BAFF et al.: novel members of the TNF ligand and receptor families as therapeutic targets

Abstract

Tumour necrosis factor (TNF) family ligands and their corresponding receptors play important roles in the immune system, where they regulate lymphoid organ development and influence immune cell proliferation, differentiation, activation and death. Several TNF family members, including TNF-α and CD154, have already provided valuable therapeutic targets for the treatment of immune-mediated diseases. Over the past three years, a new subfamily of TNF-related ligands/receptors, which also plays a role in immunity, has been discovered by sequence-homology database searches. This subfamily, which appears to be particularly important in B cell immunity, includes two ligands termed B cell activating factor of the TNF family (BAFF) and a proliferation-inducing ligand (APRIL) and at least three receptors: B cell maturation protein (BCMA) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), which bind both ligands, and BAFF receptor (BAFF-R), which binds only BAFF. Besides promoting the survival of B cells and regulating their proliferation and differentiation in collaboration with signals from the B cell antigen receptor, BAFF and APRIL may modulate T cell activation and APRIL may also act as an autocrine growth factor for certain tumour cells. There is evidence that overproduction of BAFF in mice results in a B cell-mediated autoimmune syndrome resembling systemic lupus erythematosus (SLE), and that elevated levels of this cytokine are associated with SLE and rheumatoid arthritis in humans. The discovery of this novel ligand/receptor network has provided novel insights into the mechanisms of immunoregulation. Most importantly, it offers the opportunity for developing novel treatment strategies for autoimmune diseases, immunodeficiencies, lymphoma and cancer. The prospect of exploiting this new information for therapeutic purposes has generated a flurry of recent patent applications that are discussed here.