Ruthenium red potently inhibits immune responses both in vitro and in vivo

Targeted drug screening revealed a compound, Ruthenium Red, which potently blocked proliferation of human T-cells. This compound is not generally cytotoxic or cytostatic, as judged by its lack of effect on the proliferation of a panel of transformed cell lines, but it exhibits true immunosuppressive properties. Ruthenium Red inhibits the T-cell proliferative response (with an Ic(50) similar to 100 nM) to a wide variety of agents, including viral antigens from herpes simplex virus, tetanus toroid, alloantigens and IL-2. This compound did not alter the growth of an M-CSF-dependent cell line (M-NFS-60) in response to added growth factor. Time course studies revealed that Ruthenium Red could be added as late as 24 h after the initiation of T-cell stimulation by antigen and still produce maximal inhibition, indicating that later stages of signaling events are being effected. Ruthenium Red was then tested for its ability to abrogate immune response in vivo. It was discovered that this compound dramatically reduced the expansion of lymphocytes in draining lymph nodes of mice immunized with cytochrome c in adjuvants. Furthermore, Ruthenium Red also suppressed specific antibody production in mice following challenge with this antigen. The functional properties of Ruthenium Red have been compared with other immunosuppressive agents and reveal that this compound is most similar to rapamycin in its overall profile. The chemical structure of Ruthenium Red is quite different from these other agents; therefore, it may be extremely useful in helping dissect the activation pathway of T-cells. It will be important to explore further the therapeutic potential of this unique compound.