Transplantation: What caught your interest getting into transplantation?
JVR: As so often has happened in my life: coincidence! I started my training as a resident in internal medicine in 1952. At that time, it was customary in our hospital (now the Leiden University Medical Center), that the most junior resident was also responsible for the Blood Bank, in addition to taking care of a 16-bed floor. The Blood Bank had a “production” of only 4000 units of blood per year in 1952, and supervision of this process did not come with any title or privileges. When I noticed that the needs had increased rapidly, I felt urged to see my supervisor to warn him that we may run out of donors soon. This warning did not leave a major impression on him; in turn, I was quickly promoted to “head” of the Blood Bank, a “job” that gave me the responsibility to recruit more donors in addition to advancing, at the time, the very basic Blood Bank Technology. Not to worry, I still was “allowed” to take care of my 16-bed patient floor!
Thus, my training included not only internal medicine but also blood transfusion medicine. Running a laboratory and building public relations while recruiting blood transfusion donors turned out to be an extremely busy job, but a lot of fun, especially as blood transfusions can be regarded as temporary transplants with a challenging and complex immunology linked to a myriad of side effects.1
Transplantation: Was there a particularly formative experience in your career?
JVR: There have been numerous formative experiences but the most influential was a febrile nonhemolytic transfusion reaction in a woman who had been pregnant 8 times; she had not received any previous blood transfusions.2 Pregnancy-induced antibodies against leukocytes often remain present years after delivery and provided us (and others) with a clue to unravel the complexity of the HLA system.3
An additional formative example was an experimental skin transplant on a multiparous woman. The graft survived not only the expected 10 days, but 24 days. Enhancement of graft survival was in all likelihood related to anti HLA-DR antibodies that this patient had developed during previous pregnancies. This clinical case motivated us to investigate the serological recognition of HLA-DR antigens.4
Transplantation: What would you consider the most pressing current problem in tissue typing?
JVR: In organ transplantation, apart from renal transplantation, doctors are largely ignoring the significance of tissue typing based on a rationale that novel potent immunosuppressants make HLA matching unnecessary. Moreover, time restrictions may make the selection of a “best matched recipient” for a heart, lung, or pancreas transplant challenging. Although HLA matching may have less of an impact early on after transplantation, in the long term, patients will pay a price when experiencing the side effects of these drugs in addition to multiple morbidities, graft loss, or mortality.
A different approach is seen in stem cell transplantation where a near identical HLA donor has been considered a “conditio sine qua non.” More recently, stem cell transplantation based on cord blood taught us that this source provides approximately ten times more effective regulator T cells allowing a successful outcome even in the presence of one, two or even more HLA antigen mismatches.5,6
The “anatomy” of HLA typing has made enormous progress thanks to the next-generation sequencing, although that work is not yet finished. The “physiology” of alloantigen recognition, on the other hand, is still in its infancy, although the cytotoxic T cell precursor test has been very helpful in stem cell transplantation.7
So-called in silico tests that have the capacity to predict both T and B cell alloimmunity have shown great promise in predicting the probability for graft-versus-host-disease (GVHD) or leukemic relapse.8,9
Transplantation: What thoughts do you have on the allocation and the treatment for highly sensitized patients in need of kidney transplants?
JVR: The acceptable mismatch program of Eurotransplant initiated by Prof. Frans Claas and colleagues has contributed greatly to allocating organs to highly sensitized patients. Of note, this excellent approach is based on the condition that all organ procurement organizations are willing to share donor kidneys with rare HLA phenotypes.10 Moreover, the acceptable mismatch program will also need to take into account the response against non inherited maternal antigens, which are often also acceptable mismatches.11
Transplantation: What opportunities and developments do you see in bone marrow transplantation over the next decade?
JVR: Successful bone marrow transplantation has been a clinical reality for almost 60 years for patients with inherited diseases such severe combined immune deficiency, and a steady improvement of now-acceptable outcomes have been achieved.
Unfortunately, the situation is quite different for adult patients transplanted for malignancies with expected survivals of about 50%. Moreover, many who survive suffer from GVHD, secondary malignancies, and depression. The field of hemopoietic stem cell transplantation (HSCT) is tackling those problems from different angles:
Strategies that develop agents that will treat, control or even eradicate malignancies as an alternative to HSCT are under way and have already been successfully implemented for many patients with chronic myeloid leukemia.
Hemopoietic stem cell transplants originate in general from peripheral blood of HLA-matched (un)related donors. Recently, haploidentical stem cell transplants have regained interest with the application of cyclophosphamide, an approach that offers both opportunities and many challenges including logistic issues.
HSCT based on cord blood continues to be enthusiastically supported by some. However, this approach covers only less than 20% of the total HSCT. Indeed, HSCT based on cord blood unit (CBU) appears as an underutilized approach as CBU are available for almost every patient. Moreover, HSCT based on CBUs are linked to less GVHD with outcomes that are comparable to those when utilizing adult donors as a source.
Tolerance to noninherited maternal antigens, a concept that had originally been established by Prof. Ray Owen, has been revisited and the relevance for clinical renal transplantation and for HSCT from haploidentical donors or cord blood has been demonstrated.12-14 However, this approach has already now doubled the number of rare CBU phenotypes.
Overall, interest in fetal-maternal chimerism has been limited to basic research questions and has rarely found a relevant clinical application. At the same time, maternal immune T cells that target inherited paternal antigens (IPA) might play a significant role in preventing relapse.15 The HLA match between donor and recipient remains to be of critical significance, particularly in patients suffering from malignancies; however, other factors should be taken into account as well.
For example, collecting CBU from a first or a subsequently born child can have a major impact as the immune system of the mother will be primed during the pregnancy of the first born; subsequent pregnancies will get the maternal immune response boosted. Those events can have significant consequences on the overall relapse rate.14 Whether or not IPA plays a role on outcomes after organ transplantation remains unclear.
Transplantation: What recommendations do you have for young clinicians and scientists going into transplantation?
JVR: Natura docet! Medical doctors naturally want to cure patients and often feel that they need “to do something.” With this noble approach, they often miss considering the broad options that nature offers us.
Studying immune responses during transplantation and pregnancy provides novel approaches that have not been explored extensively. I have profited most from unexplained phenomena that I have observed when treating patients. Research based on detailed and inquisitive clinical observations may pave the road to completely new approaches that will resolve “old problems” as illustrated by the 2 clinical examples (the patient with a nonhemolytic transfusion reaction and the patient with an unexpected prolonged survival of an experimental skin graft) that I mentioned earlier.
Look for your opportunities! There are no dumb questions, and most importantly, learn from the mistakes of others!
To add a personal experience: In 1958, we noticed that pregnancy could induce antibodies against IPA. It took us another 50 years before we wondered whether this anti-IPA immunity might have an effect on relapse after an HSCT in leukemic patients! Why did it take so long? We were too busy studying the genetics of HLA and forgot to wonder why “nature” may want to evoke immunity to the paternal antigens!
Transplantation: What excites you outside of your clinical and research interests?
JVR: I greatly enjoy spending time with family and friends discussing life and science. I remain to be curious and continue to be involved in science. I enjoy being active and had been sailing and skiing until recently. I love listening to music.
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