T Cell Targeted Therapies in Lupus: Do They Make Sense?

Abstract

Although systemic lupus erythematosus (SLE) is well-characterized as a B cell-driven, autoantibody mediated disease, recent studies focusing on innate immunity and on the interacting roles of other cell types, including T cells, have illuminated a wider scope of pathophysiology. The development of effective targeted therapies for SLE has been limited by the complex nature of these multiple interacting immune pathways. T cells in SLE display an activated phenotype with increased responses by effector subsets coupled to deficient regulatory responses. This singular SLE phenotype has been associated with specific intracellular signaling changes such as activation of the NFAT pathway and altered transcription of characteristic immune mediating proteins, including those related to IL6, IL23, and IL17 pathways. Some promising treatments developed to specifically regulate these pathways are currently in preclinical or early clinical development and a few have moved on to later phase trials. We propose that a specific currently identifiable subset of patients with SLE (those with altered TH17/Treg responses and/or elevated IL6 and/or BLyS signals) are likely the best candidates for treatment with appropriately targeted T cell modulating agents. Although this remains to be proven, our opinion is that advances in SLE treatment will only occur when there is a better understanding of pre-treatment biology both to optimize patient selection and to provide markers for improving dosing strategies. It may be that strategic combinations of targeted agents tailored to individual patterns of immune activation will provide the best approach to treatment in the future.