Prolongation of heterotopic heart allograft survival by portal venous injection of alloantigen: The role of hepatic nonparenchymal cells

The induction of immune hyporesponsiveness in transplantation is a complex interaction between the immune system and the alloantigen. The route by whi ch an antigen is introduced to the immune system plays an important role in the immune response. Antigen delivered via the portal circulation has the ability to induce T-cell hyporesponsiveness. In this study we examined the mechanism responsible for the induction of hyporesponsiveness by assessing immune response following portal vein (pv) injection of donor alloantigen. C57B1/6 mice were immunized via pv with splenic mononuclear cells (SMNC) fr om BALB/c mice. The recipient immune response was assessed in vivo by murin e heterotopic heart transplant survival. SMNC and hepatic nonparenchymal ce lls (NPC) were isolated from pv immunized animals and used as regulatory ce lls in a one-way mixed lymphocyte culture (MLC) as a measure of in vitro re cipient responder SMNC proliferation. Survival of murine heterotopic heart transplants was prolonged following pv injection of alloantigen (p < .04 co mpared to nonimmunized or systemically immunized mice). Stimulation of resp onder SMNCs isolated from pv immunized mice resulted in an antigen-specific hyporesponsiveness (p < .05 compared with nonimmunized or systemically imm unized mice). Cocultures of responder SMNCs from nonimmunized (naive) mice with hepatic NPC from previously pv immunized mice resulted in attenuation of T-cell proliferation in MLR following stimulation with donor alloantigen (p < .05 compared to coculture with NPC from nonimmunized mice or SMNC fro m pv immunized mice). These data would suggest that the hepatic NPC plays a n important role in the regulation of the immune response. With further ide ntification of cell subtypes responsible for induction of hyporesponsivenes s, future therapies may be directed at these specific targets, thereby mini mizing the harmful side effects of current immunosuppressive therapies.