T1D is a consequence of an autoimmune reaction driven primarily by immune cells called T effector cells or Teff cells attacking insulin producing beta cells of the pancreas. A person’s own proteins (called auto-antigens) may be used to educate and steer an autoimmune reaction away from reacting to and destroying cells that express these self-proteins. A self-protein called GAD65 is one of the main auto-antigens to which individuals with T1D mount a destructive immune response, and autoantibodies directed against GAD65 and T cells specific for GAD65 are common in people with T1D. In a phase II clinical trial, GAD-alum (a formulation of GAD with alum) was administered to children with recent-onset T1D with the objective of stopping or slowing the autoimmune process and preserving natural insulin production. Preservation of residual insulin secretion was seen in the treated children months after treatment ended. Trial participants treated with GAD-alum increased the numbers of Treg cells in response to GAD65 stimulation, showing they were responding specifically to treatment with this autoantigen. The aim of this work was to investigate whether an increase in Treg cells persisted at 4 years after GAD-alum treatment, to explain the preservation of C-peptide secretion maintained in the treated children. In addition, they further tested whether GAD-alum treatment affected the suppressive capacity of Tregs isolated from these participants after 4 years. The authors found that Tregs isolated from children with T1D participating in the GAD-alum trial had an impaired suppressive effect on Teffs and that this impairment was not due to exposure to GAD. Importantly, both cell populations specific for GAD were recoverable and responsive in these experiments. Overall, these results suggest that higher numbers of Treg cells rather than increased Treg cell function appears to be responsible for the persistent clinical benefit of GAD-alum treatment after 4 years in this specific trial.
Ramifications for Individuals with T1D:
T1D is a disease mediated by T cells that recognize key proteins/antigens on pancreatic beta cells and attack these cells. A key focus of the JDRF research portfolio is to discover and facilitate the development of effective antigen specific therapies in T1D that can slow or stop the underlying autoimmune disease process by targeting the antigens specific to T1D. The failure of two other GAD-alum trials since the success of the one in this report, have caused the T1D scientific community to take a critical look at the formulation of the trial agent as well as question whether the drug is best suited for administration in the new onset setting. Importantly, these mechanistic studies indicate that one needs to be very careful in the design of antigen specific therapies such that only the desired suppressor T cells (Tregs) are expanded or activated.
This work was partly funded by JDRF.
Investigators and Institutions:
Mikael Pihl, Linda Akerman, Stina Axelsson, Mikael Cheramy, Maria Hjorth, Roberto Mallone, Johnny Ludvigsson, Rosaura Casas from the Division of Pediatrics, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoping University, Linkoping, Sweden
Pihl M, Akerman L, and others. Regulatory T cell phenotype and function 4 years after GAD-alum treatment in children with type 1 diabetes. Clin Exp Immunol. 2013 Jun;172(3):394-402. doi: 10.1111/cei.12078.