Gene Therapy Prevents Diabetes in Mouse Model

The cytokine CCL22 displays chemotactic activity for monocytes, dendritic cells, natural killer cells, and for chronically activated T lymphocytes. It also displays a mild activity for primary activated T lymphocytes and has no chemo attractant activity for neutrophils, eosinophils, and resting T lymphocytes. CCL22 binds to chemokine receptor CCR4 and may play a role in the trafficking of activated T lymphocytes to inflammatory sites and other aspects of activated T lymphocyte physiology.

Type I diabetes is characterized by destruction of insulin-producing beta cells in the pancreatic islets by effector T cells. Tregs (regulatory T cells), defined by the markers CD4 and FoxP3, regulate immune responses by suppressing effector T cells and are recruited to sites of action by the chemokine CCL22. Investigators at the University of British Columbia (Vancouver, Canada) examined the effect of eliciting production of CCL22 in the pancreatic beta cells, the site of autoimmune attack in type I diabetes.

An adeno-associated viral vector was used to insert the gene for CCL22 into the pancreatic islets of both normal and diabetic mice of the pro-diabetic NOD line. Results published in the July 1, 2011, online edition of the Journal of Clinical Investigation revealed that adeno-associated virus encoding CCL22 recruited endogenous Tregs to the islets and conferred long-term protection from autoimmune diabetes. In addition, adenoviral expression of CCL22 in syngeneic islet transplants in diabetic NOD recipients prevented beta cell destruction by autoreactive T cells and thereby delayed recurrence of diabetes. CCL22 expression increased the frequency of Tregs, produced higher levels of TGF-beta (transforming growth factor-beta) in the CD4+ T cell population near islets, and decreased the frequency of circulating autoreactive CD8+ T cells.

“It is a novel way to turn down the immune system specifically in the region of the beta cells inside the pancreas, and that may be a big advantage over general immune suppression, which can have significant side effects,” said senior author Dr. Bruce Verchere, professor of pathology and laboratory medicine at the University of British Columbia.

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University of British Columbia