Ustekinumab Improves Active Crohn’s Disease by Suppressing the T Helper 17 Pathway

Abstract

<b><i>Background:</i></b> Ustekinumab (UST), an antibody targeting the p40 subunit of interleukin (IL)-12 and IL-23, is effective in treating Crohn’s disease (CD). To clarify the mechanism of UST, we investigated T-cell differentiation in CD patients treated with UST. <b><i>Methods:</i></b> Twenty-seven patients with active CD were enrolled in this study. Seventeen patients were treated with UST, and 10 patients were treated with anti-tumor necrosis factor (TNF)-alpha therapy. The changes in the proportions of T-cell subsets after these therapies were analyzed by flow cytometry. Comprehensive gene expression changes in the colonic mucosa were also evaluated. <b><i>Results:</i></b> The frequency of T helper (Th) 17 cells was significantly decreased in the peripheral blood of patients with active CD after UST therapy. Anti-TNF therapy had a minimal effect on Th17 cells but increased the proportion of regulatory T cells. Enrichment analysis showed the expression of genes involved in the Th17 differentiation pathway was downregulated in the colonic mucosa after UST but not anti-TNF therapy. There were no common differentially expressed genes between CD patients treated with UST and anti-TNF therapy, suggesting a clear difference in their mechanism of action. <b><i>Conclusion:</i></b> In patients with active CD, UST therapy suppressed Th17 cell differentiation both in the peripheral blood and colonic tissues.

Identifying hub genes in response to ustekinumab and the impact of ustekinumab treatment on fibrosis in Crohn’s disease

“…In our study, we saw that the expression of LCN2 was lower in patients who responded to ustekinumab treatment and may predict the treatment response to ustekinumab. The possible mechanism of LCN2 expression affecting ustekinumab treatment may be related to the effect of ustekinumab on Th17 cells ( 39 ).…”

PD-1-positive cells contribute to the diagnosis of inflammatory bowel disease and can aid in predicting response to vedolizumab

“…Additionally, setting ITB and BD as control groups could improve the differentiation of IBD and OID. Other biologics such as TNF-α inhibitors and ustekinumab are known to partially exert their anti-inflammatory effects by inhibiting T cell proliferation [42][43][44][45] . However, understanding on the alteration in T cell composition, including PD-1 + cells, following therapeutic intervention is limited.…”

Medicina de precisión en la enfermedad inflamatoria intestinal

“…Un estudio que seleccionó prospectivamente pacientes que iniciaban un tratamiento biológico (ustekinumab, infliximab y adalimumab) y cuantificó el perfil de citoquinas antes del inicio y durante el tratamiento biológico objetivó como el ustekinumab actuaba principalmente suprimiendo la vía Th17 y que tras el uso de un anti-TNF aumentaban los linfocitos Treg. 52 La importancia de la IL-23 en la patogénesis tanto de la EC como de la CU, así como en otras enfermedades autoinmunes, está fuera de toda duda. Terapias dirigidas a la subunidad p40 compartida en IL-12 e IL-23, como el ustekinumab, son útiles en la práctica clínica actual para la EII; recientes estudios de fase 2 respaldan el uso del bloqueo específico de p19 en EC y UC con fármacos más específicos como guselkumab o risankizumab.…”