Crohn's disease-associated and cryptoglandular fistulas: differences and similarities

Perianal fistulas are defined as pathological connections between the anorectal canal and the perianal skin. Most perianal fistulas are cryptoglandular fistulas, which are thought to originate from infected anal glands. The remainder of the fistulas mainly arises as complications of Crohn's disease (CD), trauma, or as a result of malignancies. Fistulas in CD are considered as a consequence of a chronic and transmural inflammatory process in the distal bowel and can, in some cases, even precede the diagnosis of CD. Although both cryptoglandular and CD-associated fistulas might look similar macroscopically, they differ considerably in their complexity, treatment options, and healing rate. Therefore, it is of crucial importance to differentiate between these two types of fistulas. In this review, the differences between CD-associated and cryptoglandular perianal fistulas in epidemiology, pathogenesis, and clinical management are discussed. Finally, a flow chart is provided for physicians to guide them when dealing with patients displaying their first episode of perianal fistulas.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Local administration of mesenchymal stromal cells is safe and modulates the immune compartment in ulcerative proctitis

BACKGROUND. Due to their immunoregulatory and tissue regenerative features, mesenchymal stromal cells (MSCs) are a promising novel tool for the management of ulcerative proctitis (UP). Here we report on a phase IIa clinical study that evaluated the impact of local MSC therapy on UP. METHODS. Thirteen refractory UP patients, with an endoscopic Mayo score (EMS) of 2 or 3, were included. Seven patients received 20-40 million allogeneic MSCs (cohort 1), while 6 patients received 40-80 million MSCs (cohort 2). Adverse events (AEs) were assessed at baseline and on weeks 2, 6, 12, and 24. Clinical, endoscopic, and biochemical parameters were assessed at baseline and on weeks 2 and 6. Furthermore, we evaluated the engraftment of MSCs, the presence of donor -specific human leukocyte antigen (HLA) antibodies (DSAs), and we determined the impact of MSC therapy on the local immune compartment. RESULTS. No serious AEs were observed. The clinical Mayo score was significantly improved on weeks 2 and 6, and the EMS was significantly improved on week 6, compared with baseline. On week 6, donor MSCs were still detectable in rectal biopsies from 4 of 9 patients and DSAs against both HLA class I and class II were found. Mass cytometry showed a reduction in activated CD8+ T cells and CD16+ monocytes and an enrichment in mononuclear phagocytes and natural killer cells in biopsies after local MSC therapy. CONCLUSION. Local administration of allogeneic MSCs is safe, tolerable, and feasible for treatment of refractory UP and shows encouraging signs of clinical efficacy and modulation of local immune responses. This sets the stage for larger clinical trials.TRIAL REGISTRATION. EU Clinical Trials Register (EudraCT, 2017-003524-75) and the Dutch Trial Register (NTR7205).Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Enhanced CD8 T Cell Responses through GITR-Mediated Costimulation Resolve Chronic Viral Infection

Tumorimmunolog

Activated HLA-DR+CD38+ Effector Th1/17 cells distinguish Crohn's disease-associated perianal fistulas from cryptoglandular fistulas

Background: Perianal fstulas are a debilitating complication of Crohn’s disease (CD). Due to unknown reasons, CD-associated fstulas are in general more diffcult to treat than cryptoglandular fstulas (non-CD-associated). Understanding the immune cell landscape is a frst step towards the development of more effective therapies for CD-associated fstulas. In this work, we characterized the composition and spatial localization of disease-associated immune cells in both types of perianal fstulas by high-dimensional analyses. Methods: We applied single-cell mass cytometry (scMC), spectral fow cytometry (SFC), and imaging mass cytometry (IMC) to profle the immune compartment in CD-associated perianal fstulas and cryptoglandular fstulas. An exploratory cohort (CD fstula, n = 10; non-CD fstula, n = 5) was analyzed by scMC to unravel disease-associated immune cell types. SFC was performed on a second fstula cohort (CD, n = 10; non-CD, n = 11) to comprehensively phenotype disease-associated T helper (Th) cells. IMC was used on a third cohort (CD, n = 5) to investigate the spatial distribution/interaction of relevant immune cell subsets. Results: Our analyses revealed that activated HLA-DR+CD38+ effector CD4+ T cells with a Th1/17 phenotype were signifcantly enriched in CD-associated compared with cryptoglandular fstulas. These cells, displaying features of proliferation, regulation, and differentiation, were also present in blood, and colocalized with other CD4+ T cells, CCR6+ B cells, and macrophages in the fstula tracts. Conclusions: Overall, proliferating activated HLA-DR+CD38+ effector Th1/17 cells distinguish CD-associated from cryptoglandular perianal fstulas and are a promising biomarker in blood to discriminate between these 2 fstula types. Targeting HLA-DR and CD38-expressing CD4+ T cells may offer a potential new therapeutic strategy for CD-related fstulas.</p

Identification of a Disease-Associated Network of Intestinal Immune Cells in Treatment-Naive Inflammatory Bowel Disease

Chronic intestinal inflammation underlies inflammatory bowel disease (IBD). Previous studies indicated alterations in the cellular immune system; however, it has been challenging to interrogate the role of all immune cell subsets simultaneously. Therefore, we aimed to identify immune cell types associated with inflammation in IBD using high-dimensional mass cytometry. We analyzed 188 intestinal biopsies and paired blood samples of newly-diagnosed, treatment-naive patients (n=42) and controls (n=26) in two independent cohorts. We applied mass cytometry (36-antibody panel) to resolve single cells and analyzed the data with unbiased Hierarchical-SNE. In addition, imaging-mass cytometry (IMC) was performed to reveal the spatial distribution of the immune subsets in the tissue. We identified 44 distinct immune subsets. Correlation network analysis identified a network of inflammation-associated subsets, including HLA-DR(+)CD38(+) EM CD4(+) T cells, T regulatory-like cells, PD1(+) EM CD8(+) T cells, neutrophils, CD27(+) TCR gamma delta cells and NK cells. All disease-associated subsets were validated in a second cohort. This network was abundant in a subset of patients, independent of IBD subtype, severity or intestinal location. Putative disease-associated CD4(+) T cells were detectable in blood. Finally, imaging-mass cytometry revealed the spatial colocalization of neutrophils, memory CD4(+) T cells and myeloid cells in the inflamed intestine. Our study indicates that a cellular network of both innate and adaptive immune cells colocalizes in inflamed biopsies from a subset of patients. These results contribute to dissecting disease heterogeneity and may guide the development of targeted therapeutics in IBD