Dual inhibition of phosphoinositide 3-kinases delta and gamma reduces chronic B cell activation and autoantibody production in a mouse model of lupus

Phosphoinositide 3-kinase delta (PI3K delta) plays key roles in normal B cell activation and is chronically activated in malignant B cells. Targeting of PI3K delta using FDA-approved drugs Idelalisib or Umbralisib has shown efficacy in treatment of multiple B cell malignancies. Duvelisib, an inhibitor targeting both PI3K delta and PI3K gamma (PI3K delta gamma i) has also been used for treatment of several leukemias and lymphomas and was suggested to offer potential additional benefits in supressing T cell and inflammatory responses. Transcriptomics analyses indicated that while most B cell subsets predominantly express PI3K delta, plasma cells upregulate PI3K gamma. We thus assessed whether PI3K delta gamma i treatment can impact chronic B cell activation in the context of an autoantibody-mediated disease. Using the TAPP1(R218L)xTAPP2(R211L) (TAPP KI) mouse model of lupus-like disease driven by dysregulated PI3K pathway activity, we performed 4 week PI3K delta gamma i treatments and found significant reduction in CD86+ B cells, germinal center B cells, follicular helper T cells and plasma cells in multiple tissues. This treatment also significantly attenuated the abnormally elevated serum levels of IgG isotypes observed in this model. The profile of autoantibodies generated was markedly altered by PI3K delta gamma i treatment, with significant reductions in IgM and IgG targeting nuclear antigens, matrix proteins and other autoantigens. Kidney pathology was also impacted, with reduced IgG deposition and glomerulonephritis. These results indicate that dual inhibition of PI3K delta and PI3K gamma can target autoreactive B cells and may have therapeutic benefits in autoantibody-mediated disease.