The Impact of IL-9 on Disease in Murine Models of Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a relapsing-remitting antibody-mediated autoimmune disease characterized by systemic immune complex deposition. A subset of SLE patients has been shown to have elevated CD4+IL-9+ T cells as well as increased secreted IL-9 and Il9 mRNA compared to healthy controls. In other antibody mediated autoimmune models, such as rheumatoid arthritis, type II innate lymphoid cells (ILC2s) secrete increased IL-9 to promote the suppressive response of regulatory T (Treg) cells. As such, the role of IL-9 may be context-dependent and requires further investigation in SLE. This thesis examines standard and novel murine models of SLE to demonstrate that IL-9 exhibits both protective and proinflammatory functions, consistent with IL-9 activity varying with disease progression. Within our model, the use of an IL-9 neutralizing antibody (Ab) for 6 weeks in 6-week-old mice results in an exacerbation of disease and an expansion of immune cell subsets that promote autoimmunity. Anti-IL-9 Ab treatment also results in a loss of Treg cells and IL-9+ ILC2s in the kidney, which suggests that IL-9 promotes a protective response. From 6 to 12 weeks of treatment, the anti-IL-9 Ab treatment does not result in significant disease exacerbation compared to the isotype control. In parallel, we used a chimeric antigen receptor (CAR)-T cell approach, which is a promising treatment option for SLE patients, to test whether a third generation CAR-T cell can be polarized to a CAR-T9 cell and mitigate SLE disease severity. Our preliminary results indicate a reduction in CD19+ B cells and lymphoproliferation in the CAR-T9 cell treated SLE mice. Ultimately, our data suggests that IL-9 has a protective effect at early time points of disease, and this finding could be harnessed for cellular therapies of disease.