A Comprehensive Review of Interventions in the NOD Mouse and Implications for Translation

Abstract

Type 1 diabetes (T1D) animal models such as the nonobese diabetic (NOD) mouse have improved our understanding of disease pathophysiology, but many candidate therapeutics identified therein have failed to prevent/cure human disease. We have performed a comprehensive evaluation of disease-modifying agents tested in the NOD mouse based on treatment timing, duration, study length, and efficacy. Interestingly, some popular tenets regarding NOD interventions were not confirmed: all treatments do not prevent disease, treatment dose and timing strongly influence efficacy, and several therapies have successfully treated overtly diabetic mice. The analysis provides a unique perspective on NOD interventions and suggests that the response of this model to therapeutic interventions can be a useful predictor of the human response as long as careful consideration is given to treatment dose, timing, and protocols; more thorough investigation of these parameters should improve clinical translation.

IL-7 receptor blockade reverses autoimmune diabetes by promoting inhibition of effector/memory T cells

“…present in the lymphoid organs or recently emigrated from the thymus. Our results add IL-7Rα blockade to the list of only a handful of treatments capable of reversing the disease (12) and is unique as a cytokine receptor blockade therapy for the treatment of autoimmune diabetes. Surprisingly, histological analysis showed only a limited reduction of the islet infiltrates ( Fig.…”

“…IL-7 is a critical cytokine for the generation and maintenance of virusspecific memory T cells, but its role in autoimmune disease is poorly defined. One of the challenges in treating autoimmune type 1 diabetes is that it is a slowly developing chronic disease, and the efficacy of most treatments highly depends on the stage of the disease at which the treatment is given (12). To assess whether blocking IL-7 signals in NOD mice would interfere with disease development, we administered anti-IL-7Rα mAbs to block IL-7 cytokine activity.…”

Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice

“…The NOD model has been widely used to test many therapeutic regimens, the majority of which have been reviewed [1]. Although many of these treatments had a successful outcome in young NOD mice (treated before 8 wks of age), fewer were tested or found to demonstrate efficacy in older NOD mice with advanced insulitis or hyperglycemia.…”

Curative and β cell regenerative effects of α1-antitrypsin treatment in autoimmune diabetic NOD mice

“…autoimmunity ͉ type 1 diabetes ͉ inflammation A destructive T cell-dependent autoimmune process directed against insulin-producing ␤ cells causes type 1 diabetes mellitus (T1DM) in humans and the nonobese diabetic (NOD) mouse model (1,2). Although many therapeutic interventions, including viral-mediated gene transfer of human ␣1-antitrypsin (AAT) (3), can prevent T1DM or resolve the T cell-rich, ␤ cell-invasive insulitis lesion in prediabetic hosts, surprisingly few therapies have succeeded in restoring long-term drug-free euglycemia and immune tolerance to ␤ cells in overtly diabetic NOD mice (4)(5)(6)(7)(8).…”