CCL22 Prevents Rejection of Mouse Islet Allografts and Induces Donor-Specific Tolerance.

Manipulation of regulatory T cell (Treg) migration by islet expression of the chemokine CCL22 prevents diabetes in NOD mice and delays recurrent autoimmunity in syngeneic islet transplants. We sought to determine whether attracting Tregs with CCL22 also prevents islet allograft rejection. Isolated Bl/6 mouse islets were transduced overnight with adenovirus expressing CCL22 (Ad-CCL22) downstream of the CMV promoter.

Cellular mechanisms of CCL22-mediated attenuation of autoimmune diabetes.

Autoimmune destruction of insulin-producing β cells in type 1 diabetes and islet transplantation involves a variety of immune pathways but is primarily mediated by self-reactive T cells. Chemokines can modulate local immune responses in inflammation and tumors by recruiting immune cells. We have reported that expression of the chemokine CCL22 in pancreatic β cells in the NOD mouse prevents autoimmune attack by recruiting T regulatory cells (Tregs), protecting mice from diabetes.

Prevention of murine autoimmune diabetes by CCL22-mediated Treg recruitment to the pancreatic islets.

Type 1 diabetes is characterized by destruction of insulin-producing β cells in the pancreatic islets by effector T cells. Tregs, 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. Here, we demonstrate that production of CCL22 in islets after intrapancreatic duct injection of double-stranded adeno-associated virus encoding CCL22 recruits endogenous Tregs to the islets and confers long-term protection from autoimmune diabetes in NOD mice.

Distinct roles of hepatocyte- and myeloid cell-derived IL-1 receptor antagonist during endotoxemia and sterile inflammation in mice.

IL-1R antagonist (IL-1Ra) is a natural inhibitor of the pleiotropic proinflammatory activities of IL-1. Although several reports described the effects of complete IL-1Ra deficiency, no study has examined the consequences of cell type-specific IL-1Ra inactivation during systemic inflammation. Previous in vitro data demonstrated high IL-1Ra production by hepatocytes and myeloid cells after endotoxin stimulation.