Dual blockade of the pro-inflammatory chemokine CCL2 and the homeostatic chemokine CXCL12 is as effective as high dose cyclophosphamide in murine proliferative lupus nephritis

Abstract

Induction therapy of proliferative lupus nephritis still requires the use of unselective immunosuppressive drugs with significant toxicities. In search of more specific drugs with equal efficacy but fewer side effects we considered blocking pro-inflammatory chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) and homeostatic chemokine stromal cell-derived factor-1 (SDF-1/CXCL12), which both contribute to the onset and progression of proliferative lupus nephritis yet through different mechanisms. We hypothesized that dual antagonism could be as potent on lupus nephritis as the unselective immunosuppressant cyclophosphamide (CYC). We estimated serum levels of CCL2 and CXCL12 in patients with SLE (n=99) and compared the results with healthy individuals (n=21). In order to prove our hypothesis we used l-enantiomeric RNA Spiegelmer® chemokine antagonists, i.e. the CCL2-specific mNOX-E36 and the CXCL12-specific NOX-A12 to treat female MRL/lpr mice from week 12 to 20 of age with either anti-CXCL12 or anti-CCL2 alone or both. SLE patients showed elevated serum levels of CCL2 but not of CXCL12. Female MRL/lpr mice treated with dual blockade showed significantly more effective than either monotherapy in preventing proteinuria, immune complex glomerulonephritis, and renal excretory failure and the results are at par with CYC treatment. Dual blockade reduced leukocyte counts and renal IL-6, IL-12p40, CCL-5, CCL-2 and CCR-2 mRNA expression. Dual blockade of CCL2 and CXCL12 can be as potent as CYC to suppress the progression of proliferative lupus nephritis probably because the respective chemokine targets mediate different disease pathomechanisms, i.e. systemic autoimmunity and peripheral tissue inflammation.