Immunomodulatory Effects of Isoprenylation Inhibitors

Stanford University, Stanford CA

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Abstract

The Ras superfamily of small GTPases play important signal transduction roles in T cell activation, anergy, apoptosis and effector function. In a post translational process called isoprenylation, small GTPases are modified with lipid moieties in order to allow these proteins to insert in the cell membrane where they become activated and activate their effector proteins. Isoprenylation inhibitors disrupt small-GTPase function by inhibiting the post-translational addition of farnesyl or geranylgeranyl groups. Because they inhibit small-GTPase functions, it is hypothesized that isoprenylation inhibitors have immunosuppressive and tolerogenic properties that may prevent allograft rejection and promote long term graft acceptance in a rat heart transplant model. The specific aims of this project are. 1. To determine if isoprenylation inhibitors abrogate T cell activation and function in vitro. 2. To determine the effects of isoprenylation inhibitors on the T cell: APC immunologic synapse formation. 3. To determine if isoprenylation inhibitors abrogate Ras, Rac and/or Rho isoprenylation. 4. To determine if isoprenylation inhibitors promote activation induced apoptosis in T cells. 5. To determine the ability and efficacy of isoprenylation inhibitors to prevent acute allograft rejection and to promote tolerance in a rat heart transplant model.