FK 506 and the purine biosynthesis inhibitors mizoribine or mycophenolic acid on lymphocyte DNA synthesis and T cell activation molecule expression in human mixed lymphocyte cultures

Abstnct: Our objective was to obtain new information on the in vitro antilymphocytic action of the cytokine synthesis inhibitor FK 506 and the punne biosynthesis inhibitors mycophcnolic acid (MPA; the active mOlctv of RS6l443) and mizoribine (MZB) when used alone or in combination. When added at the initiation of six·day human mixed lymphocyte cultures (MLC). FK 506. MPA or MZB exhibited dose·dependent inhibition 01 T·lymphocvtc DNA synthesis. FK 506. however. was «Xl· fold more potent than MPA. and ((}IXlO·fold more potent than MZB. Combination of FK 506 with either MPA or MZB. each at suboptlonal concentrations. produced no more than additive inhibitory effects on 'H thvmldine Incorporation. Two-colour !low cytometnc analvsls 01 Iymphocvtes revealed that none of the drugs affected cell surface activatIOn molecule expressIOn (CD25 = IL·2R 55 kD lJ·chain. HLA·DR or CD71 = transferrin receptor ITRJ) on allosllmulated CD4' or CD!!' cells harvested at three days 01 culture. Bv day SIX. however. all three agents. at levels which markedly inhibited proliferation. suppressed the expression of activation markers on both CD4' and CD!!' cells. Also at day six. Inhibition 01 activation molecule expression on CD4' cells was achieved with the combination of FK 506 and either MPA or MZB at concentrations which. on their own. were ineffective. These data provide new. additional informallon on the in vitro antilymphocytic action of FK 506. MPA and MZB when used alone and in combinallon.