Public opinion surveys about xenotransplantation

BACKGROUND: Xenotransplantation may eventually provide a solution to the worldwide shortage of human organs for transplantation. Xenotransplantation is surrounded by profound ethical issues, both for the potential recipients and for the society as a whole. Concurrent with increased scientific interest, there has been an increasing number of quantitative public opinion surveys conducted about xenotransplantation in the last decade. The aim of the present study was to elucidate these surveys, and to assess some factors that may affect the outcome of them. MATERIALS AND METHODS: Surveys were identified by web and literature searches using key words in Medline and ISI Web of Knowledge. Reference lists of identified surveys were checked. Data was obtained from Inter-University Consortium for Political and Social Research (ICPSR) and directly from authors whose data were presented in another way than percentages. In total, the present material covered surveys from 35 sources, including 23 countries. RESULTS AND DISCUSSION: Results showed that almost half of the respondents accept xenotransplantation, whereas the remaining half did either not accept or did not have/state an opinion. Over time, the proportions of acceptance seemed unchanged. The proportion of those who did not accept decreased and the remaining proportion increased. This pattern was evident in Europe and the US, but not in Japan. Gender and education were found to be associated with opinions to xenotransplantation. The influence of religion was not as straightforward. This may partly depend on how religiosity was measured in the polls. Wording of items influenced levels of acceptance. If a xenotransplant was the 'only choice' proportions of acceptance increased, and if a 'risk for zoonotic diseases' was stated proportions of acceptance decreased. When wording of survey items was somewhat comparable, there were often, but not always, minor differences in proportions of acceptance between surveys from different sources. Trends in opinions are best measured by the use of the same items. It is however difficult to phrase items that will not be affected by external events.     

Justifying clinical trials for porcine islet xenotransplantation

The development of the Edmonton Protocol encouraged a great deal of optimism that a cell‐based cure for type I diabetes could be achieved. However, donor organ shortages prevent islet transplantation from being a widespread solution as the supply cannot possibly equal the demand. Porcine islet xenotransplantation has the potential to address these shortages, and recent preclinical and clinical trials show promising scientific support. Consequently, it is important to consider whether the current science meets the ethical requirements for moving toward clinical trials. Despite the potential risks and the scientific unknowns that remain to be investigated, there is optimism regarding the xenotransplantation of some types of tissue, and enough evidence has been gathered to ethically justify clinical trials for the most safe and advanced area of research, porcine islet transplantation. Researchers must make a concerted effort to maintain a positive image for xenotransplantation, as a few well‐publicized failed trials could irrevocably damage public perception of xenotransplantation. Because all of society carries the burden of risk, it is important that the public be involved in the decision to proceed. As new information from preclinical and clinical trials develops, policy decisions should be frequently updated. If at any point evidence shows that islet xenotransplantation is unsafe, then clinical trials will no longer be justified and they should be halted. However, as of now, the expected benefit of an unlimited supply of islets, combined with adequate informed consent, justifies clinical trials for islet xenotransplantation.     

Students' acceptance of clinical xenotransplantation

The aim of this study was to elucidate undergraduate university students' views on clinical xenotransplantation. A total of 1875 students from eight faculties at Uppsala University and the Swedish University of Agricultural Sciences answered a questionnaire. Three out of four respondents would be prepared to receive a transplant from an animal on medical grounds if necessary. Forty percent had signed an organ donation card. There was no difference in attitude between those who had signed an allotransplantion card and those who had not. According to gender, age, length of university program, and faculty, results showed that a higher proportion of those who approved were male, young, and studying on programs longer than three years; also, they were more likely to study programs in the Faculties of Agriculture and Pharmacy. At the Medical Faculty, nursing students seemed to be less approving, compared to future biomedical analysts, biomedical scientists, and physicians. The acceptance of xenotransplantation also tended to be positively associated with morally accepting and understanding the use of animals in biomedical research, the approval of euthanasia, the approval of early abortion, and the use of human fetuses in research, as well as clinical testing of humans.     

Meta-analysis of public perception toward xenotransplantation

The shortage of donor organs for transplantation is an international problem. One promising option to meet the need is xenotransplantation (XTx; eg, pig-to-human). However, there are still questions surrounding XTx that must be answered before proceeding to clinical trials. The current work is a meta-analysis of articles published between 1985 and 2019 to analyze the factors most strongly associated with agreement and opposition toward the procedure. Although 80% (41/51) of the published studies were related to the opinions of patients, only three provided sufficient data for analysis. Thus, the bulk of what we really know about attitudes toward XTx comes from students, stakeholders, and hospital staff. The findings suggest that, before proceeding from the laboratory to clinical trials, more directed research is necessary from individual programs to achieve sufficient understanding of the attitudes of patients and the broader public, and the level of risk that is acceptable to these groups.     

The ethics of xenotransplantation: a survey of student attitudes

Xenotransplantation is a burgeoning technology that could provide a solution to the shortage of organs and tissue for transplantation. It does, however, raise many moral and ethical dilemmas. The aim of this study was to evaluate undergraduate university students' knowledge and opinions on the controversial practice. Choice of science or arts subjects and gender were also assessed to establish if they were influencing factors. A total of 100 students, 50 science students and 50 arts students, answered a questionnaire. Seventy-seven percent of the students had heard of xenotransplantation, 66% believed it would be beneficial to society and only 45% believed it to be ethically and morally acceptable. The medical need for organs was highlighted as the most important argument in favour, and the risk of infection was revealed to be the most important argument against xenotransplantation. The students would significantly prefer a human to non-human animal organ, and did not believe the genetic modification of animals for transplantation was ethically acceptable. This study, in general, did not find that knowledge and acceptance of xenotransplantation was associated with subject background (i.e., science or arts courses) or gender.     

Endoscopic features in a model of multivisceral xenotransplantation

Galvão FHF, Farias AQ, Pompeu E, Waisberg DR, Teixeira ARF, de Mello ES, Lino Costa AC, de Castro Galvão R, Santos VR, Chaib E, Carrilho FJ, D’Albuquerque LAC. Endoscopic features in a model of multivisceral xenotransplantation. Xenotransplantation 2010; 17: 423–428. © 2010 John Wiley & Sons A/S. Abstract: Introduction: Xenotransplantation and multivisceral transplantation are advanced therapeutic methods that still require a scientific basis. There are no experimental models of multivisceral transplantation available, particularly not the monitoring by endoscopy. Here, we describe the endoscopic features in a model of multivisceral xenotransplantation. Methods: The distal esophagus, stomach, intestine, colon, liver, pancreas, and the kidneys with a common vascular pedicle were harvested from rabbits and implanted in swine (group I, n = 9) or in rabbits (group II, n = 4). Endoscopy was performed in the stomach, jejunum, and ascending colon at four consecutive time points (immediate after surgery and 10, 90, and 180 min after reperfusion). Lesions were macroscopically graded as mild, moderate, and severe. Biopsies were taken following sacrifice at 180 min after reperfusion. Results: In group I, the stomach, jejunum, and colon manifested a progression of lesions with predominance of mild lesions after 10 min, mild to moderate lesions after 90 min, and moderate to severe lesions after 180 min. In animals from group II, endoscopy showed normal features at all time points after reperfusion. Histopathologic analysis confirmed the diagnosis of hyperacute rejection in group I. Grafts from group II animals presented normal or mild ischemic/reperfusion injury. Conclusion: All animals subjected to multivisceral xenotransplantation showed a progression of endoscopic lesions with time after transplantation, while animals subjected to allotransplantation showed no aberrations in endoscopy. We conclude that endoscopy is a useful tool in the assessment of hyperacute rejection of a xenograft.     

Tort liability of xenotransplantation centers

BACKGROUND: In the view of future clinical trials, defining possible legal theories under which xenotransplantation center could be held responsible for any adverse effect on public health is becoming increasingly important. METHODS: In order to better define the tort liability of xenotransplantation center, we reviewed the existing cases and statutes on tort and public health law. RESULTS: Xenotransplantation center could be sued under various tort actions, including negligence, public nuisance or strict liability for ultrahazardous activity. Prerequisites for each legal action are discussed and possible scope of tort liability is addressed. CONCLUSION: The promotion of positive public perception and the development of appropriate insurance system could prevent future class actions to succeed in abating the xenotransplantation industry.     

Compatibility of porcine and human interleukin 2: implications for xenotransplantation

BACKGROUND: Xenotransplantation provides a possible solution to the severe shortage of allogeneic organ donors. The pig, which shares many physiological similarities with humans, makes it an optimal species for preclinical experimentation and clinical applications. Interleukin 2 (IL2) is a potent growth factor secreted primarily by T helper lymphocytes and it is vital to the cellular expansion required for a productive immune response and the development and peripheral expansion of CD4+CD25+ regulatory T cells. Therefore, it is essential to understand of the compatibility of IL2 between pigs and humans. METHODS: We first compared the cDNA and protein sequences and the crystal structures of human and porcine IL2 and IL2 receptors, respectively. The effect of IL2 to induce T cell proliferation was determined by 3H-thymidine incorporation and cell cycle detection. RESULTS: Porcine IL2 induced very limited proliferation of human lymphocytes while it functioned well on porcine lymphocytes. Human IL2 had remarkably reduced effects on porcine lymphocytes whereas it worked well on human lymphocytes. CONCLUSION: Our present study showed that the interaction of IL2 and IL2R across species might have defects. Together with the wide physiological functions of IL2, our data indicated that physiological disorders could be caused by the poor function of xenogeneic donor IL2 on host cells in full hematopoietic chimera. Our data suggested an additional potential advantage for the mixed xenogeneic chimeras.     

People's attitude toward xenotransplantation: affective reactions and the influence of the evaluation context

Abstract: Background: One of the major issues in transplantation is to find a strategy to overcome the scarcity of human organs. One of the interventions under investigation is represented by xenotransplantation. The present study aimed to understand the role of psychological factors on people’s perception of xenotransplantation. In particular, we tested a condition in which different alternatives (e.g., human vs. pig donors) are presented together allowing people to compare among them (joint evaluation) and two conditions in which people are presented with only one of the two alternatives and cannot compare them (separate evaluation). Methods: The study was conducted with three different groups of participants: patients waiting for liver transplantation (N = 31 in joint evaluation and N = 30 in each of the two separate evaluation conditions); students (N = 30 in join evaluation and N = 30 in each of the two separate evaluation conditions); and healthy adults (N = 30 in joint evaluation and N = 30 in each of the two separate evaluation conditions). Participants were presented with hypothetical scenarios and asked how good (or bad) were their feelings toward one or two types of donor (e.g., human and pig). Results: Patients showed a skeptical attitude toward xenotransplantation both when it was evaluated together with the human donor (P < 0.01) or when it was evaluated separately (P < 0.01). Differently, when asked to evaluate each donor separately healthy adults and students showed similar affective reactions toward the two alternatives (human organ and xenograft). Conclusions: The present study demonstrates that the evaluation context may increase the impact of affective reactions and reduce healthy people’s ability to use information on the potential benefit of a novel biomedical technology. Regardless of the evaluation context, patients always rely on affective reactions and show an overall preference for the human organ.     

Inhibition of platelet aggregation in baboons: therapeutic implications for xenotransplantation

Methods: Drugs tested in these experiments were aurintricarboxylic acid (ATA, von Willebrand Factor-GPIb inhibitor), fucoidin (a selectin-inhibitor), 1-benzylimidazole (1-BI, thromboxane synthase antagonist), prostacyclin (PGI₂, endothelial stabilizer), heparin (thrombin antagonist), nitroprusside sodium or nicotinamide (NPN or NA, both NO-donors), and eptifibatide (EFT, GPIIb/IIIa receptor antagonist). These were infused intravenously to nine baboons. Coagulation parameters and platelet counts were monitored and baboons were observed for adverse side-effects. The efficacy of these agents in inhibiting platelet aggregation was assayed in a platelet aggregometer.
Results: Treatment with ATA and fucoidin resulted in complete inhibition of platelet aggregation but also in major perturbation of coagulation parameters. 1-BI and PGI₂ had no effect when administered alone, but in combination resulted in moderate inhibition of aggregation without disturbance in PT or PTT. NPN and NA had no substantive effects on platelet aggregation. Heparin resulted in specific inhibition of thrombin-induced platelet aggregation and, as anticipated, was associated with moderate prolongation of PTT. Importantly, EFT caused complete inhibition of platelet aggregation without changes in coagulation. Platelet counts, fibrinogen levels, and fibrinogen degradation products remained within the normal ranges in all experiments.
Conclusions: Although excellent inhibition of platelet activation was obtained with ATA and fucoidin, clinical use may be precluded by concomitant disturbances of coagulation. Combinations of heparin and EFT may prove beneficial in preventing the thrombotic disorders associated with xenograft rejection while maintaining adequate hemostatic responses. These agents are to be evaluated in our pig-to-primate xenotransplantation models.     

A health‐economic analysis of porcine islet xenotransplantation

Beckwith J, Nyman JA, Flanagan B, Schrover R, Schuurman H‐J. A health‐economic analysis of porcine islet xenotransplantation. Xenotransplantation 2010; 17: 233–242. © 2010 John Wiley & Sons A/S. Abstract: Background: Islet cell transplantation is a promising treatment for type 1 diabetes. To overcome the shortage of deceased human pancreas donors, porcine islet cell xenotransplantation is being developed as an alternative to allotransplantation. The objective of this study was to perform a cost‐effectiveness analysis of porcine islet transplantation in comparison with standard insulin therapy. The patient population for this study was young adults, ages 20 to 40, for whom standard medical care is inadequate in controlling blood glucose levels (hypoglycemia unawareness). Since trial data were lacking, estimates used extrapolations from data found in the literature and ongoing trials in clinical allotransplantation. Cost estimates were based on the data available in the USA. Methods: Markov modeling and Monte Carlo simulations using software specifically developed for health‐economic evaluations were used. Outcomes data for ongoing clinical islet allotransplantation from the University of Minnesota were used, along with probabilities of complications from the Diabetes Control and Complications Trial. Quality‐adjusted life years (QALYs) were the effectiveness measure. The upper limit of being cost‐effective is $100 000 per QALY. Cost data from the literature were used and adjusted to 2007 US dollars using the medical care portion of the Consumer Price Index. Results: In both Markov modeling and Monte Carlo simulations, porcine islet xenotransplantation was both more effective and less costly over the course of the 20‐yr model. For standard insulin therapy, cumulative cost per patient was $661 000, while cumulative effectiveness was 9.4 QALYs, for a cost of $71 100 per QALY. Transplantation had a cumulative cost of $659 000 per patient, a cumulative effectiveness of 10.9 QALYs, and a cost per QALY of $60 700. Islet transplantation became cost‐effective at 4 yr after transplantation, and was more cost‐effective than standard insulin treatment at 14 yr. These findings are related to relative high costs in the transplantation arm of the evaluation during the first years while those in the insulin arm became higher later in follow‐up. Throughout the follow‐up period, effectiveness of transplantation was higher than that of insulin treatment. In sensitivity analysis, duplication or triplication of one‐time initial costs such as costs of donor animal, islet manufacturing and transplantation had no effect on long‐term outcome in terms of cost‐saving or cost‐effectiveness, but the outcome of transplantation in terms of diabetes complications in cases with partial graft function could affect cost‐saving and cost‐effectiveness conclusions. Conclusion: Despite limitations in the model and lack of trial data, and under the assumption that islet transplantation outcomes for young adult type 1 diabetes patients are not dependent on the source of islet cells, this health‐economic evaluation suggests that porcine islet cell xenotransplantation may prove to be a cost‐effective and possibly cost‐saving procedure for type 1 diabetes compared to standard management.     

Experimental multivisceral xenotransplantation

Abstract: Background: Organ shortage impairs the proposition of multivisceral transplantation to treat multiple organ failure. Interspecies (xeno) transplantation is a valid solution for organ shortage; however, suitable models of this advance are lacking. We describe an effective model of multivisceral xenotransplantation to study hyperacute rejection. Methods: Under general anesthesia, we in block recovered the distal esophagus, stomach, small bowel, colon, liver, pancreas, spleen, and kidneys from donors and implanted heterotopically in the lower abdomen of recipients. Animals were divided into four groups: I—canine donor, swine recipient (n = 6); II – swine donor, canine recipient (n = 5); III—canine donor, canine recipient (n = 4); and IV—swine donor, swine recipient (n = 5). Groups I and II comprised experimental (xenotransplantation) and III and IV control groups (allotransplantation). During the experiment, we appraised recipient evolution and graft modification by sequential biopsy up to 3 h. At this time, we killed animals for autopsy (experimental end point). Results: We accomplished all experiments successfully. Every grafts attained customary appearance and convenient urine output immediately after unclamp. Around 15 min after reperfusion, xenografts achieved signs of progressive hyperacute rejection and absence of urine output. At the end of experiments we observed moderate to severe hyperacute rejection at small bowel, colon, mesenteric lymph node, liver, spleen, pancreas, and kidney, while stomach and esophagus achieved mild lesions. In contrast, allograft achieved normal or minimum ischemia/reperfusion injury and constant urine output. Conclusion: The present procedure assembles a simple and effective model to study multivisceral xenotransplantation and may ultimately spread researches toward hyperacute rejection.     

Potential implications of ABO blood group for vascular rejection in pig to human kidney xenotransplantation

Abstract: Background: A substantial hurdle for successful xenotransplantation is to negate the effect of xenoreactive natural antibodies [mainly Galα1–3Galβ1–4GlcNAc (α‐Gal) specific] that cause hyperacute xenograft rejection. Galα1–3Gal molecules (α‐Gal) have close structural homology with human ABO blood groups and therefore an individual's blood group might influence the formation of α‐Gal specific antibodies. Genetic heterogeneity controlling α‐Gal specific antibody formation could have important implications for future pig to human xenotransplantation clinical trials. We have investigated the relationship between ABO blood group and immunoglobulin M (IgM) and immunoglobulin G (IgG) α‐Gal specific antibody titres in sera obtained from renal dialysis patients and healthy blood donors. Methods: Serially diluted sera (n = 166) obtained from renal dialysis patients awaiting kidney transplantation (n = 116) and healthy blood donors (n = 50) were tested for IgM and IgG α‐Gal antibodies using an enzyme‐linked immunosorbent assay (ELISA) specific for α‐Gal. The study cohort comprised 62, 48, 36 and 20 sera obtained from blood group O, A, B and AB individuals, respectively. Reciprocal α‐Gal specific antibody titres were calculated from ELISA titration curves and stratified by individual blood group. Results: No significant heterogeneity was found in IgM α‐Gal specific antibody titres across ABO blood groups. In contrast, marked heterogeneity was observed in IgG α‐Gal specific antibody titres when stratified by blood group. IgG α‐Gal specific antibody titres were higher in sera obtained from blood group O renal dialysis patients [median titre 40, interquartile range (IQR) 14 to 72], compared with blood group A (median titre 18, IQR 7 to 54, P = 0.05), blood group B (median titre 6, IQR 0 to 15, P < 0.001) and blood group AB patients (median titre 3.5, IQR 0 to 16, P = 0.002). A similar correlation was found for IgG α‐Gal specific antibody titres in sera obtained from healthy blood donors with median titres of 20 (IQR 12 to 34), 37 (10 to 91), 9 (0 to 20), and 5.5 (0 to 12) in blood groups O, A, B and AB individuals, respectively. There was a strong interrelationship between α‐Gal specific antibody class and blood group, with both IgM and IgG α‐Gal specific antibodies found in 84% of the blood group O sera, 73% of blood group A sera, 50% of blood group B sera and 40% of blood group AB sera (P < 0.001). In a subgroup of 39 renal dialysis patients, IgM and IgG α‐Gal specific antibody titres were measured in two serum samples obtained at different time‐points (median time interval 581 days, range 42 to 4414), and showed a high degree of stability (correlation coefficient 0.88 and 0.90 for IgM and IgG, respectively). Conclusion: IgG α‐Gal specific antibody titres are significantly higher in the sera of blood group O and A renal dialysis patients and healthy individuals compared with blood groups B and AB. These data indicate that future clinical trials of pig to human xenotransplantation may be more problematic for non‐blood group B patients who are likely to have high levels of IgG α‐Gal specific antibodies that are associated with acute vascular rejection.     

Monomorphic and polymorphic carbohydrate antigens on pig tissues: implications for organ xenotransplantation in the pig-to-human model

The existence of the Gal epitope in 137 pigs belonging to 23 different breeds suggests that this antigen is either monomorphic or occurs at a high incidence in the porcine species. Its histological location at the surface of pig vascular endothelial cells makes it a target for human natural anti-Gal antibodies and complement, which may be responsible for the hyperacute vascular rejection of transplanted pig organs. The precursor carbohydrate chain (N-acetyllactosamine) and NeuAc-substituted epitopes are also exposed at the surface of pig vascular endothelium and were found in all pigs in this study. However, humans also have these two epitopes on vascular endothelium and, consequently, have not made natural antibodies against these carbohydrate antigens. Therefore, these two pig epitopes cannot be the main target of the hyperacute vascular rejection process. Three pig phenotpyes-A+(51%), A:H+(38%), and A-H-I+(11%) were identified among 37 Large-white pigs by the presence of polymorphic A, H, and I carbohydrate antigens on the brush border of the surface epithelium of small intestine. These antigens were also present in other exocrine secretions but were not detected on vascular endothelium of the same pigs, suggesting that they are not involved in the hyperacute vascular rejection, although the pig A tissue antigen can induce an immune response in 0 or B blood group recipients. Once the problem of the initial hyperacute vascular rejection directed against the Gal epitope is overcome, typing donor pigs for A, H, and I, as well as for the protein swine leukocyte antigens (SLA) and other pig antigens, may help in elucidating antigens involved in acute or chronic xenograft rejection.     

Short Communication: Pig islet xenotransplantation acceptance in a Latin‐American diabetic population

Abalovich A, Wechsler C, Lara S, Bervottini M. Pig islet xenotransplantation acceptance in a Latin‐American diabetic population. Xenotransplantation 2010; 17: 263–266. © 2010 John Wiley & Sons A/S. Abstract: Progress in porcine islet xenotransplantation has been accompanied by studies on acceptance of this new procedure by patients, health professionals or the general public. Such studies have not been done in the Latin‐American population. We conducted a questionnaire in 108 diabetes patients (insulin‐dependent, n = 53; insulin‐independent, n = 55) in a public hospital in Argentina. The questions addressed the general perception of the xenotransplant procedure and specific items related to the outcome (achieving insulin independence, improvement in metabolic control, delay in emergence of diabetic complications, need for repeat procedures, potential of transfer of infectious viruses, association with psychological problems, and anticipated success in relation to achieving a cure). Eighty‐six (79%) of the patients accepted islet xenotransplantation; this incidence was not different for insulin‐dependent or insulin‐independent patients, patients with or without complications, or patients with good or poor metabolic control. Also, over 75% of patients accepted the procedure if this is only associated with a reduction in insulin requirement, if the procedure just delays but not prevents the onset of complications, or if the procedure needs to be performed every 6 months. Fifty‐seven percent of patients indicated acceptance even if the potential transmission of a virus infection cannot be completely ruled out: this outcome was not affected by the outbreak of the H1N1 flu epidemic during the conduct of this study. Forty percent of patients indicated that living with porcine cells in their body could give psychological problems. We conclude that this population of Latin‐American diabetic patients shows a high acceptance rate of a porcine islet xenotransplantation product.     

In defense of xenotransplantation research: Because of,not in spite of,animal welfare concerns

It is envisioned that one day xenotransplantation will bring about a future where transplantable organs can be safely and efficiently grown in transgenic pigs to help meet the global organ shortage. While recent advances have brought this future closer, worries remain about whether it will be beneficial overall. The unique challenges and risks posed to humans that arise from transplanting across the species barrier, in addition to the costs borne by non-human animals, has led some to question the value of xenotransplantation altogether. In response, we defend the value of xenotransplantation research, because it can satisfy stringent welfare conditions on the permissibility of animal research and use. Along the way, we respond to the alleged concerns, and conclude that they do not currently warrant a cessation or a curtailing of xenotransplantation research.     

Xenotransplantation in Australia: Development of the regulatory process

In this commentary, we present a brief history of the development of a national regulatory framework for xenotransplantation clinical research in Australia, including the reasons behind the imposition of a 5-year moratorium in 2005 and its subsequent lifting. We conclude with a summary of current relevant guidelines and standards.