Can we vaccinate against Type 1 diabetes?

Abstract

Vaccination is the administration of antigenic material to stimulate the immune system to develop adaptive immunity to a disease. As the most successful prophylactic in medical history, there is now an emerging interest as to whether vaccination can be applied in autoimmune and inflammatory conditions. These are diseases of failed immune regulation; vaccination in this context aims to exploit the power of antigenic material to stimulate immune homeostasis in the form of active, adaptive, regulatory immune responses. Type 1 diabetes is an autoimmune disease that could benefit from the therapeutic potential of vaccination. The major conditions necessary to make prophylaxis feasible are in place; the self antigens are known, the failure of existing immune regulation has been demonstrated, early studies of vaccine approaches have proved safe, and the preclinical prodrome of the disease can be easily detected by simple blood tests. Challenges for future implementation include finding the best mode of delivery and the best blend of adjunctive therapies that create the favorable conditions required for a vaccine to be effective.

Figure 1.. Depiction of molecular and cellular events in the immunopathogenesis of Type 1 diabetes

β-cells are damaged as a result of an environmental insult, and with concomitant inflammation, activated dendritic cells (DC) migrate to the local lymph node, carrying β-cell remnants that include the key autoantigens (pre)proinsulin, glutamic acid decarboxylase (GAD65), islet-associated tyrosine phosphatase (IA-2) and the zinc transporter 8 (ZnT8). En route, the autoantigens are processed and presented to T cells by DCs, leading in susceptible individuals (who have the appropriate HLA molecules and hypo-functioning β-cell-specific immune regulation) to the priming of pro-inflammatory helper T-lymphocytes and cytotoxic T-lymphocytes, both of which are capable (in in vitro models [1,61]) of mediating β-cell damage, further accelerating the destructive cycle. Regulatory T-lymphocytes (Tregs) may limit this effector activity, and this balance may be critical in determining outcome in susceptible individuals. The balance can be favorably skewed by provision of β-cell autoantigens in a vaccine form (either as whole proteins or peptides), which may induce Tregs de novo or promote conversion of effector T-lymphocytes towards a regulatory phenotype. Abbreviations: DC, dendritic cell; GAD65, glutamic acid decarboxylase; HLA, human leukocyte antigen; IA-2, islet-associated tyrosine phosphatase; Treg, regulatory T lymphocyte; ZnT8, zinc transporter 8.