Inflammatory bowel diseases · 2026
Ustekinumab resistance in individuals with ulcerative colitis is associated with an alteration of a subset of proinflammatory mucosal regulatory T cells.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Briggs Kristi C, Tam Ada, Chaaban Lara, Luo Adam, Kobeissi Lynn, Lazarev Mark, Parian Alyssa, Chowdhury Reezwana, Selaru Florin M, Casella Kelly, Shenderov Eugene, Sears Cynthia L, Housseau Franck, Melia Joanna M P, Pardoll Drew M
Аннотация
BACKGROUND: Ustekinumab is a monoclonal antibody therapy targeting interleukin-12 and interleukin-23 for the treatment of inflammatory bowel diseases, including ulcerative colitis (UC). While these pathways remain quite attractive for UC therapy, response to ustekinumab can be variable. There is an urgent need to better understand the underlying mucosal immune alterations associated with treatment to guide therapy decisions. This study aims to examine the mucosal immune signatures in individuals with UC with variable treatment response to ustekinumab.
METHODS: Sigmoid colon tissue from individuals treated with ustekinumab were analyzed using a multimodal approach. Single-cell RNA and T cell receptor sequencing was performed on mucosal biopsies. In a subset of these patients, multiparameter flow cytometry and spatial transcriptomics was also completed on matched pre- and post-treatment tissue samples. Key findings were also validated on a larger cohort using immunohistochemistry.
RESULTS: Ustekinumab significantly altered the frequency and phenotype of mucosal regulatory T cells (Tregs). Nonresponders to ustekinumab had a higher frequency of Tregs that expressed OX40 and GITR, which is associated with decreased suppressive abilities. In contrast, responders had Tregs with elevated GPR15 and reduced expression of the kinase PIM2, which can alter Treg stability and function. Additionally, T helper 17 cells in nonresponders demonstrated an enhanced proinflammatory gene expression profile.
CONCLUSION: Nonresponse to ustekinumab in UC is linked to a mucosal immune environment enriched with proinflammatory T cell phenotypes and impaired regulatory T cell function. These findings suggest that Tregs are both targets and potential biomarkers of ustekinumab response, with their phenotypic and transcriptional features providing insight into mechanisms of therapeutic resistance.
METHODS: Sigmoid colon tissue from individuals treated with ustekinumab were analyzed using a multimodal approach. Single-cell RNA and T cell receptor sequencing was performed on mucosal biopsies. In a subset of these patients, multiparameter flow cytometry and spatial transcriptomics was also completed on matched pre- and post-treatment tissue samples. Key findings were also validated on a larger cohort using immunohistochemistry.
RESULTS: Ustekinumab significantly altered the frequency and phenotype of mucosal regulatory T cells (Tregs). Nonresponders to ustekinumab had a higher frequency of Tregs that expressed OX40 and GITR, which is associated with decreased suppressive abilities. In contrast, responders had Tregs with elevated GPR15 and reduced expression of the kinase PIM2, which can alter Treg stability and function. Additionally, T helper 17 cells in nonresponders demonstrated an enhanced proinflammatory gene expression profile.
CONCLUSION: Nonresponse to ustekinumab in UC is linked to a mucosal immune environment enriched with proinflammatory T cell phenotypes and impaired regulatory T cell function. These findings suggest that Tregs are both targets and potential biomarkers of ustekinumab response, with their phenotypic and transcriptional features providing insight into mechanisms of therapeutic resistance.