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In vitro immunomodulatory activity of ruthenium complexes
J R Newcomb1, B Rivnay, C M Bastos
1Amgen Inc, One Kendall Square, Cambridge, MA 02139, USA. jnewcomb@amgen.com.
Insights
Ruthenium complexes (RCs) effectively inhibit T cell receptor-mediated stimulation and proliferation in human lymphocytes. These novel compounds offer new avenues for investigating T cell signaling and immunosuppression.
Area of Science:
- Immunology
- Medicinal Chemistry
- Cell Biology
Background:
- The immunomodulatory potential of ruthenium complexes (RCs) remains underexplored.
- Understanding novel immunosuppressive agents is crucial for treating autoimmune diseases and managing organ transplantation.
Purpose of the Study:
- To investigate the in vitro immunomodulatory effects of pure ruthenium red and novel RCs.
- To assess the impact of RCs on T cell receptor (TCR)-mediated stimulation and immune cell function.
Main Methods:
- Human peripheral blood lymphocytes (hPBL) and T cells were treated with RCs.
- Assays included immune function, cytotoxicity, cell cycle progression, and IL-2 secretion.
- TCR-mediated stimulation by various agents was evaluated.
Main Results:
- RCs potently inhibited TCR-mediated stimulation of hPBL (low nM IC50) without cytotoxicity.
- RCs demonstrated antiproliferative activity against B cells and some non-lymphoid cell lines at higher concentrations.
- Inhibition occurred at the level of T cell proliferation, IL-2 secretion, CD25 upregulation, and cell cycle progression (G0/G1 to S phase).
Conclusions:
- RCs exhibit potent immunomodulatory effects, primarily through inhibition of T cell activation and proliferation.
- The distinct mechanism of action from rapamycin and cyclosporin A suggests RCs as valuable tools for T cell signaling research.
- RCs may offer novel therapeutic opportunities for immunosuppression.
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
