LYMPHOCYTE SUPPRESSION BY KUPFFER CELLS PREVENTS PORTAL VENOUS TOLERANCE INDUCTION - A STUDY OF MACROPHAGE FUNCTION AFTER INTRAVENOUS GADOLINIUM

Ag administration into the portal vein can induce specific tolerance t o that Ag, known as portal venous tolerance. Because intrahepatic mech anisms of tolerance induction are still largely undefined, we studied the in vitro response of OVA-sensitized Lewis rat lymphocytes to OVA p resented by normal syngeneic rat Kupffer cells (KC) or KC that had bee n treated in vivo with gadolinium chloride (GD), a rare earth metal, w hich prevents the induction of portal venous tolerance. KC (2.5x10(4)) were able to present OVA to 5x10(5) OVA-sensitized APC-depleted lymph ocytes as effectively as could lymph node APC. However, the use of GD- treated KC was associated with a significantly (P<0.001) impaired resp onse of OVA-sensitized APC-depleted lymphocytes to OVA. Although GD ne arly abrogated in vivo phagocytosis of fluorescent latex beads by both KC and adherent splenocytes, expression of the class II MHC molecule (1a) by KC was only slightly reduced by GD treatment. Unresponsiveness of OVA-sensitized lymphocytes to OVA was not related to enhanced PGE2 release by GD-treated KC, as determined both by PGE2 levels in cultur e supernatants and by cyclooxygenase inhibition. However, the marked a bility of GD-treated KC to inhibit the response to OVA by primed lymph node populations containing lymphocytes and APCs supports an active s uppressive mechanism. Prevention of the induction of portal venous tol erance by GD, the lack of in vitro KC Ag presentation by GD-treated KC , and active immunosuppression by GD-treated KC support a model of tol erance induction within the liver wherein Ag presentation and lymphocy te proliferation are necessary for the development of tolerance.