW, Hankins DF, et al. Migration patterns of dendritic cells in the mouse. Homing to T cell-dependent areas of spleen, and binding within marginal zone. J Exp Med. 1988; 167:646–651. doi:10.1084/jem.167.2.646
6. Kupiec-Weglinski JW, Diamantstein T, Tilney NL, et al. Therapy with monoclonal antibody to interleukin 2 receptor spares suppressor T cells and prevents or reverses acute allograft rejection in rats. Proc Natl Acad Sci U S A. 1986; 83:2624–2627. doi:10.1073/pnas.83.8.2624
7. Tanaka K, Tilney NL, Stunkel KG, et al. Pretreatment with cyclosporine and anti-interleukin 2 receptor antibody abrogates the anti-idiotype response in rat recipients of cardiac allografts. Proc Natl Acad Sci U S A. 1990; 87:7375–7379. doi:10.1073/pnas.87.19.7375
8. Di Stefano R, Mouzaki A, Araneda D, et al. Anti-interleukin 2 receptor monoclonal antibodies spare phenotypically distinct T suppressor cells in vivo and exert synergistic biological effects. J Exp Med. 1988; 167:1981–1986. doi:10.1084/jem.167.6.1981
9. 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; 322:1175–1182. doi:10.1056/NEJM199004263221702
10. Amersi F, Buelow R, Kato H, et al. Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury. J Clin Invest. 1999; 104:1631–1639. doi:10.1172/JCI7903
11. Nakamura K, Zhang M, Kageyama S, et al. Macrophage heme oxygenase-1-SIRT1-p53 axis regulates sterile inflammation in liver ischemia-reperfusion injury. J Hepatol. 2017; 67:1232–1242. doi:10.1016/j.jhep.2017.08.010
12. Nakamura K, Kageyama S, Ito T, et al. Antibiotic pretreatment alleviates liver transplant damage in mice and humans. J Clin Invest. 2019; 129:3420–3434. doi:10.1172/JCI127550
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