Dendritic cells (DCs) and monocyte-derived macrophages (M s) are key components of intestinal immunity. However, the lack of surface markers differentiating M s from DCs has hampered understanding of their respective functions. Here, we demonstrate that, using CD64 expression, M s can be distinguished from DCs in the intestine of both mice and humans. On that basis, we revisit the phenotype of intestinal DCs in the absence of contaminating M s and we delineate a developmental pathway in the healthy intestine that leads from newly extravasated Ly-6C hi monocytes to intestinal M s. We determine how inflammation impacts this pathway and show that T cell-mediated colitis is associated with massive recruitment of monocytes to the intestine and the mesenteric lymph node (MLN). There, these monocytes differentiate into inflammatory M s endowed with phagocytic activity and the ability to produce inducible nitric oxide synthase. Eur. J. Immunol. 2012. 42: 3150-3166 HIGHLIGHTS 3151 IntroductionThe intestinal lamina propria (LP) contains cells that express high levels of CX 3 CR1, the receptor for the fractalkine chemokine [1,2]. Based on their monocytic origin and on their inability to migrate to the mesenteric lymph nodes (MLNs) such CX 3 CR1 hi cells have been defined as macrophages (M s) [1][2][3]. CX 3 CR1 hi M s contribute to the intestinal LP homeostasis through the production of anti-inflammatory cytokines and the clearance of commensal bacteria that breach the epithelial barrier [4]. In contrast, during intestinal inflammation, microenvironmental signals promote the differentiation of extravasated monocytes into proinflammatory M s with the ability to produce interleukin (IL)-12, IL-23, tumor necrosis (TNF)-α and inducible nitric oxide synthase (iNOS) [5][6][7]. However, little is known about the developmental trajectories that lead extravasated monocytes to either antior proinflammatory intestinal M s. This is primarily due to the fact that a surface marker permitting unequivocal identification of M s within the intestine and their distinction from dendritic cells (DCs) is lacking. The interstitial DCs (Int-DCs) present throughout the LP derive from blood precursors known as pre-DCs [2]. Under steady-state conditions, the Int-DCs found in the intestinal LP induce oral tolerance by carrying antigens originating from food or from harmless bacteria to the MLNs [8,9]. The CD103 + Int-DCs found in the steady-state LP have the selective ability to express aldehyde dehydrogenase (ALDH) and thereby produce retinoic acid (RA). As a result, upon migration to MLNs they trigger the differentiation of naive CD4 + T cells specific for food and microbiota antigens into induced Foxp3 + regulatory T (iTreg) cells [10][11][12][13]. In contrast, the Int-DCs that develop in inflamed LP upon exposure to pathogens lose their capacity to generate iTreg cells and, upon migration to the MLNs, trigger the differentiation of naive, antigen-responsive CD4 + T cells into T helper type 1 (Th1) cells that are specific for the invading patho...

Trying to conceive and being pregnant is an emotional period for those involved. In the majority of patients suffering from inflammatory bowel disease, maintenance therapy is required during pregnancy to control the disease, and disease control might necessitate introduction of new drugs during a vulnerable period. In this updated consensus on the reproduction and pregnancy in inflammatory bowel disease reproductive issues including fertility, the safety of drugs during pregnancy and lactation are discussed.

This paper is the second in a series of two publications relating to the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the diagnosis and management of Crohn's disease [CD] and concerns the surgical management of CD as well as special situations including management of perianal CD and extraintestinal manifestations. Diagnostic approaches and medical management of CD of this ECCO Consensus are covered in the first paper [Gomollon et al JCC 2016].

We showed that healthcare costs are mainly driven by medication costs, most importantly by anti-TNFα therapy. Hospitalisation and surgery accounted only for a minor part of the healthcare costs.

Local administration of allogeneic MSCs was not associated with severe adverse events in patients with perianal fistulizing Crohn's disease. Injection of 3 × 10(7) MSCs appeared to promote healing of perianal fistulas. ClinicalTrials.gov ID NCT01144962.

Background and Aims Ustekinumab is approved for the treatment of Crohn’s disease [CD]. Systematically registered prospective real-world data are scarce. We therefore aimed to study the effectiveness, safety and usage of ustekinumab for CD in everyday practice. Methods We prospectively enrolled CD patients initiating ustekinumab in regular care between December 2016 and January 2019. Clinical (Harvey Bradshaw Index [HBI]), biochemical (C-reactive protein [CRP] and faecal calprotectin [FCP]), extra-intestinal manifestations and, peri-anal fistula activity, ustekinumab dosage, concomitant medication use, and adverse events were documented at weeks 0, 12, 24, and 52. The primary outcome was corticosteroid-free clinical remission. Results In total, 221 CD patients were included (98.6% anti-tumour necrosis factor [TNF] and 46.6% vedolizumab exposed) with a median follow-up of 52.0 weeks [interquartile range 49.3–58.4]. Corticosteroid-free clinical remission rates at weeks 24 and 52 were 38.2% and 37.1%, respectively. An initial dosing schedule of 8 weeks, compared to 12 weeks, correlated with a lower discontinuation rate [20.0% vs 42.6%, p = 0.01], but comparable corticosteroid-free clinical remission at week 52 (46.3% [q8w] vs 34.6% [q12w], p = 0.20). There was no clinical benefit of combination therapy after 52 weeks when compared to ustekinumab monotherapy [combi 40.6% vs mono 36.0%, p = 0.64]. At baseline, 28 patients had active peri-anal fistula, of whom 35.7% showed complete clinical resolution after 24 weeks. During follow-up we encountered six severe infections [3.5 per 100 patient-years], with all patients being on concomitant immunosuppressant therapies. Ustekinumab treatment discontinuation was observed in 75 [33.9%] patients mainly due to lack of response. Conclusion Ustekinumab is a relatively safe and effective treatment option for CD patients with prior failure of anti-TNF and anti-integrin therapies.

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GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.