Linda Scobie

Xenotransplantation carries the potential risk of the transmission of infection with the cells or tissues of the graft. The degree of risk is unknown in the absence of clinical trials. The clinical application of xenotransplantation has important implications for infectious disease surveillance, both at the national and international levels. Preclinical data indicate that infectious disease events associated with clinical xenotransplantation from swine, should they occur, will be rare; data in human trials are limited but have demonstrated no transmission of porcine microorganisms including porcine endogenous retrovirus. Xenotransplantation will necessitate the development of surveillance programs to detect known infectious agents and, potentially, previously unknown or unexpected pathogens. The development of surveillance and safety programs for clinical trials in xenotransplantation is guided by a "Precautionary Principle," with the deployment of appropriate screening procedures and assays for source animals and xenograft recipients even in the absence of data suggesting infectious risk. All assays require training, standardization and validation, and sharing of laboratory methods and expertise to optimize the quality of the surveillance and diagnostic testing. Investigation of suspected xenogeneic infection events (xenosis, xenozoonosis) should be performed in collaboration with an expert data safety review panel and the appropriate public health and competent authorities. It should be considered an obligation of performance of xenotransplantation trials to report outcomes, including any infectious disease transmissions, in the scientific literature. 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. Concerns over any potential hazards associated with xenotransplantation may overshadow potential benefits. Careful microbiological screening of source animals used as xenotransplant donors may enhance the safety of transplantation beyond that of allotransplant procedures. Xenogeneic tissues may be relatively resistant to infection by some human pathogens. Moreover, xenotransplantation may be made available at the time when patients require organ replacement on a clinical basis. Insights gained in studies of the microbiology and immunology of xenotransplantation will benefit transplant recipients in the future. This document summarizes approaches to disease surveillance in individual recipients of nonhuman tissues.

term to dramatically reduce the high incidence of HPAI in Bangladesh. We have progressively and dramatically increased the scope and benefi ts of our pilot PVC implementation program, but additional work is needed. To help spread PVC approaches throughout the country, community leaders, imams of local mosques, and school teachers can be trained to implement awareness programs on safe practices for raising poultry and regular cleaning and disinfection of live bird markets. The strengthening of biosecurity measures will help control the spread of HPAI virus and other zoonotic diseases.

The replication of porcine endogenous retrovirus subgroup A (PERV-A) and PERV-B in certain human cell lines indicates that PERV may pose an infectious risk in clinical xenotransplantation. We have previously reported that human-tropic PERVs isolated from infected human cells following cocultivation with miniature swine peripheral blood mononuclear cells (PBMC) are recombinants of PERV-A with PERV-C. Here, we report that these recombinants are exogenous viruses in miniature swine; i.e., they are not present in the germ line DNA. These viruses were invariably present in miniature swine that transmitted PERV to human cells and were also identified in some miniature swine that lacked this ability. These data, together with the demonstration of the absence of both replication-competent PERV-A and recombinant PERV-A/C loci in the genome of miniature swine (L. Scobie, S. Taylor, J. C. Wood, K. M. Suling, G. Quinn, C. Patience, H.-J. Schuurman, and D. E. Onions, J. Virol. 78:2502-2509, 2004), indicate that exogenous PERV is the principal source of human-tropic virus in these animals. Interestingly, strong expression of PERV-C in PBMC correlated with an ability of the PBMC to transmit PERV-A/C recombinants in vitro, indicating that PERV-C may be an important factor affecting the production of human-tropic PERV. In light of these observations, the safety of clinical xenotransplantation from miniature swine will be most enhanced by the utilization of source animals that do not transmit PERV to either human or porcine cells. Such animals were identified within the miniature swine herd and may further enhance the safety of clinical xenotransplantation.