Inhibition of Protein Geranylgeranylation Specifically Interferes with CD40-Dependent B Cell Activation, Resulting in a Reduced Capacity To Induce T Cell Immunity

摘要: Ab-independent effector functions of B cells, such as Ag presentation and cytokine production, have been shown to play an important role in a variety immune-mediated conditions autoimmune diseases, transplant rejection, graft-versus-host disease. Most current immunosuppressive treatments target T are relatively unspecific, result profound immunosuppression that places patients at increased risk developing severe infections cancer. Therapeutic strategies, which interfere with cell activation, could therefore be useful addition the armamentarium. Using transcriptomic approach, we identified upregulation genes belong mevalonate pathway key molecular event following CD40-mediated activation cells. Inhibition 3-hydroxy-3-methylglutaryl CoA reductase, rate-limiting enzyme pathway, by lipophilic statins simvastatin atorvastatin resulted specific inhibition via CD40 impaired their ability act stimulatory APCs for allospecific Mechanistically, inhibitory effect from protein geranylgeranylation subsequent depletion mevalonate, metabolic precursor geranylgeranyl. Thus, either directly through geranylgeranyl transferase inhibitors or indirectly represents promising therapeutic approach treatment diseases cells plays role.