» Articles » PMID: 32679193

Ustekinumab Inhibits T Follicular Helper Cell Differentiation in Patients With Crohn's Disease

Abstract

Background & Aims: The pathogenesis of chronic inflammatory bowel diseases (Crohn's disease [CD] and ulcerative colitis) involves dysregulated TH1 and TH17 cell responses, which can be targeted therapeutically by the monoclonal antibody Ustekinumab directed against the joint p40 subunit of IL-12 and IL-23. These cytokines may also regulate the differentiation of T follicular helper (TFH) cells, which promote B cell function in germinal centers. However, the role of TFH cells in CD pathogenesis and impact of Ustekinumab therapy on TFH cell fate in patients are poorly defined.

Methods: Lymphocytes were isolated from peripheral blood (n=45) and intestinal biopsies (n=15) of CD patients or healthy controls (n=21) and analyzed by flow cytometry to assess TFH cell phenotypes and functions ex vivo. In addition, TFH cell differentiation was analyzed in the presence of Ustekinumab in vitro.

Results: TFH cell frequencies in the intestine as well as peripheral blood were associated with endoscopic as well as biochemical evidence of CD activity. CD patients with clinical response to Ustekinumab, but not those with response to anti-TNF antibodies, displayed reduced frequencies of circulating TFH cells in a concentration-dependent manner while the TFH phenotype was not affected by Ustekinumab therapy. In keeping with this notion, TFH cell differentiation was inhibited by Ustekinumab in vitro while TFH cell maintenance was not affected. Moreover, Ustekinumab therapy resulted in reduced germinal center activity in CD patients in vivo.

Conclusions: These data implicate TFH cells in the pathogenesis of CD and indicate that Ustekinumab therapy affects TFH cell differentiation, which may influence TFH-mediated immune functions in UST-treated CD patients.

Citing Articles

Identification of potential novel targets for treating inflammatory bowel disease using Mendelian randomization analysis.

Fan J, Lu Y, Gan J, Lu H Int J Colorectal Dis. 2024; 39(1):165.

PMID: 39414629 PMC: 11485038. DOI: 10.1007/s00384-024-04744-2.


Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial.

Tatovic D, Marwaha A, Taylor P, Hanna S, Carter K, Cheung W Nat Med. 2024; 30(9):2657-2666.

PMID: 39079992 PMC: 11405276. DOI: 10.1038/s41591-024-03115-2.


INVITED COMMENTARY on Andersen S, et al. Developmental Windows of Environmental Vulnerability for Inflammatory Bowel Disease.

Simon D, Kellermayer R J Pediatr Clin Pract. 2024; 11:200104.

PMID: 38827481 PMC: 11138252. DOI: 10.1016/j.jpedcp.2024.200104.


Insights into Therapeutic Response Prediction for Ustekinumab in Ulcerative Colitis Using an Ensemble Bioinformatics Approach.

Koustenis K, Dovrolis N, Viazis N, Ioannou A, Bamias G, Karamanolis G Int J Mol Sci. 2024; 25(10).

PMID: 38791570 PMC: 11122545. DOI: 10.3390/ijms25105532.


Friend or Foe - Tc17 cell generation and current evidence for their importance in human disease.

Hipp A, Bengsch B, Globig A Discov Immunol. 2024; 2(1):kyad010.

PMID: 38567057 PMC: 10917240. DOI: 10.1093/discim/kyad010.


References
1.
Morita R, Schmitt N, Bentebibel S, Ranganathan R, Bourdery L, Zurawski G . Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity. 2011; 34(1):108-21. PMC: 3046815. DOI: 10.1016/j.immuni.2010.12.012. View

2.
Crotty S . T follicular helper cell differentiation, function, and roles in disease. Immunity. 2014; 41(4):529-42. PMC: 4223692. DOI: 10.1016/j.immuni.2014.10.004. View

3.
Wu H, Deng Y, Zhao M, Zhang J, Zheng M, Chen G . Molecular Control of Follicular Helper T cell Development and Differentiation. Front Immunol. 2018; 9:2470. PMC: 6209674. DOI: 10.3389/fimmu.2018.02470. View

4.
Cao Y, Yang Q, Deng H, Tang J, Hu J, Liu H . Transcriptional factor ATF3 protects against colitis by regulating follicular helper T cells in Peyer's patches. Proc Natl Acad Sci U S A. 2019; 116(13):6286-6291. PMC: 6442638. DOI: 10.1073/pnas.1818164116. View

5.
Horiuchi S, Ueno H . Potential Pathways Associated With Exaggerated T Follicular Helper Response in Human Autoimmune Diseases. Front Immunol. 2018; 9:1630. PMC: 6054970. DOI: 10.3389/fimmu.2018.01630. View