Background and Aims Vedolizumab is an anti-α4β7 antibody approved for the treatment of ulcerative colitis (UC). Although it is assumed that vedolizumab blocks intestinal homing of lymphocytes, its effects on different intestinal cell populations are not fully stablished. In order to establish the unique mechanisms of action of vedolizumab in UC patients, we compared its effects to those induced by anti-tumor necrosis factor (TNF). Methods Patients with active UC (endoscopic Mayo score >1) starting vedolizumab (n=33) or anti-TNF (n=45) and controls (n=22) were included. Colon biopsies (at weeks 0, 14 and 46) and blood samples (at weeks 0, 2, 6,14, 30 and 46) were used for cell phenotyping, transcriptional analysis (qPCR), and to measure receptor occupancy. Results Vedolizumab, in contrast to anti-TNF, significantly reduced the proportion of α4β7 + cells within intestinal T subsets while preserving the percentage of α4β7 + plasma cells. The marked decrease in α4β7 did not change the percentage of colonic αEβ7 + cells (at 46 weeks). Both vedolizumab and anti-TNF significantly downregulated inflammation-related genes in the colon of responders (Mayo score <2). Moreover, both treatments significantly decreased the percentage of intestinal, but not blood, total lymphocytes (T and plasma cells), as well as the proportion of α4β1 + cells within intestinal T lymphocytes. Conclusions Our data shows that while vedolizumab and anti-TNF block two unrelated targets, they induce remarkably similar effects. On the other hand, vedolizumab’s unique mechanism of action relies on blocking intestinal trafficking of α4β7 T cells, despite effectively binding to B and plasma cells that express α4β7.

Background: Crohn's disease (CD) is a multifactorial disease characterized by chronic intestinal inflammation. The increased visceral adiposity near the affected intestinal area, of which mesenteric adipose tissue (MAT) is the main component, is a feature of CD. Both protective and pathological roles have been attributed to this disease-associated tissue in CD. To understand the contribution of MAT to CD pathophysiology, a molecular and cellular signature of disease-associated MAT in CD patients was provided. Methods: We performed an observational study with whole transcriptional analysis by RNA sequencing (RNA-seq) of MAT and ileal mucosa from CD patients with active disease and controls. qPCR and immunohistology were performed for validation analysis. Results: RNA-seq identified 17 significantly regulated genes (|FC| > 1.5; FDR < 0.05) in CD-MAT compared to non-IBD controls, with a marked upregulation of plasma cell genes (i.e., IGLL5, MZB1, CD79A, POU2AF1, FCRL5, JCHAIN, DERL3, SDC1, PIM2). A less strict statistical cutoff value (|FC| > 1.5, nominal p ≤ 0.05) yielded a larger list of 651 genes in CD-MAT compared to controls. CD ileum showed the significant regulation compared to control ileum of 849 genes (|FC| > 1.5; FDR < 0.05) or 2654 genes (|FC| > 1.5, nominal p ≤ 0.05). Ingenuity Pathway Analysis revealed the significant regulation of pathways related to T-and B cell functionality in the MAT of CD patients. Despite the differences between the MAT and ileal signatures of CD patients, we identified a subset of 204 genes significantly modulated in both tissues compared to controls. This common signature included genes related to the plasma cell signature. Genes such as S100A8, S100A9 (calprotectin) and IL1B, which are associated with acute inflammatory response, were exclusively regulated in the ileal mucosa of CD disease. In contrast, some genes encoding for lymphocyte receptors

Allo-SCT has a strong curative potential for AML patients mainly due to a GVL effect. Unfortunately, GvL and GVHD are intimately linked. IFN regulatory factor-3 (IRF3), by modulating innate immune reactions, could impact on the incidence and intensity of GVL and GVHD. We analyzed two gene variants in IRF3 (rs7251 and rs2304205) on the clinical outcome of 249 AML patients submitted to HLA-identical sibling allo-SCT. Patients with a donor carrying the dominant GG gene variant in rs7251 had, as compared with GC and CC variants, a lower acute GVHD (aGVHD) III-IV incidence (4% vs 11% vs 27%; P ¼ 0.0078), a higher relapse incidence (49% vs 35% vs 26%; P ¼ 0.018), and lower TRM (7% vs 24% vs 18%; P ¼ 0.0065). In functional studies, the GG variant was associated with lower production of IFN-g, decreased lymphocyte proliferation after antigen presentation by DCs, and lower cytotoxic response of mature natural killer cells. Patients carrying the AA dominant variant in rs2304205 had higher relapse incidence (50% vs 39% vs 18%, P ¼ 0.0068). The presence of both variants (GG in rs7251 and AA in rs2304205) in donors and patients resulted in a stronger clinical impact.