Lanthanide "blockade" of antigen-presenting cells suppresses lymphocyte proliferation by inducing nitric oxide synthesis.
Introduction of antigen into the portal venous circulation can induce a state of antigen-specific tolerance. Reversal of this phenomenon by the administration of gadolinium chloride (GD) before portal venous inoculation with antigen has been thought to result from the inhibition of macrophage phagocytosis by GD, thereby permitting passage of antigen through the hepatic sinusoids into the systemic circulation where sensitization can occur. We recently demonstrated that i.v. GD also greatly enhances the ability of the hepatic macrophage, or Kupffer cell (KC), to suppress lymphocyte proliferation in vitro. In this study, lymphocytes from ovalbumin (OVA)-immunized Lewis rats were cocultured with OVA plus KC or adherent splenocytes from syngeneic rats injected i.v. with GD or saline. Whereas small numbers of either hepatic or splenic untreated macrophages enhanced lymphocyte proliferation, both macrophage populations treated with GD were markedly inhibitory. Neither the presence of lymph node macrophages nor of normal KC was able to prevent the effect of GD-treated KC indicating a mechanism of active suppression rather than defective macrophage antigen uptake, processing, and presentation. While cyclooxygenase inhibition had no effect, the addition of inhibitors of nitric oxide synthase, i.e., aminoguanidine and NG-methyl-L-arginine, fully reversed the suppression of proliferation by GD-treated macrophages. Nitrite, but not PGE2, levels correlated with the degree of inhibition by the GD-treated macrophages. The suppression of lymphocyte proliferation and elevated supernatant nitrite levels associated with the presence of GD-treated macrophages were reversed when the macrophages were preincubated with EDTA indicating that GD's effect was directly on macrophages and due to its persistence in cultured cells. The findings of this study suggest that GD's in vivo prevention of portal venous tolerance may be due to enhanced nitric oxide synthesis whose effect on lymphocytes could be to inhibit adhesion or replication in the hepatic sinusoid.
Roland
C R
CR
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110.
Mangino
M J
MJ
Flye
M W
MW
D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects*; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D015232:Dinoprostone / Q000096:biosynthesis; D004492:Edetic Acid / Q000494:pharmacology; D005682:Gadolinium / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D019323:omega-N-Methylarginine
D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D004492:Edetic Acid; D005682:Gadolinium; D015232:Dinoprostone; C038958:gadolinium chloride