Antigen-based immune therapeutics for type 1 diabetes: magic bullets or ordinary blanks?

Abstract

The ideal drug of modern medicine is the one that achieves its therapeutic target with minimal adverse effects. Immune therapy of Type 1 diabetes (T1D) is no exception, and knowledge of the antigens targeted by pathogenic T cells offers a unique opportunity towards this goal. Different antigen formulations are being considered, such as proteins or peptides, either in their native form or modified ad hoc, DNA plasmids, and cell-based agents. Translation from mouse to human should take into account important differences, particularly in the time scale of autoimmune progression, and intervention. Critical parameters such as administration route, dosing and interval remain largely empirical and need to be further dissected. T1D staging through immune surrogate markers before and after treatment will be key in understanding therapeutic actions and to finally turn ordinary blanks into magic bullets.

Figure 1

Stages of disease progression and intervention in T1D. Progression over time (X-axis) from simple genetic susceptibility to β-cell autoimmunity and T1D is plotted against residual β-cell mass (Y-axis). The time points at which immune therapies are administered are shown in red.

Figure 2

Ag-specific immune therapies. Different Ag formulations can be administered via different routes, triggering various tolerance mechanisms. APC: Ag-presenting cell; DC: dendritic cell; i.d.: intradermal; i.m., intramuscular; i.v.: intravenous; MDSCs: myeloid-derived suppressor cells; PBMC: peripheral blood mononuclear cell; s.c.: subcutaneous; Tregs: regulatory T cells.

Figure 3

“Immune staging" of T1D. Biomarkers of β-cell autoimmunity such as aAbs and T cells could help to identify at-risk subjects at an early stage (preclinical diagnosis) and to follow them up over time to decide the need for immune therapy and the best timing for treatment (prognostic stratification). Ag-specific immune therapy could be personalized for each subject by administering therapeutic formulations of those Ags targeted by aAb and/or T-cell responses. Modifications induced on such responses could be followed in real time during treatment, thus allowing to assess immune efficacy prior to and independent of clinical outcome.