Low-Dose Interleukin-2 Therapy: A Transformative Approach for the Management of Autoimmune Complications Associated with Streptococcus pyogenes Infections ^†

Acute 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 has poor adherence and requires monthly intramuscular penicillin injections for up to 10 years to prevent reinfections and disease progression. Since an imbalance between regulatory and effector CD4⁺ T-cells has been implicated in driving RHD pathogenesis, this may represent a target for therapeutic interventions.

Using a rat model that mimics post-streptococcal autoimmune complications, we investigated whether low-dose interleukin-2 (LD-IL-2) therapy could reestablish immune homeostasis and treat rheumatic fever. Our methodology combined electrocardiography, the histopathological assessment of cardiac tissue, T-cell adoptive transfer, serum antibody profiling, flow cytometry, and transcriptomics of lymphoid organs.

We show that a single course of subcutaneous LD-IL-2 therapy reduced carditis and cardiac dysfunction following injections with S. pyogenes recombinant M5 (rM5) protein. This effect was associated with decreased serum autoantibodies against cardiac tissue and the normalization of germinal center activity in the spleen. LD-IL-2 therapy also restored the balance between regulatory and effector CD4⁺ T-cell responses to physiological levels. Notably, the adoptive transfer of splenic CD4⁺ T-cells from LD-IL-2–treated rats conferred protection against cardiac dysfunction in recipient rM5-injected rats.

Although LD-IL-2 therapy has been shown to be safe and efficacious in multiple human autoimmune diseases, it has never been considered for post-streptococcal disorders. We expect that LD-IL-2 therapy can be repurposed to treat active acute rheumatic fever and prevent RHD, eliminating the need for extended antibiotic prophylaxis by possibly offering a one-time treatment alternative.