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Effect of Ibrutinib on the gene expression of CD4+ cells from patients with Peripheral T-cell lymphoma (PTCL)

ABSTRACT: Interleukin-2-inducible T-cell kinase (ITK) has essential roles in T-cell proliferation in response to T-cell receptor stimulation and promotes Th2 and Th17 cell differentiation while suppressing Treg differentiation. ITK inhibitors have not previously been investigated for their ability to modify differentiation of either normal or malignant human CD4+ T-cells. We demonstrate that normal tonsillar CD4+ T-cell differentiation to Tfh and Th17 cells is inhibited by ITK inhibitors (ITKi) while Treg differentiation is promoted. Purified CD4+ T-cells from two cases of peripheral T-cell lymphoma demonstrated the capacity to proliferate and differentiate to Tfh, Th17 or Treg subsets in vitro. Gene expression profiling showed differences in Th-cell signature genes between normal and lymphoma cells. ITKi promoted Treg differentiation while suppressing Tfh and Th17 differentiation. The majority of CD4+ T-cells within lymph node sections did not express BCL6 compatible with the in vitro results being due to differentiation and not outgrowth already differentiated populations. The novel concept suggested by this report is that some cases of PTCL-NOS show a capacity to differentiate, which can be modified by ITKi for potential therapeutic benefit.

ORGANISM(S): Homo sapiens

PROVIDER: GSE120403 | GEO | 2018/09/26

REPOSITORIES: GEO

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Project description:Leber2016 - Expanded model of Tfh-Tfr differentiation - Helicobacter pylori infection The parameters used in the model were obtained from experiments conducted by the authors, previous publications [ 1, 2, 3] and parameter optimisation carried out in the paper using particle swarm and genetic algorithms. This model is described in the article: Bistability analyses of CD4+ T follicular helper and regulatory cells during Helicobacter pylori infection. Leber A, Abedi V, Hontecillas R, Viladomiu M, Hoops S, Ciupe S, Caughman J, Andrew T, Bassaganya-Riera J. J. Theor. Biol. 2016 Jun; 398: 74-84 Abstract: T follicular helper (Tfh) cells are a highly plastic subset of CD4+ T cells specialized in providing B cell help and promoting inflammatory and effector responses during infectious and immune-mediate diseases. Helicobacter pylori is the dominant member of the gastric microbiota and exerts both beneficial and harmful effects on the host. Chronic inflammation in the context of H. pylori has been linked to an upregulation in T helper (Th)1 and Th17 CD4+ T cell phenotypes, controlled in part by the cytokine, interleukin-21. This study investigates the differentiation and regulation of Tfh cells, major producers of IL-21, in the immune response to H. pylori challenge. To better understand the conditions influencing the promotion and inhibition of a chronically elevated Tfh population, we used top-down and bottom-up approaches to develop computational models of Tfh and T follicular regulatory (Tfr) cell differentiation. Stability analysis was used to characterize the presence of two bi-stable steady states in the calibrated Tfh/Tfr models. Stochastic simulation was used to illustrate the ability of the parameter set to dictate two distinct behavioral patterns. Furthermore, sensitivity analysis helped identify the importance of various parameters on the establishment of Tfh and Tfr cell populations. The core network model was expanded into a more comprehensive and predictive model by including cytokine production and signaling pathways. From the expanded network, the interaction between TGFB-Induced Factor Homeobox 1 (Tgif1) and the retinoid X receptor (RXR) was displayed to exert control over the determination of the Tfh response. Model simulations predict that Tgif1 and RXR respectively induce and curtail Tfh responses. This computational hypothesis was validated experimentally by assaying Tgif1, RXR and Tfh in stomachs of mice infected with H. pylori. The impulse of RXR as shown in the paper (figure 7C) can be implemented by creating an event in the curated SBML file. This model is hosted on BioModels Database and identified by: BIOMD0000000625. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Effect of Ibrutinib on the gene expression of CD4+ cells from patients with Peripheral T-cell lymphoma (PTCL)

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