The immunotherapeutic potential of dendritic cells in type 1 diabetes

Abstract

Type 1 diabetes is an autoimmune disease characterized by destruction of the pancreatic islet beta cells that is mediated primarily by T cells specific for beta cell antigens. Insulin administration prolongs the life of affected individuals, but often fails to prevent the serious complications that decrease quality of life and result in significant morbidity and mortality. Thus, new strategies for the prevention and treatment of this disease are warranted. Given the important role of dendritic cells (DCs) in the establishment of peripheral T cell tolerance, DC-based strategies are a rational and exciting avenue of exploration. DCs employ a diverse arsenal to maintain tolerance, including the induction of T cell deletion or anergy and the generation and expansion of regulatory T cell populations. Here we review DC-based immunotherapeutic approaches to type 1 diabetes, most of which have been employed in non-obese diabetic (NOD) mice or other murine models of the disease. These strategies include administration of in vitro-generated DCs, deliberate exposure of DCs to antigens before transfer and the targeting of antigens to DCs in vivo. Although remarkable results have often been obtained in these model systems, the challenge now is to translate DC-based immunotherapeutic strategies to humans, while at the same time minimizing the potential for global immunosuppression or exacerbation of autoimmune responses. In this review, we have devoted considerable attention to antigen-specific DC-based approaches, as results from murine models suggest that they have the potential to result in regulatory T cell populations capable of both preventing and reversing type 1 diabetes.

Fig. 1

Different strategies of induction of peripheral tolerance by dendritic cells (DCs). Steady-state DCs can induce deletion or anergy of cognate autoreactive T cells either through lack of co-stimulation or by recruitment of co-inhibitory molecules. Another efficient method of tolerance induction is the generation and expansion of antigen-specific regulatory T cells. Apart from deletion of DCs by Fas expression, DCs can induce tolerance directly in the periphery by production of indoleamine 2,3-dioxygenase.

Fig. 2

Dendritic cell (DC)-based therapeutic strategies in the fight against diabetes. DCs have shown promising results in the treatment of type 1 diabetes when used alone or in conjunction with various other molecules (for details, see text). Targeting of DCs with islet antigens has also proved successful. However, most of these studies have been performed in non-obese diabetic (NOD) mice or other mouse models for type 1 diabetes. Although they serve as excellent models, they show significant differences from the disease in humans. Therefore, the ultimate goal, as well as challenge, is to translate these successful studies to human patients. It is hoped that the ongoing Phase I clinical trial with autologous immature DCs (iDC) (see Ref. [118]) will establish the safety of DC administration in type 1 diabetes patients.