Prospects of a type 1 diabetes vaccine

The hallmark characteristic of a vaccine is either prevention or cure of a disease by sensitizing or desensitizing the immune system to specific antigen(s) (Ags) and avoiding propagation of the pathogenic immune responses. In the case of autoimmune type 1 diabetes (T1D), in which the insulin-producing beta-cells within the pancreatic islets of Langerhans are selectively destroyed by the immune system (primarily the pathogenic T-cells), this entails reinstallment of immune tolerance to beta-cell Ags or peptides. Ag-specific therapies have the potential to reset the immune system toward long-standing tolerance to the involved Ags, if applied correctly. Tolerance induction depends heavily on the route of administration (i.e. oral or parenteral), the time of administration with respect to disease stages and the Ag dose. High doses of Ag preferentially promote anergy or apoptosis of pathogenic T-cells, while low doses favor regulatory T-cell (Treg) induction or prevent immune-cell interactions [1]. Although the primary Ag in T1D is not yet identified, several exogenous Ags like dietary wheat and cow’s milk-derived proteins, displaying molecular mimicry with beta-cell surface proteins, in addition to endogenous (pro)insulin, glutamic acid decarboxylase (GAD65), the tyrosine phosphatase-related islet antigen (IA-2), heat shock protein (HSP60), islet-specific glucose-6-phosphatase catalytic subunitrelated protein (IGRP), and zinc transporter (ZnT8) have been linked to T1D initiation and progression and are, therefore, potential therapeutic targets. Also environmental infectious agents, like viruses, contribute to triggering T1D; true vaccination against these agents could help in preventing disease. The ideal timing for a prophylactic vaccine in T1D is probably before disease-onset during the presymptomatic stages, particularly before any immune attack against the beta-cell has been initiated [2]. Intervention at this stage is often studied in T1D animal models, like the nonobese diabetic (NOD) mouse, and Ag-specific interventions with administration of the suspected autoAgs, for example insulin, are effective in arresting disease. Unfortunately, clinical translation of these findings remains tough, as timing of Ag administration, Ag dose, repetition of Ag administration etc. are crucial factors in determining success or failure. Moreover, treating humans at this stage of the disease means treating at-risk populations without clinical symptoms, namely neonates or small children (often first-degree relatives of T1D patients) identified through genetic screening with high-risk HLA genotypes and autoantibody positivity. In this population, an Ag-based vaccine should not only prevent activation of naive T-cells but also control activated effector T-cells that are already damaging the betacell, as shown by autoantibody production from bystander B-cells, in order to prevent progression of the autoimmune attack and onset of disease. Importantly, although the majority of high-risk individuals are subjected to one or multiple environmental triggers, only a limited group will progress to disease. Once hyperglycemia is present, the challenge for successful vaccination becomes even greater as not only reinstallation and regulation of tolerance is needed, but the therapeutic success will depend on the moment of intervention and the amount of functioning beta-cells around to be saved. In the two latter stages of disease, when autoimmunity is happening, pure vaccination as in ‘administration of Ag in a tolerogenic way’ will probably not suffice to achieve disease prevention. In these cases, it is to be expected that combinations with immunomodulators will be necessary to arrest progression of disease.