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Abstract

An HDAC6 inhibitor (a compound of Formula I) is shown to reduce the pathogenesis associated with the B cell mediated autoimmune disease, systemic lupus erythematosus (SLE) Administration of a compound of Formula I attenuated many of the symptoms characteristic of SLE including splenomegaly, abnormal B cell differentiation, an increase in the number double-negative thymic T cells, an increase in the level of auto-antibodies such as anti-dsDNA, immune complex-mediated glomerulonephritis and an increase in inflammatory cytokine production. Treatment with a compound of Formula I also increased the number of the subject's splenic Treg cells while removing circulating auto-antibodies Inhibition of HDAC6 altered bone marrow B cell differentiation by increasing the percentage of cells in the early-stage developmental fractions of both pro- and pre-B cells. These results demonstrate HDAC6 inhibition with a compound of Formula I can treat SLE disease by altering aberrant T and B cell differentiation.

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First Claim