Farnesyltransferase inhibition: a novel method of immunomodulation.
Farnesyltransferase inhibitors (FTIs) are anticancer compounds that inhibit Ras GTPases. Since Ras GTPases play key roles in T cell activation and function, we hypothesized that FTIs have immunomodulatory properties and are potential antirejection agents. An investigation was performed on a potent FTI to evaluate this hypothesis in the in vitro setting. The in vitro effects of the FTI A-228839 were evaluated. Lectin- or antigen presenting cell (APC)-induced lymphocyte proliferation in the presence of A-228839 was measured. The effects of A-228839 on 1E5 T cell polarity were assessed by microscopy. Intracellular calcium ([Ca(2+)](i)) kinetics of lectin-activated lymphocytes was monitored by flow cytometry. The effects of A-228839 on peripheral blood mononuclear cell (PBMC) cytokine production was assessed by a cytometric bead array method. Activation-induced apoptosis was measured with an annexin V staining assay.A-228839 inhibited lectin-induced proliferation (IC(50)=0.24+/-0.11 microM). The inhibitory effects of A-228839 on lectin induced lymphocyte proliferation were additive to those of CsA. A-228839 was more effective in inhibiting APC-induced T cell proliferation (IC(50)=0.10+/-0.09 microM). A-228839 significantly disrupted the polarized shape of 1E5 T cells at physiologic concentrations. A-228839 altered PBMC baseline [Ca(2+)](i) but did not affect [Ca(2+)](i) kinetics during lectin-induced lymphocyte activation. A-228839 inhibited lymphocyte Th1 cytokine production at submicromolar levels and promoted apoptosis in lectin-activated lymphocytes.A-228839 potently inhibits lymphocyte activation and function. Our results suggest that FTIs may represent a new class of clinically useful immunomodulatory agents. A-228839 has potent in vitro immunomodulatory properties that warrant in vivo evaluation as an antirejection agent.
Si
Ming-Sing
MS
Department of Surgery, UCI College of Medicine, University of California, Irvine, CA 92868, USA.
Ji
Ping
P
Tromberg
Bruce J
BJ
Lee
Mike
M
Kwok
Jennifer
J
Ng
Shi-Chung
SC
Imagawa
David K
DK
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D066298:In Vitro Techniques; D037102:Lectins / Q000494:pharmacology; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology
D000276:Adjuvants, Immunologic; D004791:Enzyme Inhibitors; D037102:Lectins; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D002118:Calcium