Acute Rheumatic Fever (ARF) is an autoimmune condition triggered by untreated or repeated group A streptococcal (GAS) infections. The development of antibodies and T cells that cross-react with cardiac myosin and other host tissue results in cardiac inflammation, leading to permanent valvular damage known as rheumatic heart disease (RHD). Although not completely understood, the development of ARF is mediated by several factors, including the dysregulation of interleukin (IL)-1β, differentiation of both T helper 1 and 17 cells, and IL-1β-stimulated granulocyte-macrophage colony-stimulating factor. Currently, no targeted therapies are available for the treatment of ARF/RHD. Therefore, this study evaluated the therapeutic efficacy of glyburide, a sulphonylurea with an off-target interaction with the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasomes, to target NLRP3 driven cytokine production, using the rat autoimmune valvulitis (RAV) model.
Lewis rats (n=5 per group) were injected with recombinant GAS M5 (rM5) protein, and control rats were injected with PBS. Treatment groups were injected with GAS rM5 and seven injections of glyburide (30mg/kg; s.c) commencing from either day 7 or day 22 of injection with rM5 (primary injection). All groups were euthanised on day 42 post primary injection, with blood, spleen and cardiac tissue collected.
Functional changes were evaluated by electrocardiogram, with no significant prolongation in P-R intervals observed following treatment with glyburide in contrast to those untreated rats. In conjunction with functional observations, cross-reactive antibody levels, T-cell responses and infiltration into cardiac tissue by inflammatory cells will help determine the efficacy of glyburide as an adjunct therapeutic agent.