Low dose IL-2 administration prevents but fails to treat experimental autoimmune anti-myeloperoxidase glomerulonephritis

Background and Hypothesis Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is a major cause of glomerulonephritis (GN) and kidney failure and current therapies are often limited by significant toxicity and limitations. Regulatory T cells (Tregs) play a cruical role in maintaining immune tolerance, and their dysfunction has been implicated in AAV pathogenesis. Low dose interleukin-2 (IL-2) has emerged as a promising strategy to selectively expand Tregs and restore immune balance in several autoimmune diseases. However, low dose IL-2′s therapeutic potential in AAV remains unclear, warranting further investigation into its immunoregulatory effects in experimental AAV models. Methods We tested the therapeutic efficacy of low dose IL-2 therapy (25 000 international units/day)in an experimental murine model of AAV, specifically anti-myeloperoxidase (MPO) GN, using C57BL/6 J mice. Both passive and active models of anti-MPO GN were used to assess IL-2′s effects across different disease settings. Results In GN induced by passive transfer of anti-MPO antibodies, low dose IL-2 increased intrarenal Treg numbers, limited macrophage recruitment and reduced macrophage pro-inflammatory phenotype in kidneys, demonstrating anti-inflammatory effects on innate immunity. However, these immunological changes did not translate into improvement in kidney injury. In T cell mediated active anti-MPO GN induced by MPO immunization and triggered by anti-glomerular basement membrane globulin, preventative IL-2 therapy increased splenic Tregs, attenuated anti-MPO specific Th1/Th17 responses and limited structural and functional kidney injury. In established autoimmunity, mice treated with low dose IL-2 from 12 days after MPO immunization also developed expanded splenic Tregs. However, effector T cell responses were also enhanced and glomerular injury was increased. To more specifically target Tregs and minimize low dose IL-2′s potential to promote effector leukocytes, we administered IL-2 conjugated to an anti-IL-2 monoclonal antibody (IL-2/anti-IL-2 immune complex). Although IL-2/anti-IL-2 treatmentincreased Treg frequency in mice with established anti-MPO autoimmunity, it also paradoxically amplilfied anti-MPO T cell effector responses and worsened glomerulonephritis. Conclusion In experimental anti-MPO GN, low dose IL-2 therapy has context specific effects on cellular and humoral immunity, and the potential for it to promote T effector responses in established autoimmunity may limit its utility in this condition.