Microbiological safety of xenotransplantation compared with allotransplantation

Transmission of viral, bacterial, parasitic, and fungal infections via organ allografts is uncommon but may be associated with life‐threatening disease. Internationally, programs for screening of human organ donors for infectious risk are non‐uniform and vary with national standards and the availability of screening assays. Further, the failure to recognize and/or to report transmission events limits the utility of available data regarding the incidence of allograft‐associated disease transmission. Advances in xenotransplantation biology have allowed some limited clinical trials with the prospect for increased opportunities for clinical xenotransplantation. As with human allotransplantation, the examination of infectious risk has been a central theme in these studies. Significant advances have been made in the breeding and screening of swine for preclinical studies including the identification of novel, potential human pathogens derived from source animals. Thus far, “expected” xenograft‐derived pathogens such as porcine cytomegalovirus (PCMV) have become activated in immunosuppressed primates but have not resulted in systemic infection outside the xenograft. PCMV has been bred out of swine herds by early weaning strategies. Conversely, host pathogens such as primate‐derived cytomegalovirus (CMV) have become activated and have produced serious infectious complications. These infections are preventable using antiviral prophylaxis. Xenogeneic tissues appear to be relatively resistant to infection by common human pathogens such as HIV, HTLV and the hepatitis viruses. Concerns regarding the potential activation of latent porcine retroviruses from xenograft tissues have resulted in the development of novel assays for xenotropic porcine endogenous retrovirus (PERV). PERV transmission to primate xenograft recipients or to human cells in in vivo models has not been detected. Multiple intrinsic cellular mechanisms appear to be active in the prevention of infection of human cells by PERV. Further, PERV appears to be susceptible to available antiretroviral agents. Thus, while the absolute risk for such infections remains unknown in the absence of human studies with prolonged graft survival in immunosuppressed xenograft recipients, the risk of transmission to human recipients appears limited. Some general principles have been developed to guide clinical trials: Outcomes of xenotransplantation trials, including any infectious disease transmissions, should be reported in the scientific literature and to appropriate public health authorities. Surveillance programs should be developed to detect known infectious agents as well as previously unknown or unexpected pathogens in the absence of recognizable clinical syndromes. Standardization of procedures and validation by expert and/or reference laboratories are needed for microbiological assays. Such validation may require international collaboration. Repositories of samples from source animals and from recipients prior to, and following xenograft transplantation are essential to the investigation of possible infectious disease events. Infection is common in allograft recipients. Thus, in advance of clinical trials, policies and procedures should be developed to guide the evaluation of any infectious syndromes that may develop. (e.g. fever of unknown origin [FUO], leukocytosis, leukopenia, graft dysfunction, pneumonia, hepatitis, abscess formation) in xenograft recipients. Based on preclinical experience these procedures will include: (i) Exclusion of infectious syndromes commonly associated with allotransplantation (e.g. CMV, bacterial pneumonia); (ii) Evaluation of PERV infection by serologic and NAT testing; (iii) Assessment of other recipients of xenografts derived from the same herd or source of swine; and (iv) Evaluation of social contacts of the recipient. Consideration of investigation of xenograft recipients for unknown pathogens may require application of advanced research technologies, possibly including use of broad‐range molecular probes, microarrays or high throughput pyrosequencing. References: 1. Meije Y, TÖnjes RR, Fishman JA. Retroviral restriction factors and infectious risk in xenotransplantation. Amer J Transplant 2010; 10: 1511–1516. 2. Fishman JA, Scobie L, Takeuchi Y. Xenotransplantation‐associated infectious risk: A WHO consultation. Xenotransplantation 2012; 19: 72–81.     

Xenotransplantation: Infectious Risk Revisited

Xenotransplantation is a possible solution for the shortage of tissues for human transplantation. Multiple hurdles exist to clinical xenotransplantation, including immunologic barriers, metabolic differences between pigs--the source species most commonly considered--and humans, and ethical concerns. Since clinical trials were first proposed almost 10 years ago, the degree of risk for infection transmitted from the xenograft donor to the recipient has been extensively investigated. A number of potential viral pathogens have been identified including porcine endogenous retrovirus (PERV), porcine cytomegalovirus (PCMV), and porcine lymphotropic herpesvirus (PLHV). Sensitive diagnostic assays have been developed for each virus. Human-tropic PERV are exogenous recombinants between PERV-A and PERV-C sequences and are present in only a subset of swine. Porcine cytomegalovirus can be excluded from herds of source animals by early weaning of piglets. In contrast, the risks associated with PLHV remain undefined. Microbiologic studies and assays for potential xenogeneic pathogens have furthered understanding of risks associated with xenotransplantation. Thus far, clinical xenotransplantation of pig tissues has not resulted in transmission of viral infection to humans; significant risks for disease transmission from swine to humans have not been confirmed. If immunologic hurdles can be overcome, it is reasonable to initiate carefully monitored clinical trials.     

Infectious disease risks in xenotransplantation

Hurdles exist to clinical xenotransplantation including potential infectious transmission from nonhuman species to xenograft recipients. In anticipation of clinical trials of xenotransplantation, the associated infectious risks have been investigated. Swine and immunocompromised humans share some potential pathogens. Swine herpesviruses including porcine cytomegalovirus (PCMV) and porcine lymphotropic herpesvirus (PLHV) are largely species‐specific and do not, generally, infect human cells. Human cellular receptors exist for porcine endogenous retrovirus (PERV), which infects certain human‐derived cell lines in vitro. PERV‐inactivated pigs have been produced recently. Human infection due to PERV has not been described. A screening paradigm can be applied to exclude potential human pathogens from “designated pathogen free” breeding colonies. Various microbiological assays have been developed for screening and diagnosis including antibody‐based tests and qualitative and quantitative molecular assays for viruses. Additional assays may be required to diagnose pig‐specific organisms in human xenograft recipients. Significant progress has been made in the evaluation of the potential infectious risks of clinical xenotransplantation. Infectious risk would be amplified by intensive immunosuppression. The available data suggest that risks of xenotransplant‐associated recipient infection are manageable and that clinical trials can be performed safely. Possible infectious risks of xenotransplantation to the community at large are undefined but merit consideration.     

Miniature swine as organ donors for man: Strategies for prevention of xenotransplant-associated infections

Abstract: Xenotransplantation could potentially overcome limitations in organ transplantation resulting from a shortage of donor organs. Transplantation from miniature swine raises concerns over the potential introduction of new infectious agents into humans. These "direct zoonotic infections" or "xenoses" derived from swine fall into four categories: (1) microbial agents known to cause infection in humans (traditional zoonoses);(2) "species specific" organisms restricted to infection of the donor xenograft tissues by the absence of receptors or other factors needed for growth in human cells;(3) organisms of broad "host range" capable of infection of tissues outside the xenograft in the immunocompromised transplant recipient;and (4) organisms, such as retroviruses, of unknown quantity and with unmeasured capacity for causing disease in humans. The behavior of donor-derived xenoses in immunocompromised xenotransplant recipients cannot be predicted. The ability of human-derived microbial agents to infect porcine xenografts, and the capacity of the human immune system to inhibit such infections, also merit investigation. Experimental assessment of the infectious disease risks associated with xenotransplantation is important and practical.     

Pig endogenous retroviruses and xenotransplantation

Xenotransplantation of porcine organs might provide an unlimited source of donor organs to treat endstage organ failure diseases in humans. However, pigs harbour retroviruses with unknown pathogenic potential as an integral part of their genome. While until recently the risk of interspecies transmission of these porcine endogenous retroviruses (PERV) during xenotransplantation has been thought to be negligible, several reports on infection of human cells in vitro and spread of PERV from transplanted porcine islets in murine model systems have somewhat challenged this view. Here, we compile available data on PERV biology and diagnostics, and discuss the significance of the results with regard to the safety of clinical xenotransplantation.     

Chapter 1: Key ethical requirements and progress toward the definition of an international regulatory framework

Abstract:  The outstanding results recently obtained in islet xenotransplantation suggest that porcine islet clinical trials may soon be scientifically appropriate. Before the initiation of such clinical studies, however, it is essential that a series of key ethical and regulatory conditions are satisfied. As far as ethics is concerned, the fundamental requirements have been previously reported in a position paper of the Ethics Committee of the International Xenotransplantation Association. These include aspects related to the selection of adequately informed, appropriate recipients; animal breeding and welfare; safety issues and the need for a favorable risk/benefit assessment based on strong efficacy data in relevant xenotransplantation studies in the primate. As most diabetic patients are not at risk of short-term mortality without islet transplantation, only a small subset of patients could currently be considered for any type of islet transplant. However, there are potential advantages to xenotransplantation that could result in a favorable benefit-over-harm determination for islet xenotransplantation in this subpopulation and ultimately in a broader population of diabetic patients. With regard to regulatory aspects, the key concepts underlying the development of the regulatory models in existence in the United States, Europe and New Zealand are discussed. Each of these models provides an example of a well-defined regulatory approach to ensure the initiation of well-regulated and ethically acceptable clinical islet xenotransplantation trials. At this stage, it becomes apparent that only a well-coordinated international effort such as that initiated by the World Health Organization, aimed at harmonizing xenotransplantation procedures according to the highest ethical and regulatory standards on a global scale, will enable the initiation of clinical xenotransplantation trials under the best auspices for its success and minimize any risk of failure.     

Prevention of infection in xenotransplantation: Designated pathogen-free swine in the safety equation

Post-transplantation infections are common. In immunosuppressed human xenograft recipients, infection is most likely to be due to the same pathogens seen in human allotransplantation. However, organisms derived from swine and transmitted with xenografts have the potential to cause novel infections in xenograft recipients. The specific organisms likely to cause infection or “xenosis” are unknown but are postulated to be like those causing infection in allograft recipients. On this basis, theoretical exclusion criteria have been developed to guide the development of source animal herds. Herds developed based on the exclusion of potential human pathogens have been termed “designated pathogen-free” (DPF). Lists of potential pathogens will require revision with changing epidemiology of infection in swine worldwide and clinical experience. Development of new microbiological assays is required both for animal screening and in clinical diagnosis should infections occur. Genetic modifications of swine have the potential to eliminate certain infectious agents such as the porcine endogenous retrovirus; infectious complications of such modifications have not been observed. Unexpected, off target effects of genetic modifications require further study. Monitoring for infection in asymptomatic recipients is important to define infectious risks which are unknown in the absence of clinical trials data. Advanced microbiological techniques may be applied to diagnose and prevent infection in xenograft recipients.     

Donor‐derived infections and infectious risk in xenotransplantation and allotransplantation

Post‐transplantation infections are common in allograft recipients and should be expected in all immunocompromised hosts. Based on the need for immunosuppression in xenotransplantation, procedures developed to enhance safety in allotransplantation can be applied in future xenotransplantation clinical trials. Standardized approaches can be developed to guide the evaluation of common infectious syndromes in xenograft recipients. The opportunity created by screening of swine intended as xenograft donors has equal applicability to allotransplantation—notably broader screening strategies for allograft donors such as use of advanced sequencing modalities including broad‐range molecular probes, microarrays, and high‐throughput pyrosequencing. Considerations in management of allotransplant‐ and xenotransplant‐associated infections are largely the same. Experience in xenotransplantation will continue to inform thinking regarding donor‐derived infections in allotransplantation. We expect that experience in managing complex allotransplant recipients will similarly inform clinical trials in xenotransplantation.     

The production of transgenic pigs for potential use in clinical xenotransplantation: microbiological evaluation

Debate over the infection hazards of pig-to-human xenotransplantation has focused mainly on the porcine endogenous retroviruses (PERV). However, hazards of exogenous infectious agents possibly associated with the xenograft have also been evaluated (Xenotransplantation 2000; 7: 143). We report the results of a health monitoring program demonstrating the exclusion of more than 80 potential pathogens from nine cohorts of pigs reared in a high welfare bioexclusion facility as potential xenograft source animals. A dynamic bacterial flora of pigs reared under barrier conditions was characterized, emphasizing the significance of monitoring for multiresistant antimicrobial sensitivity patterns. Evidence was found for exclusion of two commonly residual exogenous viruses, porcine cytomegalovirus and porcine lymphotropic herpesviruses, among a proportion of the cohorts tested. Finally, there was histopathological evidence for low grade pneumonitis among sentinel pigs, likely to have been associated with the use of quaternary ammonium disinfectants during the production process, indicating a need for review of toxicology data for disinfectant agents used in such bioexclusion systems. Intensive health monitoring programs, based upon regularly updated recommendations from the microbiological research community, will enable significant reductions in the potential hazards associated with pig-to-human xenotransplantation.     

Xenotransplantation: the challenge to current psychosocial attitudes

Because of the limited availability of transplantable human organs, xenotransplantation, the use of animal organs as an alternative source, has received considerable attention in recent years. Xenotransplantation would provide an unlimited supply of organs, and these organs would be available whenever required. Although the pig is considered the best source for organs, significant immunologic barriers currently prohibit the implementation of a clinical trial of organ transplantation. However, as medical research gains more insight into the mechanisms underlying rejection of pig organs in primates, therapeutic xenotransplantation is becoming more feasible. Clinical trials of porcine cell transplants are currently underway. Although xenotransplantation will minimize the waiting period for an organ and obviate the feelings of guilt or indebtedness commonly experienced by recipients of human organs, several psychosocial issues may hinder the reintegration of patients into society. For example, concerns that infectious pathogens could be transferred to recipients of pig organs will necessitate life-long monitoring and perhaps even temporary isolation of patients. The possible risk of the spread of a xenozoonosis from the patient to other members of the community may inspire public controversy and even fear, which may have an adverse impact on the patient's emotional state. Additionally, some patients may be psychologically disturbed by the need to incorporate pig organs into their body. This article addresses these and other psychosocial issues that may be associated with clinical xenotransplantation.     

Reduction of consumptive coagulopathy using porcine cytomegalovirus-free cardiac porcine grafts in pig-to-primate xenotransplantation

BACKGROUND: Xenotransplantation using pigs as the source species for organs carries a potential risk for transmission and activation of porcine herpesviruses. Activation of porcine cytomegalovirus (PCMV) in pig-to-baboon xenotransplantation is associated with xenograft injury and possibly an increased incidence of consumptive coagulopathy (CC). METHODS: To further investigate the role of PCMV activation in the occurrence of CC, a strategy to exclude PCMV from the donor was developed. To exclude PCMV, piglets were early-weaned and raised separated from other swine. These piglets were used as donors in an experimental protocol of pig-to-baboon heart xenotransplantation. RESULTS: Early weaning of piglets was successful in excluding PCMV. Use of PCMV-free cardiac porcine xenografts in baboons resulted in prolonged graft survival and prevented consumptive coagulopathy in all recipients. CONCLUSIONS: The use of PCMV-free cardiac grafts is beneficial in reducing the direct effects of PCMV activation in the graft (tissue damage) and the indirect effects of PCMV activation in the recipient (consumptive coagulopathy).     

Retroviral Restriction Factors and Infectious Risk in Xenotransplantation

The clinical application of xenotransplantation poses immunologic, ethical, and microbiologic challenges. Significant progress has been made in the investigation of each of these areas. Among concerns regarding infectious risks for human xenograft recipients is the identification in swine of infectious agents including porcine endogenous retroviruses (PERV) that are capable of replication in some human cell lines. PERV replication has, however, been difficult to demonstrate in primate‐derived cell lines and in preclinical studies of non‐human primates receiving porcine xenografts. Endogenous ‘retroviral restriction factors’ are intracellular proteins and components of the innate immune system that act at various steps in retroviral replication. Recent studies suggest that some of these factors may have applications in the management of endogenous retroviruses in xenotransplantation. The risks of PERV infection and the potential role of retroviral restriction factors in xenotransplantation are reviewed in detail.     

Early weaning of piglets fails to exclude porcine lymphotropic herpesvirus

BACKGROUND: Xenotransplantation using pigs as source species carries a risk for the activation of latent herpesviruses from the porcine donor and potential transmission to the recipient. In pig-to-baboon xenotransplantation, activation of porcine cytomegalovirus (PCMV) has been associated with xenograft injury and an increased incidence of consumptive coagulopathy and graft loss. Activation of porcine lymphotropic herpesvirus (PLHV)-1 was not observed in pig-to-baboon solid organ xenotransplantation, but was associated with a syndrome of post-transplantation lymphoproliferative disorder (PTLD) after allogeneic stem cell transplantation in pigs. MATERIAL and METHODS: Early weaning of piglets was used to try to reduce the viral burden of xenograft donors. This consisted of separating the piglets of a litter from the sow within the first 2 weeks after birth and raising them in isolation from the remaining herd. RESULTS: We have previously demonstrated that PCMV could be excluded from source animals by early weaning of piglets. However, early weaning failed to exclude PLHV-1 from source pigs. CONCLUSIONS: This disparity between PCMV and PLHV-1 reflects differing pathogenesis of infection of these herpesviruses. New approaches will be needed to exclude PLHV-1 from pig colonies.     

Executive summary

Abstract:  The International Xenotransplantation Association islet xenotransplantation consensus statement describes the conditions for undertaking clinical trials of porcine islet products in type 1 diabetes. Chapter 1 reviews the key ethical requirements and progress toward the definition of an international regulatory framework for clinical trials of xenotransplantation. Chapters 2 to 7 provide in depth and agreed-upon recommendations on source pigs, pig islet product manufacturing and release testing, preclinical efficacy and complication data required to justify a clinical trial, strategies to prevent transmission of porcine endogenous retrovirus, patient selection for clinical trials, and informed consent. It is planned to update this initial consensus statement in a year's time in light of progress in research, changes in the regulatory framework, and comments submitted after publication.     

Safety of xenotransplantation: screening the donor pig and the recipient

Introduction: Xenotransplantation using pig cells and tissues may be associated with the transmission of porcine microorganisms including bacteria, parasites, fungi and viruses to the human recipient and may result in zoonones. Porcine endogenous retroviruses (PERVs) represent a special risk since PERV‐A and PERV‐B are present in the genome of all pigs and infect human cells. PERV‐C is not present in all pigs and does not infect human cells. However, recombinants between PERV‐A and PERV‐C have been observed in normal pigs characterised by higher replication rates compared with PERV‐A, and they are also able to infect human cells (1). Methods: In the past years numerous assays based on the PCR technology have been developed to screen for the prevalence and expression of PERV and other porcine microorganisms in the donor pig (2). Whereas most microorganisms may be eliminated by designated pathogen‐free breeding, PERVs cannot be removed this way. In addition, assays have been developed to analyse the recipient for the transmission of PERV and other microorganisms, either using PCR methods or immunological assays to detect an antibody production as a result of infection (3). Results: Using these assays, no transmission of PERV as well as of other porcine microorganisms has been observed in first preclinical and clinical xenotransplantations or animal infection experiments. This was especially true for the first clinical transplantation of pig islet cells approved by the New Zealand government (4). Until now there is no susceptible animal model to study PERV transmission and transplantations of porcine cells or organs to non‐human primates as they are associated with limitations concerning the safety aspect, which do not allow transmitting the negative findings to humans (5). Different experimental approaches are under development to reduce the probability of PERV transmission, e.g. the generation of transgenic pigs expressing PERV‐specific siRNA inhibiting PERV expression by RNA interference (6), genotypic selection of pigs with a low prevalence and expression of PERV and neutralising antibodies against the envelope proteins inhibiting PERV infection (7). Conclusion: Investigations of the last years resulted in highly sensitive and specific methods to study PERV and other microorganisms in donor pigs and human recipients of xenotransplants. These methods showed absence of PERV transmission in all investigated cases, both in more than 200 human xenotransplant recipients, mostly recipients of cellular xenotransplants, as well as in non‐human primates and small animals. New technologies under development may further decrease the probability of transmission. References: 1. Denner J. Recombinant porcine endogenous retroviruses (PERV‐A/C): A new risk for xenotransplantation? Arch Virol 2008; 153: 1421–1426. 2. Kaulitz D, Mihica D, Dorna J, Costa MR, Petersen B, Niemann H, TÖnjes RR, Denner J. Development of sensitive methods for detection of porcine endogenous retrovirus‐C (PERV‐C) in the genome of pigs J Virol Methods 2011; 175(1): 60–65. 3. Denner, J. Infectious risk in xenotransplantation – what post‐transplant screening for the human recipient? Xenotransplantation 2011; 18(3): 151–157. 4. Wynyard S, Garkavenko O, Nathu D, Denner J, Elliott R. Microbiological safety of the first clinical pig islet xenotransplantation trial in New Zealand, submitted. 5. Mattiuzzo G, Takeuchi Y. Suboptimal porcine endogenous retrovirus infection in non‐human primate cells: implication for preclinical xenotransplantation. PLoS One 2010; 5(10): e13203. 6. Semaan M, Kaulitz D, Petersen B, Niemann H, Denner J. Long‐term effects of PERV‐specific RNA interference in transgenic pigs. Xenotransplantation 2012; 19(2): 112–21. 7. Kaulitz D, Fiebig U, Eschricht M, Wurzbacher C, Kurth R, Denner J. Generation of neutralising antibodies against porcine endogenous retroviruses (PERVs). Virology 2011; 411(1): 78–86.     

First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes—Executive summary

The International Xenotransplantation Association has updated its original “Consensus Statement on Conditions for Undertaking Clinical Trials of Porcine Islet Products in Type 1 Diabetes,” which was published in Xenotransplantation in 2009. This update is timely and important in light of scientific progress and changes in the regulatory framework pertinent to islet xenotransplantation. Except for the chapter on “informed consent,” which has remained relevant in its 2009 version, all other chapters included in the initial consensus statement have been revised for inclusion in this update. These chapters will not provide complete revisions of the original chapters; rather, they restate the key points made in 2009, emphasize new and under‐appreciated topics not fully addressed in 2009, suggest relevant revisions, and communicate opinions that complement the consensus opinion. Chapter 1 provides an update on national regulatory frameworks addressing xenotransplantation. Chapter 2 a, previously Chapter 2, suggests several important revisions regarding the generation of suitable source pigs from the perspective of the prevention of xenozoonoses. The newly added Chapter 2b discusses conditions for the use of genetically modified source pigs in clinical islet xenotransplantation. Chapter 3 reviews porcine islet product manufacturing and release testing. Chapter 4 revisits the critically important topic of preclinical efficacy and safety data required to justify a clinical trial. The main achievements in the field of transmission of all porcine microorganisms, the rationale for more proportionate recipient monitoring, and response plans are reviewed in Chapter 5. Patient selection criteria and circumstances where trials of islet xenotransplantation would be both medically and ethically justified are examined in Chapter 6 in the context of recent advances in available and emerging alternative therapies for serious and potentially life‐threatening complications of diabetes. It is hoped that this first update of the International Xenotransplantation Association porcine islet transplant consensus statement will assist the islet xenotransplant scientific community, sponsors, regulators, and other stakeholders actively involved in the clinical translation of islet xenotransplantation.     

Methods for the exclusion of circoviruses and gammaherpesviruses from pigs

Abstract: The use of porcine tissues is being developed as a means to alleviate the shortage of allogeneic tissues and organs available for transplantation. To reduce the possibility of a microorganism of pigs being inadvertently transferred to the recipient of the xenograft, recommendations have been published on the microbiological specifications for organ source pigs. The porcine circoviruses (PCV1 and PCV2) and porcine lymphotropic herpesviruses (PLHV1 and PLHV2) are two infectious agents of pigs which are considered to be of significance for the microbiological safety of xenotransplantation. To ensure the exclusion of these microorganisms from animals destined for use under clinical conditions, reliable breeding methodologies are required. We investigated the efficiency of established derivation procedures for the removal of PCV and PLHV. In comparison with conventionally reared pigs, caesarian and barrier derived animals showed a markedly reduced prevalence of PCVs and PLHVs. Our results indicate that the derivation of animals free of both of these microorganisms is achievable and will enhance the microbiological safety of xenotransplantation.     

How the COVID-19 pandemic may impact public support for clinical xenotransplantation in the United States?

Many patients who would undergo organ transplantation cannot proceed due to the inability of human organ donation to satisfy medical needs. Xenotransplantation has the potential to offer unlimited availability of pig organs for transplantation, and pig-to-non-human primate models have demonstrated outcomes that may soon justify clinical trials. However, one of the unique ethical challenges faced by xenotransplantation is that the risk of introducing potential zoonotic disease into the community must be weighed along with the benefit to the patient. While most experts believe that zoonosis is manageable, apprehension over disease transmission from animal donors to human recipients remains a frequent concern of many who are undecided or opposed to clinical xenotransplantation. The COVID-19 pandemic represents a scenario (rapid worldwide spread of a highly contagious novel zoonotic disease with no natural defense in humans) that would seem to justify apprehension, especially in the United States, which has largely avoided previous pandemic outbreaks. However, there are many differences between zoonosis found in the wild or after xenotransplantation that favor the safety of the latter. Still, these differences, as well as the benefits of xenotransplantation, are not widely understood outside of the field. We must therefore ask what impact the COVID-19 pandemic will have on attitudes toward xenotransplantation.     

Absence of PERV specific humoral immune response in baboons after transplantation of porcine cells or organs

Xenotransplantation of pig organs seems a promising way of overcoming the prevailing limitation on allotransplantation due to donor numbers. However, as porcine endogenous retroviruses (PERVs) can infect human cells in vitro, there is substantial concern regarding the risk of a PERV infection in xenogeneic transplant recipients. Cultured porcine endothelial cells, stimulated peripheral blood mononuclear cells, and pancreatic islet cells can release PERV infectious for human cells in vitro, but it is currently unknown whether PERV is released in vivo, whether these viral particles can infect the transplant recipient, and whether they are pathogenic. In a retrospective study 15 immunosuppressed baboons were tested for a specific immune response against PERV after transplantation of porcine endothelial cells, mononuclear blood cells, and lungs. Anti-PERV antibody expression was analyzed with peptide-based, enzyme-linked immunosorbent assays and highly sensitive Western Blot assays. This xenotransplantation study using nonhuman primates found no evidence of PERV specific humoral immune response. Our data suggest that no productive PERV infection and no continuous PERV release takes place in the nonhuman primates analyzed in this study.     

Infection in xenotransplantation

Advances in transplantation immunology have enhanced the possibility of xenotransplantation as a therapeutic option for end-stage organ failure. The potential spread of animal-derived pathogens to the recipient and to the general population, termed "xenosis," is a potential complication of interspecies transplantation. Recognition of such novel infections may be complicated by infections due to altered microbiologic behavior and clinical symptomatology of these organisms, particularly in the immunocompromised xenograft recipient. Particular concern exists over the activation of latent viruses, including retroviruses, from xenograft tissues. Based on experience with human allogeneic transplantation, those pathogens considered most likely to cause human disease can be excluded prospectively from herds of animals developed for organ donation. Research is needed into the activation and behavior of retroviruses and other potential pathogens in xenotransplantation. Xenotransplantation may also provide unique opportunities not only for the care of patients with organ failure, but in the therapy of individuals with chronic infections to which the xenograft may be resistant. Clinical protocols must be developed so as to enhance the safety of the recipient and of the community-at-large.