Xenotransplantation has been proposed as a solution to the shortage of human organs available for transplantation. Infection and malignancy are the main complications of long-term immune suppression used to maintain allograft function. Concerns about the clinical application of xenotransplantation have focused on the risk of introducing novel infectious agents derived from on-human species into the xenograft recipient and the community at large. The isolation of a family of porcine endogenous retroviruses (PERV) from tissues of normal swine, which are also infectious for human cells in vitro, has contributed to these concerns. The goal of this project is to assess some of the infectious risks associated with xenotransplantation and the immune deficits that predispose to such infections. Infectious will be studied using miniature swine as organ donors for non-human primate (baboon) recipients with clinically relevant immune suppression and/or modification. The approaches used to enhance discordant xenograft survival will include the induction of donor- specific, cellular immune tolerance induced by mixed chimerism, xenogeneic thymic transplantation, and/or suppression of humoral immune responses using gene transduction and pharmacological modulation of B-cell function (Projects 1 and 2). Using techniques developed and available in this laboratory (for PERV and porcine herpesviruses), the biology of known organisms from swine will be investigated. Attempts will also be made to detect and characterize novel organisms in xenograft recipients. Specifically this project will study: 1. The expression of PERV in pig-to-primate xenotransplantation models; 2. The genetics of PERV in a unique herd of in-bred miniature wine; 3. The activation of porcine cytomegalovirus and other herpesviruses in xenograft recipients; 4. un-characterized pathogens in the pig to non- human primate model. These data will assist in the assessment of infectious risks associated with xenotransplantation from swine and, ultimately, will facilitate the development of strategies for the prevention of infection in human xenograft recipients.
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