Circulating and mucosal predictors and effects of therapeutic interleukin-23 blockade in crohn's disease

The National Institute of Allergy and Infectious Diseases awarded $267,000 to the Benaroya Research Institute at Virginia Mason on June 11, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855).

The award funds research into circulating and mucosal immune cell populations affected by therapeutic interleukin-23 blockade in Crohn's disease patients treated with risankizumab. The project will quantify and characterize TH17 cells, mucosa-associated invariant T cells, gamma-delta T cells, and type 3 innate lymphoid cells, tracking their gene expression and T cell receptor sequences to detect phenotypic differences in treated and untreated patients. The recipient will apply single-cell sequencing of sort-enriched immune populations and spatial transcriptomics to colon samples to characterize immune cells in situ and determine how IL-23 blockade affects their microenvironment. By contrasting immune cell responses in patients who respond therapeutically to IL-23 blockade with those who do not, the research aims to identify predictive biomarkers to guide treatment decisions and reveal potential future molecular targets to prevent treatment failure.

Work is performed in Seattle, Washington. The period of performance runs from the award date through May 31, 2028. This is assistance type Project Grant.

Abstract

Since its discovery 20 years ago, the cytokine interleukin (IL)-23 has increasingly been implicated in the pathogenesis of immune mediated diseases, such as crohn's disease (CD). Consequently, four monoclonal antibodies that block IL-23 are currently approved CD therapies, including risankizumab. Although suppression of pathogenic TH17 cells has been widely cited as the mechanism by which IL-23 blockade controls disease, there is a paucity of data to indicate that this is how such therapy works, and a few other immune cell populations expressing the IL-23 receptor could instead be its target. We therefore propose to study how risankizumab affects not only TH17 cells, but also mucosa-associate invariant t (mait) cells ΓΔ t cells and (in the colon) type 3 innate lymphoid cells (ILC3S). In addition to quantifying these cells, we will study their gene expression to detect phenotypic differences in treated patients, and in the case of t cells, track their clonal expansion and deletion through their unique t cell receptor sequences. In colon samples, we will use a combination of single cell sequencing of sort-enriched immune cell populations and spatial transcriptomics to characterize cells in situ, at the site of disease, and determine how IL-23 blockade affects their microenvironment in vivo. By contrasting results in patients who do or do not respond therapeutically to IL-23 blockade, we will reveal valuable insights into how this treatment succeeds or fails in CD, in the process identifying predictive biomarkers to guide treatment decisions, and potentially identifying future molecular targets with which to prevent treatment failure.