Regulatory T-cell therapy in Crohn’s disease: challenges and advances

Clough, Jennifer; Omer, Omer Serhan; Tasker, Scott; Lord, Graham M.; Irving, Peter M

doi:10.1136/gutjnl-2019-319850

Cited by 122 publications

(84 citation statements)

References 155 publications

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“…Consequently, it is generally believed that Th17 cells mainly mediate the proinflammatory response. CD4 + CD25 + Treg cells have multiple immune inhibitory functions, mainly reflecting in (1) expressing CD39 and CD73 to disrupt the metabolism of effector T cells, (2) secreting perforin and granzyme B to exert cytotoxic effects on effector T cells, and (3) promoting the secretion of anti-inflammatory cytokines such as IL-10 and TGF- β , thereby restraining the function of Th17 and Th1 cells [ 12 ]. CD4 + CD25 + Treg cells play a significant role in maintaining intestinal immune tolerance and alleviate inflammation [ 13 ], and a therapeutic strategy of using Tregs for controlling excessive immune response in UC has been proposed in recent years [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Baicalein Restores the Balance of Th17/Treg Cells via Aryl Hydrocarbon Receptor to Attenuate Colitis

Liu

Chen

et al. 2020

Mediators of Inflammation

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As one of the ligands of aryl hydrocarbon receptor (AhR), baicalein, isolated from Scutellaria baicalensis Georgi, has been proved to exert potential therapeutic effects on ulcerative colitis (UC), but its therapeutic mechanism remains obscure. Authentically, ulcerative colitis can be alleviated by regulating the differentiation of naïve CD4+ T cells via AhR activation. So, our study planned to prove the hypothesis that baicalein protected mice against UC by regulating the balance of Th17/Treg cells via AhR activation. Immunofluorescence and western blot results showed that baicalein could promote AhR activation and induce it to transfer to the nucleus. We further determined the effect of baicalein on naïve CD4+ T cell differentiation in vitro by magnetic cell separation and drug intervention. The results showed that baicalein could promote Treg cell differentiation by activating AhR. In vivo study, UC mice were established by free drinking of dextran sulfate sodium (DSS) for 7 days and then were orally administrated by baicalein (10, 20, and 40 mg/kg), TCDD (AhR agonist), and CH223191 (antagonist). The results demonstrated that baicalein improved the symptoms of UC mice, regulated the balance of Th17/Treg cells, and restored the balance of proinflammatory cytokines such as IL-17, IL-6, and TNF-α; anti-inflammatory cytokines such as IL-10 and TGF-β; and epithelial protective cytokine IL-22 in UC mice, and these effects were related to AhR. Taken together, our research found that baicalein might be a potential drug for UC via regulating Treg cell differentiation and maintaining immune homeostasis and attempted to shed a light on the pivotal role of AhR in these effects.

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Section: Introductionmentioning

confidence: 99%

Baicalein Restores the Balance of Th17/Treg Cells via Aryl Hydrocarbon Receptor to Attenuate Colitis

Liu

Chen

et al. 2020

Mediators of Inflammation

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“…Regulatory T cells (Tregs, CD4 + CD25 + FOXP3 + ) have been described to play an important role suppressing inflammation in IBD ( 50 – 52 ). However, there are contradicting reports about their relative frequency in the gut ( 52 – 55 ) and only little is known about their interaction with γδ + T cells ( 56 , 57 ).…”

Section: Discussionmentioning

confidence: 99%

Decreased Frequency of Intestinal CD39+ γδ+ T Cells With Tissue-Resident Memory Phenotype in Inflammatory Bowel Disease

et al. 2020

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The ectoenzymes CD39 and CD73 play a major role in controlling tissue inflammation by regulating the balance between adenosine triphosphate (ATP) and adenosine. Still, little is known about the role of these two enzymes and ATP and its metabolites in the pathophysiology of inflammatory bowel disease (IBD). We isolated mononuclear cells from peripheral blood and lamina propria of the large intestine of patients diagnosed with IBD and of healthy volunteers. We then comprehensively analyzed the CD39 and CD73 expression patterns together with markers of activation (HLA-DR, CD38), differentiation (CCR7, CD45RA) and tissue-residency (CD69, CD103, CD49a) on CD4 + , CD8 + , γδ + T cells and mucosa-associated invariant T cells using flow cytometry. CD39 expression levels of γδ + and CD8 + T cells in lamina propria lymphocytes (LPL) were much higher compared to peripheral blood mononuclear cells. Moreover, the frequency of CD39 + CD4 + and CD8 + , but not γδ + LPL positively correlated with T-cell activation. The frequency of CD39 + cells among tissue-resident memory LPL (Trm) was higher compared to non-Trm for all subsets, confirming that CD39 is a marker for the tissueresident memory phenotype. γδ + Trm also showed a distinct cytokine profile upon stimulation-the frequency of IFN-γ + and IL-17A + cells was significantly lower in γδ + Trm compared to non-Trm. Interestingly, we observed a decreased frequency of CD39 + γδ + T cells in IBD patients compared to healthy controls (p = 0.0049). Prospective studies need to elucidate the exact role of this novel CD39 + γδ + T-cell population with tissue-resident memory phenotype and its possible contribution to the pathogenesis of IBD and other inflammatory disorders.

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“…For Tregs therapy to be optimal, infused cells need to migrate to inflammatory sites where they can be activated in the target tissue [42]. β7 integrins have been implicated in intestinal T cell homing and retention [43].…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, we decided to evaluate the Tregs and MulTregs isolated from patients with CD; a debilitating autoimmune disorder of the gut that results in chronic inflammation. Treg treatment is being clinically evaluated in CD [42], however, isolation of Tregs from CD patients results in lower Treg numbers compared to healthy donors, which further supports the need to develop more robust expansion protocols for Tregs isolated from this patient population [42,44]. Similar to the results with healthy Treg donors, MulTreg isolated and expanded from CD patients had greater expansion potential and higher levels of β7 integrin expression but similar FoxP3 methylation expression, and suppression of polyclonal stimulated T cell proliferation compared to Tregs.…”

Section: Discussionmentioning

confidence: 99%

Augmented expansion of Treg cells from healthy and autoimmune subjects via adult progenitor cell co-culture

Reading

Roobrouck

Hull

et al. 2020

Preprint

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Recent clinical experience has demonstrated that adoptive regulatory T cell therapy is a safe and feasible strategy to suppress immunopathology via induction of host tolerance to allo- and autoantigens. However, clinical trials continue to be compromised due to an inability to manufacture a sufficient Treg cell dose. Multipotent adult progenitor cells (MAPCⓇ) promote regulatory T cell differentiation in vitro, suggesting they may be repurposed to enhance ex vivo expansion of Tregs for adoptive cellular therapy. Here, we use a GMP compatible Treg expansion platform to demonstrate that MAPC cell-co-cultured Tregs (MulTreg) exhibit a log-fold increase in yield across two independent cohorts, reducing time to target dose by an average of 30%. Enhanced expansion is linked with a distinct Treg cell-intrinsic transcriptional program, characterized by diminished levels of core exhaustion (BATF, ID2, PRDM1, LAYN, DUSP1), and quiescence (TOB1, TSC22D3) related genes, coupled to elevated expression of cell-cycle and proliferation loci (MKI67, CDK1, AURKA, AURKB). In addition, MulTreg display a unique gut homing (CCR7lo β7hi) phenotype and importantly, are more readily expanded from patients with autoimmune disease compared to matched Treg lines, suggesting clinical utility in gut and/or Th1-driven pathology associated with autoimmunity or transplantation. Relative to expanded Tregs, MulTreg retain equivalent and robust purity, FoxP3 TSDR demethylation, nominal effector cytokine production and potent suppression of Th1-driven antigen specific and polyclonal responses in vitro and xeno graft vs host disease (xGvHD) in vivo. These data support the use of MAPC cell co-culture in adoptive Treg therapy platforms as a means to rescue expansion failure and reduce the time required to manufacture a stable, potently suppressive product.

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Regulatory T-cell therapy in Crohn’s disease: challenges and advances

Abstract: The prevalence of IBD is rising in the Western world.

Cited by 122 publications

References 155 publications

Baicalein Restores the Balance of Th17/Treg Cells via Aryl Hydrocarbon Receptor to Attenuate Colitis

Baicalein Restores the Balance of Th17/Treg Cells via Aryl Hydrocarbon Receptor to Attenuate Colitis

Decreased Frequency of Intestinal CD39+ γδ+ T Cells With Tissue-Resident Memory Phenotype in Inflammatory Bowel Disease

Augmented expansion of Treg cells from healthy and autoimmune subjects via adult progenitor cell co-culture

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