Antigen-Based Therapy for the Treatment of Type 1 Diabetes

Abstract

Antigen-based therapies (ABTs) seek to prevent or inhibit autoimmune diseases by inducing regulatory T-cell responses (active tolerance) or anergizing/deleting pathogenic T-cells (passive tolerance). The theoretical appeal of this therapeutic approach is that it may promote tolerance with little debilitation of the immune system. The clinical application of ABTs for autoimmune disease is still in its infancy. Although initial attempts to apply this therapeutic strategy in multiple sclerosis, rheumatoid arthritis, and type 1 diabetes met with failure, recent results from clinical studies hold promise that this approach may be able to delay the onset of type 1 diabetes as well as preserve β-cell function in latent autoimmune diabetes in adults (LADA) patients and in children newly diagnosed with type 1 diabetes. If verified, it would be an important translation of NOD mouse findings to clinical applications. NOD mouse studies, however, indicate that the immunological impact of ABTs is much more dynamic and complex than previously appreciated. The differences in type 1 diabetes pathogenesis between rodents and humans, as well as other immunotherapeutic approaches, have been extensively reviewed elsewhere (e.g., [1–3]). Here, we will focus on ABTs and discuss what has been learned about their immunological impact, the theoretical factors affecting their efficacy and safety, as well as potential markers of their therapeutic efficacy. ### Inflammatory T-cell responses spread among β-cell antigens during the development of murine and human type 1 diabetes. Type 1 diabetes is mediated by autoreactive T-cells recognizing β-cell autoantigens (β-CAAs). In NOD mice, autoreactive CD4+ T-cells are generally Th1 type (interferonγ secreting), and autoimmunity progressively spreads intra- and intermolecularly among β-CAAs such as insulin, GAD, heat shock protein (HSP), and IGRP during the disease process (4,5). Similarly, spontaneous CD8+ T-cell responses develop to β-CAAs such as insulin, GAD, IGRP, and others (6). Paralleling observations in NOD mice, autoreactive Th1-biased CD4+ and CD8+ T-cells arise in human …