Xenotransplantation: INFECTIOUS CONCERNS
Infections have proven to be a substantial cause of morbidity and mortality after allotransplantation. This is owing in large part to the immunosuppressive treatment needed to prevent graft rejection. Interspecies transplantation may require greater levels of immune suppression than are currently used for allotransplantation, thereby further increasing the risk of opportunistic infection. An additional risk of xenotransplantation is that of ‘xenosis’, the transfer of animal-derived infectious pathogens with xenotrans- plants (Figure 2). This is in contrast to the natural spread of infection between species, referred to as ‘zoon- osis’. While xenograft recipients are susceptible to infection by bacteria, fungi and parasites, much attention has focused on infection by viral pathogens (Table 2).
Several mechanisms of xenogeneic infection have been identified. A pathogen may be infectious for both the donor species and the human recipient (eg, Toxoplasma gondii). Some animal viruses that are similar to their human counterparts, such as primate cytomegalovirus (CMV), have been documented to produce clinical disease in human xenograft recipients. A major concern is retrovi- ruses such as simian immunodeficiency virus, which can be transmitted across species and produce a more virulent reaction in the new host. Some pig retroviruses have been shown to reactivate after radiation exposure and might similarly reactivate when exposed to immunosup- pressive medication. Indeed, many of the conditions associated with retroviral activation (eg, immune suppression, graft rejection, cytotoxic therapy) are present in the transplant recipient. Latent animal viruses present in the xenograft, such as porcine CMV, may be unable to infect human tissue but may later reactivate in the animal organ, resulting in graft failure. Finally, concern has been raised regarding the possibility of crossover of an animal virus with a human virus, leading to a more virulent recombinant organism. Indeed, dual infections can lead to recombination, as has been observed with in vitro mixing of CMV isolates from transplant recipients. Concurrent inoculation of two avirulent herpes simplex viruses into mice has been demonstrated to produce lethal recombinations. Recognition of xenogeneic infections may be complicated by the presence of novel pathogens for which laboratory testing is not available, new clinical syndromes and altered behaviour of these pathogens in the im- munocompromised recipient.
Table 2
Zoonosis in xenotransplantation
Infectious agents
Parasites
Bacteria
Fungi Viruses
Prions
Viruses of concern Polyomavirus
Parvoviruses Circoviruses
Cytomegaloviruses
Respiratory syncitial viruses
Influenza viruses
Retroviruses
Pathogens considered most likely to cause human disease should be screened for and excluded from source animals. Careful thought must be given to determining the organisms to be screened. Algorithms have been developed for baboon bone marrow transplantation into a human to help classify potential microorganisms in source baboons. Pathogens were designated as absolute contraindications if they were known to causes zoonoses in primates and known to be hazardous to humans. In particular, organisms that could be secondarily transmitted from an infected recipient to close contacts, such as simian immunodeficiency virus, T gondii and Mycobacterium tuberculosis, were placed in this category. Viruses at high risk for recombination, such as parvovirus and rotavirus, were also designated absolute contraindications. Relative contraindications included organisms suspected to be transmissible but of unproven or unclear clinical significance, such as baboon herpesviruses. Treatable infections were those that could be identified and eradicated successfully before harvest, such as Babesia species. Lastly, a category called ‘unavoidable’ included baboon endogenous virus and all organisms yet to be recognized. Similar categories have been designed for microbial agents in pigs. Molecular techniques to screen source animals for retrovi- ruses, herpesviruses and other organisms are being developed, but much remains to be learned in this field. Source animals should be raised in a gnotobiotic environment to eliminate microbial agents. Maintaining pathogen-free environments is an arduous task because colonies can easily be contaminated by unwanted organisms introduced from outside animals or human caretakers.
Prevention of disease from human donors has relied on protocols for donor screening, recipient prophylaxis and intensive post-transplantation surveillance. Similar protocols for screening of source animals and surveillance of xe- nograft recipients can help prevent and monitor infections. Research must, therefore, focus on the behaviour of known pathogens in the transplant recipient. Newer potential pathogens must be isolated and characterized, and diagnostic tests must be developed.
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Figure2 ) Zoonosis in xenotransplantation. Pathogens can be infections both from human to pig or from pig to human. In addition, recombination events can occur, resulting in novel pathogens
