Out with the old, in with the new: Virtual versus physical crossmatching in the modern era.

The virtual crossmatch (VXM) is gaining acceptance as an alternative approach to assess donor:recipient compatibility prior to transplantation. In contrast to a physical crossmatch, the virtual crossmatch does not require viable donor cells but rather relies on complete HLA typing of the donor and current antibody assessment of the recipient. Thus, the VXM can be performed in minutes which allows for faster transplant decisions thereby increasing the likelihood that organs can be shipped across significant distances yet safely transplanted. Here, we present a brief review of the past 50 years of histocompatibility testing; from the original complement-dependent cytotoxicity crossmatch in 1969 to the new era of molecular HLA typing, solid-phase antibody testing and virtual crossmatching. These advancements have shaped a paradigm shift in our approach to transplantation. That is, foregoing a prospective physical crossmatch in favor of a VXM. In this review, we undertake an in-depth analysis of the pros- and cons- of physical and virtual crossmatching.Finally, we provide objective data on the selected use of the VXM which demonstrate the value of a VXM in lieu of the traditional physical crossmatch for safe and efficient organ transplantation.

Historical overview of transplantation.

Except for legends and claims of miracles, most histories of transplantation cover only the last 60 years because there were no earlier successes. However, the story of even this era has been documented in such rich detail that a full account would fill several volumes. Thus, this brief summary must be limited to highly selected "landmarks." Some landmarks had an immediate impact, but the importance of others went unrecognized for decades. Some findings that deserved landmark status were overlooked or forgotten, whereas others of no biological significance had major impact. Placing these events in perspective is challenging. Several of transplantation's pioneers are still alive, and most of the others are within living memory. Virtually all of them have produced their own accounts. For the most part, they agree on what the "landmarks" are, but their differences in emphasis and perspective make an interesting story.

Fifty years later.

That concludes my remarks. If I have not made my purpose clear, let me summarize simply. I, like all others gathered here, have come to pay homage to Paul Terasaki, a man who bent in the winds of his time but never broke. Over the last 50 years, I have worked with many people. No collaboration has been dearer than that with Paul (Fig. 7).

A personal perspective: 100-year history of the humoral theory of transplantation.

The humoral theory states that antibodies cause the rejection of allografts. From 1917 to 1929, extensive efforts were made to produce antibodies against tumors. It was finally realized that the antibodies were produced against the transplant antigens present on transplantable tumors, not against the tumor-specific antigens. To get around this problem, inbred mouse strains were developed, leading to identification of the transplant antigens determined by the H-2 locus of mice. The antibodies were hemagglutinating and cytotoxic antibodies. The analogous human leukocyte antigen system was established by analysis of lymphocytotoxic alloantibodies that were made by pregnant women, directed against mismatched antigens of the fetus. The human leukocyte antigen antibodies were then found to cause hyperacute rejection, acute rejection, and chronic rejection of kidneys. Antibodies appeared in almost all patients after rejection of kidneys. With Luminex single antigen bead technology, donor-specific antibodies could be identified before rise in serum creatinine and graft failure. Antibodies were shown to be predictive of subsequent graft failure in kidney, heart, and lung transplants: patients without antibodies had superior 4-year graft survival compared with those who did have antibodies. New evidence that antibodies are also associated with chronic failure has appeared for liver and islet transplants. Four studies have now shown that removal or reduction of antibodies result in higher graft survival. If removal of antibodies prevents chronic graft failure, final validation of the humoral theory can be achieved.

History of solid organ transplantation and organ donation.

Solid organ transplantation is one of the most remarkable and dramatic therapeutic advances in medicine during the past 60 years. This field has progressed initially from what can accurately be termed a "clinical experiment" to routine and reliable practice, which has proven to be clinically effective, life-saving and cost-effective. This remarkable evolution stems from a serial confluence of: cultural acceptance; legal and political evolution to facilitate organ donation, procurement and allocation; technical and cognitive advances in organ preservation, surgery, immunology, immunosuppression; and management of infectious diseases. Some of the major milestones of this multidisciplinary clinical science are reviewed in this article.

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"The Leeds Idea": an historical account of the spondarthritis concept.

In the 1960s, Professor Verna Wright became increasingly interested in possible relationships between certain seronegative "variants of rheumatoid arthritis", as they were then generally known. At the Rheumatism Research Unit, a department within the division of medicine at Leeds University, he gathered around him a succession of research workers, whom he inspired to study aspects of these relationships. The focus was on family studies, as it was thought that genetic factors could be important. The striking association previously noted between sacroiliitis or full-blown ankylosing spondylitis and several of these disorders to be studied - e.g., psoriatic arthritis, ulcerative colitis, and the arthritis associated with Crohn's disease - was to be central for each of these studies. As a provisional collective name for these possibly related conditions, the term "Spondarthritides" was chosen. These were the days before HLA B27, and so the research tools were simply clinical, radiological (for sacroiliitis) and serological (for rheumatoid factor). The research programme confirmed not only links between the primary disorders with ankylosing spondylitis, but also links between the disorders themselves. Over subsequent years, the spondarthritis concept (dubbed by some "The Leeds Idea") has gained further strength from HLA studies internationally. And membership of the group of conditions fulfilling spondarthritis criteria has grown substantially. It is hoped that this now consolidated framework of spondylitis-related entities will pave the way for further research, with exciting prospects of gene-based prevention and/or cure through the increasing sophistication of molecular biology.

'Incongruous juxtapositions': the chimaera and Mrs McK.

A century ago, the German botanist Hans Winkler (best known for coining the term 'genome') accomplished two novel transplantations. First, he produced a single plant that grafted together two completely disparate species: tomato and nightshade. Second, he chose the descriptive word 'chimaera' to name his innovation, transplanting the term from mythology to biology. This paper features Mrs McK, the first human chimera, and thus follows the term from botany to clinical medicine. Her remarkable story, pieced together from the notes, drafts and correspondence of Robert Race and his colleagues at the MRC Blood Group Unit, draws attention to the significance of names and naming.

Jon Van Rood: pioneer at the crossroad of human leukocyte antigens and transplantation.

Jon Van Rood (born in 1926) has made major contributions to the fields of transfusion medicine as well as organ and stem cell transplantation. His group was the first to start unraveling the complexity of the human leukocyte antigen (HLA) system through collaborative studies that used panels of sera and leukocyte samples. Furthermore, using HLA typing, he introduced the first HLA-matched platelet transfusions and developed routine leukocyte depletion as a means to prevent HLA alloimmunization. Van Rood has also been active in the fields of kidney transplantation (Eurotransplant) and stem cell transplantation (Europdonor). He combined scientific laboratory research with application to clinical medicine. He retired from his university position in 1991 but remains active in the field.

[Transplantation medicine in Norway through 50 years]. / Norsk transplantasjonsmedisin gjennom 50 år.

2006 marks the 50th anniversary of the first clinical organ transplantation performed in Norway and in the Nordic countries. In 1956, just two years after the first successful clinical renal transplantation had been performed between two monozygotic twins in Boston, USA; professor Leif Efskind and his team at Rikshospitalet transplanted a kidney from an unrelated donor to a patient in end stage renal disease. The patient lived for 30 days with his new kidney, which is quite impressive given the very insufficient immunosuppressive therapy available at that time. Norway has in many ways been an international forerunner in the field of transplantation. Some of the reasons behind the success are competent and enthusiastic pioneers who were active researchers within the field, early establishment of cooperation across specialities and hospitals all over the country and centralisation of this highly specialised form of medicine to one hospital.

Women, pregnancy and serendipity: a personal story about the discovery of HLA.

The discovery of HLA was an adventure in many ways very much like the discovery of a new continent with many people entering it from different angles. This has been a truly global effort with laboratories from all over the world voluntarily collaborating. The picture that finally emerged of a highly complex genetic system and its role in biology and medicine was and is fascinating. I have been involved from almost the beginning in the HLA story and have watched--often from nearby--the breakthroughs insights that opened new aspects of HLA. A discovery is not a gradual process, but one, which goes with jumps and laps. I will therefore not give a chronological summing up what happened, but limit myself to turning points, the sudden flashes of insight, which made working in HLA so exciting and rewarding.