Introduction:
Nanoparticles containing gliadin (TAK-101) are under development to induce gliadin tolerance in patients with celiac disease (CeD). We previously reported modulation of cellular responses in bulk and single-cell (sc) transcriptomics, mainly affecting B cell activation, proliferation and signaling, but also T cell cytokine production, in an HLA-DQ8 transgenic mouse model of CeD. Here, we assessed the targeted immune gene expression profile modified by TAK-101 treatment, and quantified gliadin-specific IgG1/IgG2c antibody secreting cells (ASCs).
Materials & Methods:
HLA-DQ8 mice were pretreated on Days −11 and −3 with 2.5 mg TAK-101 i.v., or were not pretreated (‘gliadin immunization-only’). Animals were then immunized with gliadin on Day 0 and boosted on Day 14. Mice from both groups were sacrificed after 1 month. Spleen cells were either used in gliadin-specific IgG1/IgG2c ELISpots or cultured for 3 days with gliadin. Transcriptomic profiling was performed using RNA of cultured spleen cells from two groups (n=12) with the NanoString nCounter® Autoimmune Panel.
Results & Summary:
Differential expression of 93 genes from a total of 770 genes was demonstrated in spleen cells following TAK-101 treatment vs. gliadin immunization-only. Gene expression changes in B cell activation and signaling pathways were significantly associated with TAK-101 treatment, confirming earlier results from bulk/sc-transcriptomics. T-cell cytokine/cytokine receptor gene signatures were captured with higher sensitivity in the targeted panel, now demonstrating increases in Il4 and Il4ra, and decreases in Il7, Il12b, Il17a, c and f and Il17rc by TAK-101.
In addition, TAK-101 reduced the number of gliadin-specific IgG2c ASCs (to 42%, mean), and increased gliadin-specific IgG1 ASCs (to 134%), consistent with reduced Th1-associated, complement-fixing serum anti-gliadin IgG2c (but unchanged IgG1) levels, as shown previously.
In summary, this study confirmed robust immunomodulatory effects of TAK-101 on T and B cell effector molecule secretion in mice, informing TAK-101 trials in celiac patients.