Title:Abatacept and Glomerular Diseases: The Open Road for the Second Signal as a New Target is Settled Down
Volume: 9
Issue: 1
Author(s): Hernan Trimarchi
Affiliation:
Keywords:
Abatacept, B7-1, CD28, CD80, CTLA-4, glomerulopathy, podocyte, proteinuria.
Abstract: Glomerulopathy is the third most important cause of kidney disease. Proteinuria is the
hallmark of glomerular damage, and a marker of progression of kidney disease, cardiovascular morbidity
and mortality. Strategies to reduce proteinuria are partially successful, and despite proteinuria
management, renal disease may still progress. Immunosuppression to treat glomerulopathies is nonspecific,
partially effective and presents side-effects. It is critical to find safe drugs with specific podocyte
molecular targets. Podocytes contain a complex array of proteins. Lymphocyte activation antigen
B7-1 (CD80) is located on antigen presenting cells modulating CD4+ and CD8+ T cells by interacting with co-stimulator
CD28, a glycoprotein located on T-cells, or with cytotoxic T-lymphocyte protein 4 (CTLA-4) co-inhibitor. Normally,
podocytes do not express B7-1. However, certain glomerulopathies are associated with an increase on the surface of
podocytes of B7-1, which reduces the ability of podocytes to attach to the surrounding glomerular basement membrane,
favouring podocyturia and proteinuria. When the B7-1-CTLA-4 interaction takes place, the immune response is abrogated,
while a B7-1-CD28 coupling leads to T cell activation. Abatacept binds to B7-1 by blocking the CD28 or potentiating
the CTLA-4 signals. In B7-1 positive podocytes, abatacept may be a specific tool to decrease proteinuria. Selected
patents are also briefly presented in this review.