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Inhibition of lymphocyte activation and function by the prenylation inhibitor L-778,123

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Abstract

Prenylated Ras GTPases transduce signals from the T cell receptor, CD28 costimulatory receptor and IL-2 receptor. Since signals from these receptors mediate T cell activation, proliferation and survival, we hypothesized that the prenylation inhibitor L-778,123 would impart immunomodulation.

The effect of L-778,123 on T cell activation (CD71 or CD25 surface expression) was determined by flow cytometry. Peripheral blood mononuclear cell (PBMC) proliferation in the presence of L-778,123 and/or cyclosporine (CsA) was determined by [3H]thymidine incorporation. The ability of L-778,123 to inhibit IL-2 receptor signaling was investigated by measuring IL-2 induced proliferation in CTLL-2 cells and IL-2 prevention of apoptosis in activated human PBMC.

L-778,123 inhibited lectin induced expression of CD71 and CD25 with IC50's of 6.48 ± 1.31 μM and 84.1 ± 50.0 μM, respectively. PBMC proliferation was inhibited by L-778,123 with an IC50 of 0.92 ± 0.23 μM, and addition of CsA did not increase the potency. L-778,123 did not inhibit IL-2 and IFN-γ production by T cells. L-778,123 abrogated IL-2 induced proliferation of CTLL-2 cells with an IC50 of 0.81 ± 0.44 μM. However, L-778,123 minimally reversed the prosurvival effect of IL-2 in activated lymphocytes.

IL-2 ligand and receptor production during T cell activation are relatively unaffected by L-778,123. However, the activation and proliferative effects of IL-2 on T cells are potently blocked by L-778,123. These results reveal a selective blockade of the IL-2 cytokine axis distal to the IL-2 receptor by the L-778,123 and warrant evaluation of prenylation inhibitors in treating transplant rejection and autoimmune diseases.

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  1. Transplantation Immunology Laboratory, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, 95305-5407, USA

    Ming-Sing Si, Bruce A. Reitz & Dominic C. Borie

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Si, MS., Reitz, B.A. & Borie, D.C. Inhibition of lymphocyte activation and function by the prenylation inhibitor L-778,123. Invest New Drugs 23, 21–29 (2005). https://doi.org/10.1023/B:DRUG.0000047102.26698.08

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