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 which 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) from BALB/c mice. The recipient immune response was assessed in vivo by murine heterotopic heart transplant survival. SMNC and hepatic nonparenchymal cells (NPC) were isolated from pv immunized animals and used as regulatory cells in a one-way mixed lymphocyte culture (MLC) as a measure of in vitro recipient responder SMNC proliferation. Survival of murine heterotopic heart transplants was prolonged following pv injection of alloantigen (p < .04 compared to nonimmunized or systemically immunized mice). Stimulation of responder SMNCs isolated from pv immunized mice resulted in an antigen-specific hyporesponsiveness (p < .05 compared with nonimmunized or systemically immunized 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 from pv immunized mice). These data would suggest that the hepatic NPC plays an important role in the regulation of the immune response. With further identification of cell subtypes responsible for induction of hyporesponsiveness, future therapies may be directed at these specific targets, thereby minimizing the harmful side effects of current immunosuppressive therapies.
Smith
R M
RM
Department of Surgery, Vancouver General Hospital, University of British Columbia, Canada.
Chen
Y
Y
McKenna
G J
GJ
Ong
C
C
Zhang
R
R
Chung
S W
SW
D000818:Animals; D002455:Cell Division / Q000276:immunology; D005260:Female; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology / Q000379:methods* / Q000401:mortality; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology*; D007519:Isoantigens / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D011169:Portal Vein; D013045:Species Specificity; D013154:Spleen / Q000166:cytology; D015996:Survival Rate; D016042:Transplantation, Heterotopic / Q000276:immunology / Q000379:methods* / Q000401:mortality; D014184:Transplantation, Homologous
D007519:Isoantigens