A novel therapeutic approach for SLE
Our studies have found that some high-fiber diets can protect mice from type I diabetes and lupus, diseases that result when the immune system attacks patients’ own cells. When broken down by bacteria in the intestines, the food produces large amounts of fatty acids called butyrate and acetate that may reduce inflammation and induce other beneficial effects. We now plan to test whether diet is protective in lupus. We will feed mice that are prone to lupus different diets designed to increase the levels of butyrate, acetate, or other molecules that may reduce immune system attacks. However, the diets may not be enough. To give them a boost, we will also treat the animals with monoclonal antibodies that eliminate immune cells that cause tissue damage.
What this study means for people with lupus:
“We plan to test a novel combination approach to reverse lupus in mice. We will treat the animals with molecules that kill off harmful immune cells and feed them diets that may protect against the disease. If the approach works in mice, clinical trials could test it in people.”
Systemic lupus erythematosus (SLE, lupus) is an autoimmune disease where breakdown of immune tolerance leads to autoreactive B and T cells, as well as autoantibodies. The team leader, Prof Fabienne Mackay, was a pioneer in the one field that has seen the only successful new drug in the last 50 years – anti-BAFF/Blys mAbs. The long list of failed clinical trials in this heterogenous multisystem disease is why we propose a radical new approach, which has a sound scientific basis. In recent studies, we showed a striking reversal of autoimmunity in the non-obese diabetic (NOD) mouse, through administration of specialized, high fiber diets that release very high amounts of short chain fatty acids (SCFAs), particularly acetate and butyrate (Marino et al, Nat. Immunol. 2017). We showed that SCFAs completely protected NOD mice against diabetes through numerous mechanisms: expanding regulatory T cell numbers and regulatory function, improved gut homeostasis, reduced inflammatory cytokine production, increased expression of the homeostasis cytokine IL-22, reduced autoreactive CD4+ and CD8+ T cells, and improved microbiome composition (Marino et al, Nat. Immunol. 2017). This result has led us to propose that a diet/SCFA approach may be equally applicable to other autoimmune diseases including SLE. We have conducted preliminary studies in two separate mouse models of SLE, with pathology underpinned by different molecular mechanisms driving autoimmunity. Mice in these models were fed diets rich in fermentable fiber and were greatly protected from autoantibody-mediated glomerulonephritis, with levels of circulating autoantibodies vastly reduced. We now propose to explore different diets, including sophisticated High Amylose Maize Starch (HAMS) diets that were so effective in our Type 1 diabetes studies. However, treatment with diets, even those optimized for super production of SCFAs, may not be enough. Thus, we plan a completely new approach to SLE: deplete key pathogenic immune cells first (Th1, Th17, Tfh, B cells) (immune cell surgery), and then follow with diets/bacterial metabolites, as a strategy to correct autoimmunity in SLE and restore normal immunological tolerance. We believe this dual approach will be safe and particularly powerful, operating at many levels, to reverse pathogenic inflammation in SLE. In this proposal, we will combine numerous experimental SLE animal models, with CCR6 mAb (Th17, Tfh depleting) or CXCR3 mAb (Th1 depleting). We will explore the ideal diet in combination with these drugs to reverse and possibly even eliminate disease in SLE. We believe that these studies are highly innovative on many levels, and the assembled investigators are the perfect team, world-wide, to do these studies. If successful, human clinical trials could follow soon thereafter.