A Preclinical Consortium Approach for Assessing the Efficacy of Combined Anti-CD3 Plus IL-1 Blockade in Reversing New-Onset Autoimmune Diabetes in NOD Mice.

There is an ongoing need to develop strategic combinations of therapeutic agents to prevent type 1 diabetes (T1D) or to preserve islet ß-cell mass in new-onset disease. Although clinical trials using candidate therapeutics are commonly based on preclinical studies, concern is growing regarding the reproducibility as well as the potential clinical translation of reported results using animal models of human disorders. In response, the National Institutes of Health Immune Tolerance Network and JDRF established a multicenter consortium of academic institutions designed to assess the efficacy and intergroup reproducibility of clinically applicable immunotherapies for reversing new-onset disease in the NOD mouse model of T1D. Predicated on prior studies, this consortium conducted coordinated, prospective studies, using joint standard operating procedures, fixed criteria for study entry, and common reagents, to optimize combined anti-CD3 treatment plus interleukin-1 (IL-1) blockade to reverse new-onset disease in NOD mice. We did not find that IL-1 blockade with anti-IL-1ß monoclonal antibody or IL-1trap provided additional benefit for reversing new-onset disease compared with anti-CD3 treatment alone. These results demonstrate the value of larger, multicenter preclinical studies for vetting and prioritizing therapeutics for future clinical use.

Beta-cell specific production of IL6 in conjunction with a mainly intracellular but not mainly surface viral protein causes diabetes.

Inflammatory mechanisms play a key role in the pathogenesis of type 1 and type 2 diabetes. IL6, a pleiotropic cytokine with impact on immune and non-immune cell types, has been proposed to be involved in the events causing both forms of diabetes and to play a key role in experimental insulin-dependent diabetes development. The aim of this study was to investigate how beta-cell specific overexpression of IL-6 influences diabetes development. We developed two lines of rat insulin promoter (RIP)-lymphocytic choriomeningitis virus (LCMV) mice that also co-express IL6 in their beta-cells. Expression of the viral nucleoprotein (NP), which has a predominantly intracellular localization, together with IL6 led to hyperglycemia, which was associated with a loss of GLUT-2 expression in the pancreatic beta-cells and infiltration of CD11b(+) cells, but not T cells, in the pancreas. In contrast, overexpression of the LCMV glycoprotein (GP), which can localize to the surface, with IL-6 did not lead to spontaneous diabetes, but accelerated virus-induced diabetes by increasing autoantigen-specific CD8(+) T cell responses and reducing the regulatory T cell fraction, leading to increased pancreatic infiltration by CD4(+) and CD8(+) T cells as well as CD11b(+) and CD11c(+) cells. The production of IL-6 in beta-cells acts prodiabetic, underscoring the potential benefit of targeting IL6 in diabetes.

Combination therapy with an anti-IL-1ß antibody and GAD65 DNA vaccine can reverse recent-onset diabetes in the RIP-GP mouse model.

Type 1 diabetes is thought to be an autoimmune condition in which self-reactive T cells attack insulin-secreting pancreatic ß-cells. As a proinflammatory cytokine produced by ß-cells or macrophages, interleukin-1ß (IL-1ß) represents a potential therapeutic target in diabetes. We reasoned IL-1ß blockade could be combined with islet antigen-specific approaches involving GAD of 65 kDa (GAD65)-expressing plasmids, as previously shown in combination therapies (CTs) with anti-CD3. Thus, we investigated whether anti-IL-1ß antibody alone or combined with GAD65 vaccine could reverse diabetes development in a virus-induced mouse model. Given alone, anti-IL-1ß had no effect on diabetes, while GAD65 plasmid resulted in 33% disease reversal after a 5-week observation. However, CTs cured 53% of animals and prevented worsening of glycemic control in nonprotected individuals for up to 12 weeks. While the GAD65 vaccine arm of the CT was associated with increased forkhead box p3(+) regulatory T-cell frequency in pancreatic lymph nodes, islet infiltration by CD11b(+/high) cells was less frequent upon CT, and its extent correlated with treatment success or failure. Altogether, our CTs provided prolonged improvement of clinical and immunological features. Despite unsuccessful clinical trials using anti-IL-1ß monotherapy, these data hold promise for treatment of type 1 diabetic patients with IL-1ß blockade combined with antigen-specific vaccines.