Monitoring islet specific immune responses in type 1 diabetes clinical immunotherapy trials

Abstract

The number of immunotherapeutic clinical trials in type 1 diabetes currently being conducted is expanding, and thus there is a need for robust immune-monitoring assays which are capable of detecting and characterizing islet specific immune responses in peripheral blood. Islet- specific T cells can serve as biomarkers and as such can guide drug selection, dosing regimens and immunological efficacy. Furthermore, these biomarkers can be utilized in patient stratification which can then benchmark suitability for participation in future clinical trials. This review focusses on the commonly used immune-monitoring techniques including multimer and antigen induced marker assays and the potential to combine these with single cell transcriptional profiling which may provide a greater understanding of the mechanisms underlying immuno-intervention. Although challenges remain around some key areas such as the need for harmonizing assays, technological advances mean that multiparametric information derived from a single sample can be used in coordinated efforts to harmonize biomarker discovery and validation. Moreover, the technologies discussed here have the potential to provide a unique insight on the effect of therapies on key players in the pathogenesis of T1D that cannot be obtained using antigen agnostic approaches.

Keywords: ELISpot; T cell; immuno-monitor; immunotherapy; multimer; trial.

Figure 1

PBMCs were stimulated with the hexavalent vaccine, Infanrix and Candida albicans, and IL-22 (blue), interferon-γ (green), IL-10 (yellow) and IL-17 (red) T cell responses were measured. T cells making all 4 cytokines are shown in white.

Figure 2

Use of the AIM 10x assay to investigate islet-specific T cells. A schematic diagram showing combination of AIM and s.c. RNA-Seq to characterize antigen-specific T cells.