Investigating the role of IL-12 in Lupus

While tremendous progress has been made, remaining gaps in understanding lupus are barriers to successful clinical trials. Although recent therapeutic developments like belimumab (Benlysta) and CD19-targeted chimeric antigen receptor (CAR) T cells show promise in reducing disease, they broadly target B cells (a central component of the immune system) rather than B cells that are typically harmful in lupus.

Plasmablasts are a type of B cell that strongly predict severe lupus disease and flares. In lupus, plasmablasts can be formed through extrafollicular responses, a rapid immune response where B cells quickly produce antibodies outside of germinal centers (specialized structures in lymphoid tissues critical for the body’s immune response). These extrafollicular responses are much larger and longer-lived in people with lupus. Dr. Elsner recently found that B cells can produce two cytokines (chemical messengers) called interleukin-12 (IL-12) and interferon gamma (IFNγ), creating a “snowball effect” that amplifies the extrafollicular response. Despite data showing the value of IL-12 as a treatment target in SLE, there has been limited clinical success. Dr. Elsner predicts that blocking IL-12 or IFNγ alone may not be sufficient in a highly inflammatory environment. Using both genetic and blocking approaches, Dr. Elsner will test whether dual blockade of both IL-12 and IFNγ is more effective in preventing harmful B cell differentiation (when immature cells develop into specialized cell types with distinct functions) and disease in a mouse model. She will assess its efficacy in reducing disease features like proteinuria (elevated levels of protein in the urine), skin disease, pro-inflammatory cytokines, and autoantibodies (antibodies that recognize the body’s own tissues, organs or cells). She will also study the role of these two molecules in B cells from healthy individuals and those with SLE to find future drug development candidates or potential biomarkers of IL-12/IFNγ-driven disease.

What this means for people with lupus:

Despite recent advances, 40-50% of patients fail to show reduced disease measures, meaning potentially 50% of people with SLE still need effective treatment options. Dr. Elsner’s study could reveal strategies to repurpose and combine currently existing therapeutics to improve treatments and clinical trial design.

Some immune responses produce only extrafollicular (EF) plasmablasts (PB) in the absence of germinal centers (GC). EF-dominant responses have been described in diverse mouse and human infections and are characteristic of Systemic Lupus Erythematosus (SLE) in some patients, and in the MRL/lpr and other mouse models of lupus. The mechanisms directing EF vs GC responses are largely unknown. Recently, we identified IL-12 as an upstream cytokine switch, directly promoting EF and suppressing GC responses by acting on both B and CD4+ T cells. IL-12 initiates a B cell intrinsic feed-forward loop between IL-12 and IFNg that amplifies their production from B cells. IL-12 and IFNg each has its own effect, but in combination they synergize to strongly promote B cell differentiation to PB. EF PB and EF derived memory B cells, termed DN2 cells, are elevated in the blood of SLE patients and correlate with severe disease and flares. We hypothesize that the SLE EF responses during flares and in severe disease are driven by high IL-12 activity and the synergistic feedforward effects of IL-12 and IFNg, termed “IL-12/IFNg synergy”. An IFN signature is associated with SLE, but type I (IFNa/b) and type II (IFNg) signatures overlap considerably. Type I IFN blockade reduced disease in only 50% of patients, suggesting that IL-12/IFNg may instead drive disease in some patients. Polymorphisms in IL-12 signaling proteins are among the highest associations with SLE. Disappointingly, clinical trials blocking the common subunit of IL-12 and IL-23 failed in phase III, however reduced serum IFNg correlated with responding patients. To better understand the role of IL-12 in lupus, we have generated a novel IL-12R KO MRL/lpr mouse that does not impact IL-23, and preliminary data has shown reduced kidney disease and a striking near-absence of skin disease. Additional preliminary data using mouse and human B cells indicates that both IL-12 and IFNg have individual effects, and combined effects. This proposal will explore the potential individual and combinatorial roles of IL-12 and IFNg in SLE. We will first assess whether combined targeting of IL-12 and IFNg is necessary and sufficient to prevent pathogenic B cell differentiation and disease in the MRL/lpr mouse model. We will then examine the individual and combinatorial effect of these cytokines on naïve and memory B cell populations from SLE patients in comparison to healthy controls, focusing on identifying new combination-specific signaling pathways and transcription factors that may drive pathogenic B cell differentiation. We will also knockdown genes identified from mouse and human studies to determine the roles of the proteins they encode in IL-12/IFNg induced B cell differentiation. Collectively, this proposal has the potential to suggest novel treatment strategies, and to identify novel targets in the longer term by investigating the mechanisms of IL-12/IFNg synergy.