Researchers have discovered a new method of immune intervention for the treatment of autoimmune disease. This novel immunotherapy induces the long-term inactivation of self-reactive CD4+T cells through the use of novel prodrugs based on the G1 blocker butyric acid. Studies have shown 1) when pretreated with n-butyrate and antigen, but not n-butyrate alone, murine CD4+T cells of the T helper type 1 (Th1) become unresponsive to a subsequent stimulation with antigen even though n-butyrate has been removed from the cultures; and, 2) when administered briefly in vivo during immune responses, a member of the butyrate/tributyrin family of drugs converts activated antigen- specific T cells to an unresponsive state, but has no effect on the majority of T cells that are resting. In order to improve the in vivo efficacy of the buyrate family of drugs, researchers have synthesized three ester and amide derivatives of butyric acid, which has increased activity in vivo. These compounds will serve as prototypical prodrugs for a series of analogues that are being prepared as part of a structure- active relationship study aimed at developing an in vivo delivery system. Because of their ability to block and anergize all antigen-activated T cells, it is expected that the butyrate prodrugs will be able to induce unresponsiveness in the autoreactive T cells that are mediating an ongoing autoimmune response.

99-03 (E 19)

Patent Status: ISSUED U.S. Patent #6,407,107

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