Pig-to-non-human primate heart transplantation: Immunologic progress over 20 years

Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation (Impact Factor: 5.61). 04/2007; 26(3):210-8. DOI: 10.1016/j.healun.2006.12.005
Source: PubMed

ABSTRACT The major developments in pig-to-non-human primate heart xenotransplantation during the past 20 years are summarized, largely through the experience of one investigator. Genetic modifications to organ-source pigs have been important steps in increasing heart xenograft survival from a few minutes in 1986 to 2 to 6 months in 2005.

  • [Show abstract] [Hide abstract]
    ABSTRACT: The shortage of human organs for transplantation has focused research on the possibility of transplanting pig organs into humans. Many factors contribute to the failure of a pig organ graft in a primate. A rapid innate immune response (natural anti-pig antibody, complement activation, and an innate cellular response; e.g., neutrophils, monocytes, macrophages, and natural killer cells) is followed by an adaptive immune response, although T-cell infiltration of the graft has rarely been reported. Other factors (e.g., coagulation dysregulation and inflammation) appear to play a significantly greater role than in allotransplantation. The immune responses to a pig xenograft cannot therefore be controlled simply by suppression of T-cell activity. Before xenotransplantation can be introduced successfully into the clinic, the problems of the innate, coagulopathic, and inflammatory responses will have to be overcome, most likely by the transplantation of organs from genetically engineered pigs. Many of the genetic manipulations aimed at protecting against these responses also reduce the adaptive response. The T-cell and elicited antibody responses can be prevented by the biological and/or pharmacologic agents currently available, in particular, by costimulation blockade-based regimens. The exogenous immunosuppressive regimen may be significantly reduced by the presence of a graft from a pig transgenic for a mutant (human) class II transactivator gene, resulting in down-regulation of swine leukocyte antigen class II expression, or from a pig with "local" vascular endothelial cell expression of an immunosuppressive gene (e.g., CTLA4-Ig). The immunomodulatory efficacy of regulatory T cells or mesenchymal stromal cells has been demonstrated in vitro but not yet in vivo.
    Transplantation 07/2013; 96(11). DOI:10.1097/TP.0b013e31829bbcb2 · 3.78 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background The pig-to-non-human primate model is the standard choice for in vivo studies of organ and cell xenotransplantation. In 1998, Lambrigts and his colleagues surveyed the entire world literature and reported all experimental studies in this model. With the increasing number of genetically engineered pigs that have become available during the past few years, this model is being utilized ever more frequently.Methods We have now reviewed the literature again and have compiled the data we have been able to find for the period January 1, 1998 to December 31, 2013, a period of 16 yr.ResultsThe data are presented for transplants of the heart (heterotopic and orthotopic), kidney, liver, lung, islets, neuronal cells, hepatocytes, corneas, artery patches, and skin. Heart, kidney, and, particularly, islet xenograft survival have increased significantly since 1998.DiscussionThe reasons for this are briefly discussed. A comment on the limitations of the model has been made, particularly with regard to those that will affect progression of xenotransplantation toward the clinic.
    Xenotransplantation 09/2014; 21(5). DOI:10.1111/xen.12127 · 1.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Baertschiger RM, Buhler LH. Xenotransplantation literature update March–April, 2007. Xenotransplantation 2007; 14: 360–365. © Blackwell Munksgaard, 2007
    Xenotransplantation 07/2007; 14(4):360-365. DOI:10.1111/j.1399-3089.2007.00411.x · 1.78 Impact Factor