Rheumatic fever is an autoimmune inflammatory reaction to Streptococcus pyogenes infections, leading to progressive heart valve damage and rheumatic heart disease (RHD). Current management of RHD requires monthly intramuscular penicillin injections for up to 10 years to prevent reinfections and disease progression. However, adherence to this regimen is poor.
Using a rat model of RHD that replicates post-streptococcal autoimmune complications, we demonstrate that a single course of subcutaneous injections of low-dose interleukin-2 (LD-IL-2) selectively expands regulatory T cells (Tregs) in the mediastinal lymph nodes, reducing cardiac inflammation and preventing heart dysfunction. Additionally, LD-IL-2 therapy decreases autoreactive antibodies in serum against cardiac, brain and connective tissues.
Supported by the Heart Foundation, we are currently investigating in the rat model whether adoptively transferred Tregs expanded by LD-IL-2 can prevent cardiac inflammation and dysfunction following exposure to Strep A antigens. In parallel, we are determining whether LD-IL-2 therapy can also modulate pro-inflammatory cytokines and germinal center activation. The efforts to uncover insights into immune regulation are reinforced by RNA sequencing of lymphoid organs. The results will be presented at LISSSD 2025.
Although LD-IL-2 therapy has been shown to be safe and efficacious in treating other human autoimmune disease, it has never before been considered for post-streptococcal autoimmune complications. We expect that LD-IL-2 therapy can be repurposed to treat active rheumatic fever and prevent RHD, eliminating the need for extended antibiotic prophylaxis by offering a one-time treatment alternative.