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Int Immunopharmacol. 2003 Apr;3(4):475-83.

Farnesyltransferase inhibition: a novel method of immunomodulation.

Author information

1
Department of Surgery, UCI College of Medicine, University of California, Irvine, CA 92868, USA.

Abstract

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.

PMID:
12689653
DOI:
10.1016/S1567-5769(02)00278-3
[Indexed for MEDLINE]
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