Modulation of Immune Responses after Portal Venous Injection of Antigen

Background: How the localization of antigen to the liver, through means such as oral ingestion, induces tolerance is poorly understood. Methods: To elucidate potential mechanisms we used an adoptive transfer system wherein ova-specific T cells were infused into a syngeneic host, and antigen-specific T-cell responses after delivery of soluble antigen into the liver were monitored. Results: After infusion of antigen into the portal vein, the frequency of antigen-specific T cells in lymph nodes draining the liver was lower than the frequency in peripheral lymph nodes. These findings were the reverse of what is typically observed after subcutaneous injection of antigen with adjuvant. Infusion of antigen with adjuvant into the portal vein did not alter this pattern of antigen-specific T-cell localization; however, an increased frequency of T cells, compared with antigen alone, was observed in peripheral lymph nodes and spleen. After exposure to antigen via the portal vein, T cells isolated from lymph nodes draining the liver and challenged with antigen in vitro exhibited a diminished proliferative response compared with T cells isolated from nondraining lymph nodes. This hyporesponsiveness was not observed when the antigen was administered with adjuvant. Conclusions: Our findings suggest that the influence of the liver on immune responses might reflect two processes: (1) loss of antigen-specific T cells after primary antigen injection, and (2) hyporesponsiveness on reexposure to antigen. These mechanisms may contribute to the prevention of undesirable immune responses to foods and enteric bacteria in the gastrointestinal tract. Furthermore, these results underscore the importance of minimizing inflammation in circumstances such as islet transplantation, if endogenous mechanisms of tolerance induction are to be maximized

Expression of Intrahepatic Inducible Nitric oxide Synthetase mRNA Correlates With Production of Nitric Oxide During Intraportal Isogeneic and Allogeneic Rat Islet Transplantation

Intrahepatic NO production is related to the islet mass transplanted. Nitric oxide production is higher in recipients of allogeneic rather than syngeneic islets. In addition, in allogeneic recipients a possible second peak of NO production was observed at 120 hours corresponding to the time of cellular rejection of the islet grafts (P = .22 vs 96 hours). Finally, the time to rejection of Wistar rat donor islets transplanted into Lewis rat diabetic recipients treated with NMA was not affected. However, inhibiting NO production in the minimal islet transplant model decreased the time to islet function, it does not affect the time to clinical rejection in recipients of a high number of allogeneic islet, which functions immediately. High-level NO has been shown to inhibit T-cell activation in vitro, and thus decreasing the levels by administrating NMA may accentuate the rejection response, canceling out the beneficial effect that might otherwise have occurred on islet function. Further experiments are required to clarify these issues

Modulation of Immune Responses after Portal Venous Injection of Antigen

Background: How the localization of antigen to the liver, through means such as oral ingestion, induces tolerance is poorly understood. Methods: To elucidate potential mechanisms we used an adoptive transfer system wherein ova-specific T cells were infused into a syngeneic host, and antigen-specific T-cell responses after delivery of soluble antigen into the liver were monitored. Results: After infusion of antigen into the portal vein, the frequency of antigen-specific T cells in lymph nodes draining the liver was lower than the frequency in peripheral lymph nodes. These findings were the reverse of what is typically observed after subcutaneous injection of antigen with adjuvant. Infusion of antigen with adjuvant into the portal vein did not alter this pattern of antigen-specific T-cell localization; however, an increased frequency of T cells, compared with antigen alone, was observed in peripheral lymph nodes and spleen. After exposure to antigen via the portal vein, T cells isolated from lymph nodes draining the liver and challenged with antigen in vitro exhibited a diminished proliferative response compared with T cells isolated from nondraining lymph nodes. This hyporesponsiveness was not observed when the antigen was administered with adjuvant. Conclusions: Our findings suggest that the influence of the liver on immune responses might reflect two processes: (1) loss of antigen-specific T cells after primary antigen injection, and (2) hyporesponsiveness on reexposure to antigen. These mechanisms may contribute to the prevention of undesirable immune responses to foods and enteric bacteria in the gastrointestinal tract. Furthermore, these results underscore the importance of minimizing inflammation in circumstances such as islet transplantation, if endogenous mechanisms of tolerance induction are to be maximized