科研之友
微信
新浪微博
Facebook
分享链接
摘要
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 immumomodulatory 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 ([Ca2+](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 (IC50 = 0.24 +/- 0.11 muM). 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 (IC50 = 0.10 +/- 0.09 muM). A-228839 significantly disrupted the polarized shape of 1E5 T cells at physiologic concentrations. A-228839 altered PBMC baseline [Ca2+](i) but did not affect [Ca2+](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.
- 出版日期2003-4
