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, njes 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.