The past decade has seen a significant increase in the number of potentially tolerogenic therapies for treatment of new-onset diabetes. However, most treatments are antigen nonspecific, and the mechanism for the maintenance of long-term tolerance remains unclear. In a recent study reported and published in the Journal of Experimental Medicine by UCSF investigators Brian T. Fife, Ph.D. and Jeffrey A. Bluestone, Ph.D., an antigen-specific therapy has been developed using insulin-coupled antigen-presenting cells to treat diabetes in non-obese diabetic mice after disease onset.
Type 1 diabetes mellitus (T1DM) is an autoimmune disorder resulting from the T cell mediated destruction of the insulin producing cells within the pancreas. This research study focused on developing and understanding methods to induce antigen specific tolerance, to selectively target the T cells responsible for autoimmune diabetes without compromising the body’s ability to fight infectious agents. In this study, a powerful treatment protocol was created to target these cells. Using this type of approach allowed the researchers to “re-educate” the immune system to selectively silence destructive immune responses -- in effect, restore a state of self-tolerance and prevent further tissue destruction.
The discovery, from a mouse model of a human autoimmune condition, suggests that insulin is a major autoantigen during the progression of autoimmune diabetes and selectively targeting the insulin specific T cells is an effective strategy to treat autoimmune diabetes. The success of this treatment relies on a negative regulatory pathway for T cells. This pathway, Programmed Death-1 (PD-1), when engaged with PD-1 Ligand (PD-L1) inhibits T cell function, including the destruction of beta cells. Blocking this pathway reversed tolerance weeks after tolerogenic therapy by promoting antigen-specific T cell activity directly in infiltrated pancreas. PD-1/PD-L1 blockade did not limit T regulatory cell activity, suggesting direct effects on pathogenic T cells. Finally, we describe a critical role for PD-1/PD-L1 in another powerful immunotherapy model using anti-CD3, suggesting that PD-1/PD-L1 interactions form part of a common pathway to selectively maintain tolerance within the target tissues.
The research is supported in part by the National Institutes of Health and the Juvenile Diabetes Research Foundation.