Ingenol-3-Angelate Enhances the B Cell Inhibitory Potential of Mesenchymal Stem Cells, Leading to Marked Alleviation of Lupus Symptoms in MRL.Mice.

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by autoantibody production by hyper-activated B cells. Although mesenchymal stem cells (MSCs) relieve lupus symptoms by inhibiting mainly T cells, whether MSCs also inhibit B cells has been controversial. Here, we found that naïve MSCs inhibited IFN-γ production by T cells, but not IgM production by B cells. We used a chemical approach to prime MSCs to inhibit B cells. We found that ingenol-3-angelate (I3A), a non-tumor-promoting phorbol ester, activated MSCs to inhibit B cells in a TGF-β1-dependent manner. We also showed that IL-1β induced MSCs to continuously secrete TGF-β1, which directly inhibited IgM production by B cells, whereas IL-1β did not. I3A-treated MSCs were better than naïve MSCs at ameliorating SLE symptoms in MRL.mice. In summary, our data provide information on how to generate MSCs that are effective for the treatment of SLE characterized by excessive B cell activation.