In vitro immunomodulatory activity of ruthenium complexes

OBJECTIVE AND DESIGN: We have explored the in vitro immunomodulatory effects of pure ruthenium red and a series of pyridine and imidazole substituted ruthenium complexes (RCs). MATERIAL: Human peripheral blood lymphocytes and purified T cells were used in these studies along with various cell lines. METHODS: Cells were treated with dilutions of RCs and assessed in various assays of immune function, cytotoxicity and cell cycle progression. RESULTS: RCs efficiently blocked T cell receptor (TCR)-mediated stimulation (IC(50)'s in the low nM range) of human peripheral blood lymphocytes (hPBL) by various agents, including tetanus toxoid, alloantigens, superantigens, and receptor-specific antibodies. RCs are not cytotoxic to T cells. Antiproliferative activity was also observed for B cells. Some non-lymphoid cell lines or primary cultures showed sensitivity to the RCs, but only at higher concentrations. The inhibitory effect on human T cells was assessed and demonstrated at the level of proliferation (DNA synthesis), IL-2 secretion, and IL-2 receptor (CD25) upregulation. RCs also inhibited IL-2-mediated proliferation of antigen-induced T-cell blasts and the IL-2-dependent T cell line Kit-225. Cell cycle analysis indicates that RCs inhibit the progression of activated T cells from G(0)/G(1) to S phase. CONCLUSIONS: Since the mechanism of T cell inhibition by RCs appears to be different than that of rapamycin (RAP) or cyclosporin A (CsA), they may provide a new tool to investigate intracellular signaling in T cells, and may present novel opportunities for immunosuppression