Specific targeting of PI 3-kinase p110δ for the treatment of rheumatoid arthritis (P5177)

Abstract The p110δ isoform of PI3K is a therapeutic target for rheumatoid arthritis, but the cellular and molecular mechanisms by which PI3K mediates inflammation are poorly understood. Here we describe a novel highly selective p110δ small molecule inhibitor, G-286, that allowed dissecting the contribution specifically of p110δ to cellular pathways that are implicated in arthritis disease pathogenesis in human and mice. Using G-286, we demonstrate that p110δ regulates B cell- but not myeloid-cell dependent inflammatory arthritis in mice. G-286 blocks B cell receptor dependent proliferation and reduces autoantibody levels in collagen-induced arthritis abrogating disease. However, G-286 does not significantly inhibit FcγR-mediated inflammatory cytokine production in murine macrophages. Accordingly, selective p110δ inhibition did not significantly affect disease progression in FcγR- and myeloid cell-dependent autoantibody-induced arthritis. Importantly, we provide evidence that human and mice diverge in their relative dependency on p110δ to regulate FcγR responses. In addition to B cells and myeloid cells, T cells and osteoclasts contribute to rheumatoid arthritis pathogenesis. Utilizing G-286, we dissect the relative impact of p110δ inhibition on human and mouse T cell and osteoclast function. These results provide new insight in the role of p110δ in arthritis disease processes and offer a compelling rationale for targeting p110δ for the treatment of human rheumatoid arthritis.