Repurposed Small Molecule immunomodulators (RSMIs) as adjunct therapy for Rheumatic Fever and Rheumatic Heart Disease

Acute rheumatic fever (ARF) is a multi-organ autoimmune disorder triggered by streptococcal throat and/or skin infections. ARF can affect heart, joints, skin, connective tissues and brain. Irreversible damage to the heart leads to Rheumatic heart disease (RHD) which is uniquely a human disease. Animal models are useful tools to study anti-streptococcal antibody and T-cell mediated pathology. We have developed and characterised an animal model that reflects cardinal features observed in ARF/RHD patients.

The antibody and T-cell mediated cardiac damage was assessed in the Lewis Rat Autoimmune Valvulitis model (RAV) following injection of streptococcal M proteins. Rats injected with streptococcal proteins showed significant (p=0.001) prolongation in P-R interval in ECG compared to controls. We have also identified that a robust inflammatory response is required to initiate interferon γ/interleukin-17A induced myocarditis and valvulitis, which are hallmarks of ARF/RHD. Furthermore, passive transfer of hyper immune serum from rats injected with streptococcal M proteins induced cardiac damage in naïve rats, demonstrating the role of antibodies in inducing cardiac changes.

In this model, we have identified that upregulated interleukin (IL)-1β may promote Th1/Th17 cells following exposure to streptococcal M proteins and has been implicated in the autoimmune process. Therefore, small molecule inhibitors that target these molecules would potentially reduce the risk of progression of ARF to RHD. In this study, we aim to determine the efficacy of selected small molecules as adjunct therapy for ARF/RHD using RAV model.

Australian and New Zealand Society for Immunology
Awarded amount: A$2,937.00