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P084 Clinical response to Ustekinumab in Crohn’s disease is linked to a dose-dependent reduction of T follicular helper cells

A-M. Globig*1,2, N. P. Sommer1, A. K. Thomann3, W. Reindl3, R. Schreiner4, M. Hofmann1, C. Schempp5, R. Thimme1, P. Hasselblatt1

1Medical Center – University of Freiburg, Department of Medicine II, Freiburg, Germany, 2Faculty of Medicine, University of Freiburg, Berta-Ottenstein-Programme, Freiburg, Germany, 3Medical Faculty Mannheim, Heidelberg University, Department of Medicine II, Mannheim, Germany, 4Limbach Group, Heidelberg, Germany, 5Medical Center – University of Freiburg, Department of Dermatology, Freiburg, Germany

Background

The pathogenesis of Crohn’s disease (CD) is characterised by strongly dysregulated CD4+ T-cell responses. The differentiation and function of pro-inflammatory Th1 and Th17 cells is supposed to be efficiently targeted by Ustekinumab (UST), a human monoclonal antibody directed against the shared p40-subunit of interleukin-12 (IL-12) and interleukin-23 (IL-23). However, IL-12 and IL-23 are also involved in the differentiation of other T-cell subsets such as T follicular helper (Tfh) cells, which are essential for the formation and maintenance of germinal centres and promote B cell function. We therefore investigated the impact of UST therapy on Tfh cell profiles in CD patients.

Methods

Peripheral blood mononuclear cells (PBMCs) were longitudinally isolated from CD patients before and during UST therapy (n = 25) and analysed by flow cytometry. CD patients treated with anti-TNF antibodies (n = 21) and healthy donors (n = 22) served as controls. The results were correlated with plasma UST concentrations and clinical response status.

Results

Overall, the peripheral Tfh cell frequencies were comparable in UST and anti-TNF treated patients and healthy donors. However, subgroup analyses revealed that patients with clinical response to UST displayed a significant reduction of Tfh cell frequencies following initiation of therapy. Moreover, Tfh cell frequencies in responders were lower than in non-responders to UST therapy, but not affected by the clinical response status in anti-TNF treated patients. These findings suggest that the Tfh phenotype observed in UST-treated patients is mediated by UST rather than differences in disease activity. In keeping with this notion, Tfh cell frequencies were significantly reduced in patients with UST plasma concentrations > 4 mg/l when compared with concentrations below 4 mg/l, suggesting a dose-dependent effect.

Conclusion

Our data indicate that UST affects peripheral Tfh cell frequencies in CD patients. This interaction appears to be associated with the clinical response status as well as UST plasma concentrations. These findings may therefore have clinically significant implications for Tfh-mediated immune functions such as vaccine responses.