Comparison of the effect of the aerobic glycolysis inhibitor dichloroacetate and of the Krebs cycle inhibitor LW6 on cellular and humoral alloimmunity.

Abstract

Cell metabolism is altered during T-cell and B-cell activation and differentiation. Clarifying the exact metabolic shifts may lead to the development of new immunosuppressive medications. In this study, the effect of the aerobic glycolysis inhibitor dichloroacetate (DCA) and of the Krebs cycle enzyme malate dehydrogenase 2 (MDH2) inhibitor LW6 on T-cell alloimmune clonal expansion and on alloantibody production, was evaluated. T-cell clonal expansion was assessed in two-way mixed lymphocyte reaction (MLR). Humoral alloimmunity was evaluated by the alloantibody production in one-way MLR. For this purpose, an antibody-mediated complement-dependent cytotoxicity assay was developed in which the supernatants from one-way MLRs were used against resting peripheral blood mononuclear cells (PBMCs) derived from the same individual that contributed the stimulator cells for the respective MLR. DCA had a minimum effect on alloimmune T-cell clonal expansion, whereas it increased humoral immunity significantly. LW6 decreased both alloimmune T-cell proliferation and alloantibody production. The results indicate that MDH2 may be a perfect target for the development of new immunosuppressive medications, especially when inhibition of both cellular and humoral alloimmunity is desirable.