Targeting immunometabolism and co-stimulation in combination therapies in lupus
The goal of this project is to use the NZB/WF1 mouse model of lupus to test the hypothesis that metabolic inhibitors will synergize with existing biologics to significantly improve therapeutic outcomes. Cellular metabolic programs control the effector phase of the immune system. Metabolic checkpoints have been best described for T cells and macrophages, and targeting T cell metabolism has been proposed as a novel approach to manipulate the immune response toward therapeutic outcomes in immune mediated diseases, including lupus. We have shown that two metabolic inhibitors normalized the functions of human and murine lupus CD4+ T cells, and that treatment with the combination of these two drugs reversed autoimmune pathology in multiple mouse models of the disease. This and other of our findings suggest that metabolic inhibitors can safely improve clinical outcomes in lupus. Given the complexity of lupus etiology and presentation, as well as the mixed results obtained with biologics in clinical trials, we propose that the best use of metabolic inhibitors may be in combination with other treatments. We will test the effect of metabolic inhibitors in combination with three biologics that have each shown a modest effect in human lupus: CTLA4-Ig (abatacept), anti-BAFF (belimumab), and anti-CD40L (dapirolizumab), that respectively target CD4+ T cells, B cells, or B:T cell interactions. We propose three specific aims to achieve this goal: 1) To characterize the metabolic effects of CTLA4-Ig, BAFF-R Ig and anti-CD40L on CD4+ T and B cell metabolism in NZB/WF1 mice. We will use a combination of metabolic assays, flow cytometry and gene expression measurements to determine the metabolic signature of CD4+ T and B cells, and as well as the follicular helper (Tfh) and germinal center (GC) B cell subsets, to determine which metabolic inhibitor would best target a complementary pathway to synergize with each biologic for maximal clinical effect. 2) To test combinations of metabolic inhibitors with biologics to prevent disease progression in NZB/WF1 mice. Based on the results obtained in aim 1, we will compare the efficacy of monotherapy with each biologic or a single candidate metabolic inhibitor to the combined treatments with both. We will treat anti-dsDNA IgG+ mice and assess treatment efficacy on renal disease as well as cellular and serological phenotypes. 3) To test combinations of metabolic inhibitors with biologics to reverse disease in NZB/WF1 mice. Combined therapies identified in Aim 2 will be tested in mice with early clinical signs of nephritis with the same general approach as in Aim 2.