ARGININE-SPECIFIC SUPPRESSION OF MIXED LYMPHOCYTE CULTURE REACTIVITY BY KUPFFER CELLS—A BASIS OF PORTAL VENOUS TOLERANCE

Abstract

Portal venous administration of alloantigen abrogates the DTH response and prolongs heart and kidney allograft survival. Within the hepatic microenvironment, negligible L-arginine levels result from the effects of the highest tissue arginase activity of any organ (25 times greater than kidney). This study evaluated the effects of arginine availability on Kupffer cell immune function in the rat mixed lymphocyte culture. When 5 x 10(5) Wistar-Furth unfractionated lymph node cells (LNC) were cultured with 5 x 10(5) irradiated Lewis LNC in standard RPMI-1640 medium containing 1200 microM L-arginine, the proliferative response was not effected by the addition of 1 x 10(5) WF KC. However, when L-arginine-depleted medium (6 microM) was used, the MLC response was markedly reduced by the addition of KC. This was specific to arginine since media depletion of L-lysine, a similar basic amino acid, did not affect MLC/KC responses. When syngeneic WF KC were added as antigen-presenting cells to fractionated stimulator and responder T lymphocytes, WF/LEW MLC proliferation was restored in standard and L-lysine-depleted media, but did not increase in L-arginine-depleted RPMI 1640 medium. These responses correlated with a fivefold increase in KC prostaglandin-E2 (PGE2) production in the L-arginine-depleted medium. These findings support the hypothesis that diminished immune responsiveness in the low-arginine hepatic environment is effected, at least in part, by locally increased production of the immunosuppressant prostaglandin-E2.