Costimulatory blockade: A novel approach to the treatment of glomerular disease?

Abstract

Costimulatory pathways (Cluster of differentiation 28, tumor necrosis factor-related, adhesion and T Cell Ig- and mucin-domain molecules) regulating the interactions between receptors on the T cells and their ligands expressed on several cell types, have a key role in controlling many immunological and non immunological processes. Indeed, accumulating evidence indicate that these molecules are involved in the pathogenesis of numerous conditions, such as allograft rejection, atherosclerosis, rheumatoid arthritis, psoriasis and renal diseases, including glomerulonephritis. Primary or secondary (i.e., associated with infections, drugs or systemic diseases, such as systemic lupus erythematosus, diabetes, etc.) glomerulonephritis represent a group of heterogeneous diseases with different pathogenic mechanisms. Since costimulatory molecules, in particular CD80 and CD40, have been found to be expressed on podocytes in the course of different experimental and clinical glomerulonephritis, costimulation has been thought as a new therapeutic target for patients with glomerular diseases. However, although experimental data suggested that the blockade of costimulatory pathways is effective and safe in the prevention and treatment of glomerular diseases, clinical trials reported contrasting results. So, at this moment, there is not a strong evidence for the general use of costimulatory blockade as an alternative treatment strategy in patients with primary or secondary glomerulonephritis. Here, we critically discuss the current data and the main issues regarding the development of this innovative therapeutic approach.

Keywords: Costimulation, Glomerulonephritis, Cluster of differentiation 80, Cytotoxic T-lymphocyte-associated antigen-4, Lupus nephritis, Abatacept, Proteinuria, Podocytes

Core tip: Glomerulonephritis refer to a group of renal disorders, primary or secondary to infections, drugs or systemic diseases, characterized by inflammation within the glomerulus. Among glomerular diseases there is a great clinical, histological and prognostic heterogeneity and several different pathogenetic mechanisms have been implied. Current standard treatments include steroids and cytotoxic agents, which present important side effects and an unsatisfactory remission rate. Therefore, experimental and clinical research is addressed to the development of alternative therapies. Here, we critically discuss new therapeutic opportunities provided by the use of agents acting on the modulation of costimulatory pathways.