DALLAS, Texas—Kidney damage associated with systemic lupus erythematosus is linked to a malfunction of immune cells that causes them to congregate in and attack the organs, with warring genes acting to either heighten or protect against the autoimmune attack. Two studies that explain separate bits of this process have been reported by research teams led by Edward Wakeland, MD, chairman of immunology, and Chandra Mohan, MD, professor of internal medicine at the University of Texas Southwestern Medical Center in Dallas.1,2


“This study indicates that drugs acting against CXCR4 might become useful therapies.”—Chandra Mohan, MD
“Collectively, these studies indicate that lupus nephritis is polygenic and multi-factorial in origin, with 2 of the players being kallikrein and CXCR4/CXCL12. Whether either of these might turn out to be a good therapeutic target in lupus nephritis remains to be established,” Dr. Mohan told MSKreport.com

CXCR4 is over-expressed in lupus

The first study, reported in The Journal of Immunology, examined the role of the G-protein-coupled receptor CXCR4, which is upregulated on monocytes, neutrophils, B cell subsets, and plasma cells in mouse models of lupus with active nephritis. The researchers found that kidney damage was associated with higher levels of the ligand for CXCR4, CXCL12, and that blocking CXCR4 prolonged survival in lupus mice. Blocking CXCR4 also reduced serum autoantibodies, splenomegaly, intrarenal leukocyte trafficking, and end organ damage in the mouse model.

“In screening several different molecules, we observed that one molecule that was hyper-expressed on leukocytes from mice with spontaneously developing lupus is a molecule called CXCR4,” Dr. Mohan said. “This is a molecule that allows cells to target sites expressing the complementary molecule (or ligand) called CXCL12. Interestingly, we found that mice with lupus nephritis had increased expression of CXCL12 in their kidneys. In fact, the degree of lupus nephritis could be significantly reduced by administering to these mice a drug that inhibits CXCR4:CXCL12 interaction. Collectively, these findings demonstrate that this molecular axis plays a critical role in mediating the renal disease in lupus, and that it is an attractive therapeutic target. This study indicates that drugs acting against CXCR4 might become useful therapies.”

The compound used to block CXCR4 in this study, CTCE-9908, was made by Chemokine Therapeutics, which subsequently filed for chapter 11 bankruptcy filing.

Can kallikreins protect kidneys from lupus nephritis?

The second study, reported in The Journal of Clinical Investigation, showed that kallikrein genes help protect the kidneys from autoimmune damage in both mice and humans.

For this mouse study, the researchers administered antibodies that attack the glomerular basement membrane. They then looked for genes that turned on or off in response to the antibody assault.

They found that in normal mice given the anti-kidney antibodies, 9 forms of the kallikrein, or klk, gene became more active, resulting in a two- to six-fold increase in kallikreins, and that this did not happen in the lupus-prone mice. Blocking kallikreins worsened lupus symptoms.

The researchers also studied 340 German patients with systemic lupus, matched with 400 healthy control subjects. The patients with lupus and kidney damage had klk genes that were different from those in the healthy patients. Similar findings were noted in a larger, more varied group of patients from Europe, the United States, and Korea.

Genes and lupus nephritis: Translating research into practice

The researchers now have to determine if the CXCR4/CXCL12 axis is also upregulated in human SLE. If so, this axis might be therapeutically targeted in humans as well as in mice.

They will also look more closely at the kallikrein gene in humans.

“All humans have klk genes, but our findings show that some of us have a particular version that increases our risk for systemic lupus,” Dr. Wakeland said.

These findings have clinical potential for diagnosis and monitoring of lupus nephritis (based on kallikrein gene polymorphisms or urinary kallikrein levels) and for therapy (by raising kallikrein levels locally in the kidneys).

References
1. Wang A, Fairhurst A-M, Tus K, et al. CXCR4/CXCL12 hyperexpression plays a pivotal role in the pathogenesis of lupus. J Immunol. 2009;182:4448-4458.
2. Liu K, Li Q-Z, Delgado-Vega AM, et al. Kallikrein genes are associated with lupus and glomerular basement membrane-specific antibody-induced nephritis in mice and humans. J Clin Invest. 2009; doi:10.1172/JCI36728.