Using an innovative nanotechnology-based "vaccine," researchers were able to successfully restore normal blood sugar in mice with type 1 diabetes, and also slow the onset of diabetes in mice at risk for the disease. The study, co-funded by JDRF and published today in the online edition of the journal Immunity, has several key implications:
* First, it provides important new insights into how to stop the immune attack that causes type 1 diabetes.
* Second, it underscores the potential of "antigen-specific" therapies. Because the nanoparticle vaccine was designed with specific immune system proteins, it effectively blunted the targeted autoimmune response that causes diabetes without compromising the overall immune system - an issue that continues to be a challenge in developing treatments for diabetes.
* And third, it suggests that antigen-specific nanovaccines, because of the effectiveness shown here, might also be developed to treat other autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis. That could make the science more attractive to drug development companies.
The researchers produced a unique vaccine comprising nanoparticles, which are thousands of times smaller than the size of a cell. They coated the particles with type 1 diabetes-relevant peptides, or protein fragments, that were bound to certain molecules that play a critical role in immune cell communication (called MHC molecules).
In the mice, the nanoparticle treatment expanded a type of regulatory T cell -- these cells ultimately suppressed the aggressive immune attack that destroys the insulin-producing beta cells of the pancreas. The researchers noted that the expanded cells shut down the immune attack by preventing autoreactive immune cells from being stimulated, either by the peptide contained in the vaccine or by any other diabetes autoantigen presented simultaneously by antigen-presenting cells. With the immune response that causes diabetes blocked, mice with type 1 diabetes regained normal blood sugars. And those that would have contracted the disease didn't.
The study also provides important - and promising - insight into the ability to translate these findings into therapeutics for people: Nanoparticles that were coated with molecules specific to human type 1 diabetes were able to restore normal blood sugar levels in a humanized mouse model of diabetes (that is, a mouse that has been genetically altered to biologically simulate type 1 diabetes in people).
Immunity Journal - Reversal of Autoimmunity by Boosting Memory-like Autoregulatory T Cells
* In T1D, naive low-avidity autoreactive T-cells become memory like and autoregulatory
* This differentiation process requires chronic exposure to autoantigen
* Memory autoregulatory T cells suppress and kill autoantigen-loaded APCs
* Monospecific pMHC-NP suppress T1D by expanding cognate memory autoregulatory cells
Blunting autoreactivity without compromising immunity remains an elusive goal in the treatment of autoimmunity. We show that progression to autoimmune diabetes results in the conversion of naive low-avidity autoreactive CD8+ T cells into memory-like autoregulatory cells that can be expanded in vivo with nanoparticles coated with disease-relevant peptide-major histocompatibility complexes (pMHC-NP). Treatment of NOD mice with monospecific pMHC-NPs expanded cognate autoregulatory T cells, suppressed the recruitment of noncognate specificities, prevented disease in prediabetic mice, and restored normoglycemia in diabetic animals. pMHC-NP therapy was inconsequential in mice engineered to bear an immune system unresponsive to the corresponding epitope, owing to absence of epitope-experienced autoregulatory T cells. pMHC-NP-expanded autoregulatory T cells suppressed local presentation of autoantigens in an interferon--, indoleamine 2,3-dioxygenase-, and perforin-dependent manner. Nanoparticles coated with human diabetes-relevant pHLA complexes restored normoglycemia in a humanized model of diabetes. These observations expose a paradigm in the pathogenesis of autoimmunity amenable for therapeutic intervention.
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