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Transplantation in The New Millennium

The 18th International Congress of the Transplantation Society

Rome, 27 August-1 September 2000

A. Slavcev

Institute for Clinical and Experimental Medicine, Prague, Czech Republic

The XVIII Congress of the Transplantation Society, with its 4000 participants from 60 countries and a busy scientific programme, was certainly one of the most important healthcare events of the year. The congress was opened with a Solemn Mass in the Saint Peter's Basilica in Vatican City, which was attended by more than 5,500 people. Then, after a cocktail in the Vatican Gardens, we had the opportunity to visit the Vatican Museum and to admire the renovated Sistine Chapel. The scientific programme was very intensive with parallel sessions covering practically all fields of organ and stem cell transplantation. As it would be impossible to touch all the topics of importance, I will mention some of the sessions I attended and the presentations, which seemed to me of particular interest from the immunogenetical point of view.

The plenary session on lymphocyte activation was opened by A. Lanzavecchia (Switzerland). He reported how different T cell responses (type 1, type 2, or unpolarised T cells) can be generated by modulating the state of activation of dendritic cells and the duration of the dendritic cell-T cell interaction. The different roles played by "central memory" and "effector memory" T cells in secondary immune responses were also discussed. During the symposium Life and Death of Lymphocytes chaired by M. Davis (USA) and J. Vives (Spain), various aspects of apoptosis were reviewed. Speakers talked in detail about the receptors, the molecular regulation, and the possibilities for tolerance induction. D. Green (USA) gave a nice presentation of the cytochrome C-mediated pathway of apoptosis and the possibility of its inhibition by Bcl-2. The effects of HLA conventional and CREG matching, pre-transplant panel reactive antibody (PRA), recipient and donor race and age, cold ischaemia time, and other factors on the outcome of more than 14,000 cardiac transplant patients from the UNOS registry were reported by J. S. Thomson (USA) (session Clinical Heart Transplantation). It was reported that PRA was a highly significant risk factor, and this effect was even more pronounced when the PRA was analysed as 20% increments above zero. DR matching had a powerful effect on graft survival. It was calculated that 24-36% 0 CREG, 0 DR mm, ABO compatible transplants could be prospectively achieved in a waiting list having 50-100 patients. In conclusion, HLA incompatibility and prior sensitisation were shown to have an impact on cardiac transplant survival, a finding, which confirmed previously published studies. New and faster HLA-typing techniques make it possible to include these factors in the allocation process to improve the long-term graft outcome.

The impact of the new Eurotransplant kidney allocation system, which was implemented in 1996, was analysed by G. Persijn (The Netherlands). The reason for replacing the former HLA match allocation scheme by the new system was that patients with rare HLA phenotypes and children were accumulating on the waiting list, leading to extremely long waiting times. Another reason was the imbalance between procurement and transplantation rates in the different Eurotransplant countries. The proportion of kidney transplants with no HLA-A, -B or -DR mismatches in the period from 1996 with 1-year follow-up was 23% and less than 3% were done with 5 to 6 mismatches. Longer-waiting patients were transplanted: 21% vs. 10% (in 1995) and, also, more children were transplanted, the proportion increased by 25%. The number of transplanted highly sensitised patients increased from 2% to 3%, and the discrepancy between procurement and transplantation rates among the different Eurotransplant countries disappeared. Graft survival rates after 1 year were 90%, 88%, 84%, 82%, 79%, and 75% for 0, 1, 2, 3, 4, 5, and 6 mismatches, respectively.

Downregulation of the alloimmune response by regulatory CD4+ T cells was reported by D. Roelen (The Netherlands) (session Immunoregulatory T cells). It is speculated that pre-transplant blood transfusions sharing one HLA-DR antigen with the recipient may enhance graft survival. The hypothesis behind this work was that, during rejection, organ donor specific T cells become targets for the transfusion-induced self-DR restricted CD4+ T cells, leading to abrogation of the rejection process. This hypothesis was tested on the basis of reactivity of a self-restricted alloreactive CD4+ T cell line, which recognised a peptide derived from an allo DR3 molecule, and a CD4+ T cell clone recognising an HLA-A2 peptide in the context of the DRB1*1501 molecule. Addition of the CD4+ T cell line to limiting dilution assays resulted in the suppression of the anti-donor response only when the DR3 peptide was added as well. The addition of the T cell clone to limiting dilution analysis experiments induced an almost complete inhibition when the proper HLA-A2 peptide was added. Furthermore, these cells produced considerable amounts of IL-10 after stimulation with the proper MHC/peptide combinations.

During the session Kidney Transplantation Outcome: Recipient Factors, H.-U. Meier-Kriesche (USA) discussed the recipient age as an independent risk factor for chronic renal allograft failure. Utilising the USRDS data, 42,193 primary adult Caucasian renal transplants from 1988 through 1997 were analysed. In the older age groups of ³65 and 50-64 years, more patients had chronic allograft failure than in the reference group of 18-49-year olds. In conclusion, an older recipient age was estimated as an important independent risk factor. In addition, there was a synergistic effect of donor and recipient age in determining chronic allograft failure. Caution was therefore advised in situations when exclusive allocation of older donor kidneys to older recipients was performed.

J.L. Touraine (France) described the progress in stem cell transplantation in utero for the treatment of genetic diseases (session Advances in Bone Marrow Transplantation). In 1988, the first in utero transplantation of stem cells to a human fetus was performed, with engraftment of the donor allogeneic cells. It is estimated that, to date, 30 to 40 fetal patients have been treated world-wide by in utero stem cell transplantation. Donor stem cells have been either fetal liver cells, or T-cell depleted, adult bone marrow cells. The transplants were carried out by the intravenous or the intraperitoneal route. Four of 10 patients with immunodeficiency had sustained engraftment together with correction of the deficient T-cell immunity. By contrast, only 2 out of 9 thalassemic patients have had demonstrable donor cells for more than one year, and none achieved prolonged reconstitution of a sufficient degree of haematopoiesis. In 7 fetal patients with other inborn errors of metabolism, in utero transplantation led to an incomplete clinical benefit. In utero transplantation of stem cells was therefore suggested as a feasible treatment for prenatally detected immunodeficiencies but additional research is required for its application in inherited haemoglobinopathies and inborn errors of metabolism.

Of major interest was the lecture of I. Wilmut (UK) "Cloning and transplantation" (session Horizons in Transplantation). Research that led to the birth of the first cloned sheep Dolly is stimulating investigation in two major directions. These are the provision of organs, tissues, and cells from animals for xenotransplantation, and the development of methods for the production of human cells for therapy. To prevent hyperacute rejection, it is possible to perform genetic modifications in animal cells before nuclear transfer. On the other hand, cells can be derived from human pluripotential stem cells with the ability to treat various degenerative diseases, such as diabetes or stroke. HLA-matched cells could be obtained by "reprogramming" the nucleus of a donor cell from the patient. To achieve this objective, an embryo has to be produced from which stem cells may be obtained. However, this approach has major ethical implications. Further research is necessary to test the possibility of obtaining embryo stem cells without producing an embryo. At the end of his lecture, I. Wilmut dismissed the idea of the use of cloning for human reproduction and pointed out that the cloning technique works, even though not quite efficiently, and that precise genetic changes can be effected before nuclear transfer.

During the session Kidney Transplantation Outcome: Influencing Factors, W E. Braun (USA) analysed the results of 105 recipients of renal allografts functioning for 20-35 years. For a period from 20.1 to 35.9 years, patient survival was 76.2% (80/105), overall graft survival 70.5%, and death-censored graft survival was 92.3%. Graft losses were due to chronic rejection and obstruction. Causes of death were cardiac, malignancy, cerebrovascular, infection, HCV hepatic failure, etc. In conclusion, despite 20 years of graft function, recipients had a substantial mortality rate (24%) due mainly, over the next more than 10 years, to cardiovascular disease and malignancy. Chronic graft dysfunction was the typical background of fatal diseases.

The presentation of M.S. Sever (Turkey) addressed the outcome of living unrelated (commercial) renal transplants performed in third-world countries. Despite of the ethical problem, due to organ shortage many end-stage renal disease patients go to third-world countries for living unrelated transplantation from paid organ donors, although this type of transplantation carries a high risk of complications. The post-transplant course was associated with numerous medical and/or surgical complications. Selected unconventional complications included malaria, pneumonia due to various opportunistic agents, and severe wound infections. At 5 years, the allograft and patient survival rates were 72%, and 84%, respectively. Causes of allograft failure were chronic allograft nephropathy, therapy-resistant acute rejection, transplant mucormycosis, transplant pyelonephritis, and recurrent glomerulonephritis. Causes of death included various infections, cardiovascular complications, hepatic failure and other complications. It was concluded that commercial transplantation carries an extremely high risk of unconventional complications, especially so in the early post-transplant period, and is unacceptable both for medical and ethical reasons.

Very intriguing was the presentation of S. Martin (UK) about the association between post-transplant antibody production and renal transplant rejection (session HLA in Transplantation). The study used enzyme-linked immunoabsorbent assays (ELISA) for an increased sensitivity of detection and characterisation of HLA antibodies to re-evaluate their role in transplant outcome. A total of 115 consecutive primary cadaveric renal transplants were carried out in a single centre in 1990. Pre- and post-transplant sera were selected from each patient and screened using LATM ELISA (One Lambda, USA) to detect the presence of HLA class I and class II specific antibodies. The results were correlated with transplant outcome. Fifty-two patients remained negative post-transplant (-/-), 13 patients developed HLA class I specific antibodies, 8 HLA class I and class II specific antibodies, and 5 developed HLA class II specific antibodies after transplantation. Ten-year follow-up data showed that 6% of the -/- transplants failed as compared with 76% of the -/+ transplants, a highly significant difference. This study indicated that HLA specific antibodies produced post-transplant are strongly associated with transplant rejection and graft failure.

The presentation of G. Opelz (Germany) dealt with the influence of HLA compatibility and new immunosuppression on organ allograft survival. Although HLA matching has been established over the years as an important factor governing the outcome of kidney transplants, the question has been raised whether new, more powerful immunosuppressive drugs might suppress the anti-graft immune response to such an extent that HLA compatibility would no longer play a role. Based on the world-wide Collaborative Transplant Study data, the influence of HLA compatibility was analysed in patients receiving either the cyclosporine-Neoral formulation, FK506 (tacrolimus), or mycophenolate mofetil (CellCept). Kidney transplants performed over the 1996-1999 period were analysed. Preliminary results showed a statistically significant effect of HLA matching in patients receiving any of the three new drugs. Prof. Opelz showed that even though the application of new drugs reduced the early rejection rates, the impact of HLA matching was the same, i.e., the number of rejections increased with increasing numbers of HLA mismatches, and poorly matched kidneys had worse prognosis. In conclusion, no change in the allocation policy would be necessary at the moment.

One of the most important events of the congress beyond doubt was the visit by Pope John Paul II. It is noteworthy that, for the first time in history, a pope came and delivered a speech at a scientific conference. As John Paul said, "Transplants are a great step forward in science's service of man and not a few people today owe their lives to an organ transplant". It was emphasised that any procedure, which tends to commercialise human organs or to consider them as items of exchange or trade, must be considered morally unacceptable. From the moral standpoint, the criteria for assigning donated organs should in no way be "discriminatory" (i.e. based on age, sex, race, religion, social standing etc.) or utilitarian (based on work capacity, social usefulness, etc.). Instead, judgements should be made on the basis of immunological and clinical factors. Further, the Pope stressed that attempts at human cloning with a view to obtaining organs, as they involve the manipulation and destruction of human embryos, are not morally acceptable, even though their proposed goal is good in itself. Careful and competent reflection of philosophers and theologians on the ethical problems associated with transplant therapy can help clarify the criteria for assessing what kinds of transplants are morally acceptable under what conditions, especially with regard to the protection of each individual's personal identity.

Last, but not least, it was a pleasure to spend a week in the Eternal City, and to have the unique opportunity to see some of its cultural treasures. So we are looking forward to the next meeting of the Transplantation Society in Buenos Aires in 2002, and thank the Italian organisers for their warm welcome and enormous efforts which made this conference such a successful and inspiring event.

Acknowledgement: The participation of the author at the congress of the Transplantation Society was supported by a travel award from BSHI.