In vivo immune response to allogeneic hepatocytes

Abstract

T HE PURPOSE of the following study was to determine the in vivo fate of allogeneic hepatocytes (Hc) in a functional model of hepatocyte transplantation (Hc TX) in mice. The Hc TX model used in this study involved the creation of mice which expressed the transgene human alpha-1-antitrypsin (hAlAT) (under control of the hAlAT promoter) in the liver. Hc isolated from the transgenic donors produce and secrete hAlAT such that detection of the genetic “marker” protein (hAlAT) in recipient serum after Hc TX reflects the survival and intact metabolic function of the transplanted Hc. The advantages of this model include (1) the use of a direct method for monitoring graft function and survival (secretion of hAlAT), (2) histologic confirmation of hepatocellular graft survival can be determined easily by immunohistochemical analysis for Hc bearing the transgene hAlAT, (3) transgenic donor Hc may be transplanted into a variety of murine hosts which allows us to assess the influence of particular immunodeficient states as well as differences in host/donor MHC disparities on hepatocellular graft survival, and (4) permits the distinction between immunologic and nonimmunologic factors (including primary nonfunction, poor engraftment, and senescence of transplanted Hc) which may affect graft function and survival after Hc TX. One potential disadvantage of the model is that the genetic marker protein (hAlAT) may elicit an immune response which adversely affects graft survival. In the current study, this functional model of Hc TX was used to determine the fate of the transplanted Hc in syngeneic, allogeneic, and immunoincompetent hosts.