BAFF and its homolog APRIL are TNF-like cytokines that support the survival and differentiation of B cells. BAFF binds to three receptors, BAFF-R, TACI, and BCMA that are expressed on B cells at different developmental stages, whereas APRIL binds only to TACI and BCMA. Overexpression of BAFF causes a lupus-like illness in animal models and high levels of BAFF are found in several autoimmune diseases. Therefore the BAFF/APRIL family has been a target of extensive drug development over the last decade, culminating in the approval in 2011 of the anti-BAFF antibody belimumab for the treatment of lupus. Although much has been learned about this family of cytokines over the last decade, important questions remain about the mechanism of action of BAFF inhibition, the precise role of APRIL and the relative role of each of the three receptors, especially TACI. The experiments proposed here are designed to give us tools that will yield new insights into the basic biology of BAFF and APRIL and their receptors and thereby suggest ways in which therapeutic targeting of these cytokines may be most beneficial for patients. We will therefore generate two new models, an APRIL reporter mouse that allows us to visualize where APRIL protein is being made and a conditionally deficient TACI mouse that allows us to determine the role of TACI on specific cell types. These mice, together with tools we already have, will allow us to better define the microenvironments in which BAFF and APRIL are expressed during homeostasis and during immune activation, and to better understand the relative importance of TACI in regulating B cell responses.
The BAFF/APRIL cytokines and their three receptors are important mediators of immune function, especially the development and survival of B lymphocytes. Excess BAFF causes a lupus-like illness and a drug that targets BAFF is the first new biologic approved for the treatment of lupus in humans. Nevertheless, questions remain about the function of BAFF and APRIL and their receptors;these need to be answered in order to better target this cytokine family. The goal of this proposal is to generate two new models that will allow us to better define where each of the cytokines is made during normal resting conditions and during immune activation and to better understand the role of each of the receptors.