In vitro immunomodulatory activity of ruthenium complexes.
OBJECTIVE
We have explored the in vitro immunomodulatory effects of pure ruthenium red and a series of pyridine and imidazole substituted ruthenium complexes (RCs).


METHODS
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
Newcomb
J R
JR
Amgen Inc, One Kendall Square, Cambridge, MA 02139, USA. jnewcomb@amgen.com.
Rivnay
B
B
Bastos
C M
CM
Ocain
T D
TD
Gordon
K
K
Gregory
P
P
Turci
S M
SM
Sterne
K A
KA
Jesson
M
M
Krieger
J
J
Jenson
J C
JC
Jones
B
B
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis; D004285:Dogs; D005455:Fluorescent Antibody Technique; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D007111:Immunity, Cellular / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000096:biosynthesis; D007959:Lymphocyte Culture Test, Mixed; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D017975:Ruthenium Compounds / Q000494:pharmacology*; D012430:Ruthenium Red / Q000494:pharmacology; D016196:S Phase / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D018089:Superantigens / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013745:Tetanus Toxoid / Q000494:pharmacology
D007093:Imidazoles; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011725:Pyridines; D015375:Receptors, Interleukin-2; D017975:Ruthenium Compounds; D018089:Superantigens; D013745:Tetanus Toxoid; D012430:Ruthenium Red; D016572:Cyclosporine; D004247:DNA; D020123:Sirolimus