Locally injected MSCs represent a feasible, safe and beneficial therapy in refractory fistulising Crohn's disease.

Background and aims: Epithelium derived interleukin (IL)-15 signalling via IL-15Ra is critical for the development, activation, and survival of intraepithelial lymphocytes (IEL). We aimed to better understand the IL-15 driven effects on IEL underlying mucosal damage and lymphomagenesis in coeliac disease (CD). Methods: Enterocytes, IEL, and lamina propria mononuclear cells (LPMC) were isolated from 46 patients with uncomplicated CD (25 untreated and 21 treated) and 22 controls. IL-15 and IL-15Ra expression were determined by immunoblotting. Secretion of IL-15, interferon c (IFN-c), tumour necrosis factor a (TNF-a), and granzyme B into cell culture supernatants was assessed by ELISA. The ability of IL-15 to regulate IEL proliferation, perforin/granzyme dependent cytotoxicity, and apoptosis was tested by adding different combinations of IL-15, IL-15 blocking antibody, or chloroquine to IEL cultured alone or with Caco-2 cells as target. IL-15 mucosal levels were also determined by ELISA in five patients with complicated CD (two ulcerative jejunoileites, one refractory sprue, and two enteropathy associated T cell lymphomas) tested for T cell receptor c chain clonality. Results: IL-15 was overexpressed in untreated CD enterocytes and LPMC, and in the mucosa of complicated CD patients and uncomplicated untreated CD patients, where its levels correlated with the degree of mucosal damage. Enterocytes from untreated, but not treated, CD patients and controls secreted IL-15. Untreated CD IEL, characterised by higher IL-15Ra expression, showed increased proliferation, production of IFN-c and TNF-a, and perforin/granzyme dependent cytotoxicity, and a decreased propensity to apoptosis in response to IL-15. Conclusions: Our findings suggest that IL-15 plays a crucial role in the generation of epithelial damage in active CD. Its promotion of IEL survival in CD may predispose to the emergence of T cell clonal proliferations. Blocking IL-15, by suppressing uncontrolled IEL activation and survival, has the potential to provide new therapeutic tools to prevent tissue damage and lymphomagenesis in CD.

SummaryCoeliac disease, the most common intestinal disorder of western populations, is an autoimmune enteropathy caused by an abnormal immune response to dietary gluten peptides that occurs in genetically susceptible individuals carrying the HLA-DQ2 or -DQ8 haplotype. Despite the recent progresses in understanding the molecular mechanisms of mucosal lesions, it remains unknown how increased amounts of gluten peptides can enter the intestinal mucosa to initiate the inflammatory cascade. Current knowledge indicates that different gluten peptides are involved in the disease process in a different manner, some fragments being 'toxic' and others 'immunogenic'. Those defined as 'toxic' are able to induce mucosal damage either when added in culture to duodenal endoscopic biopsy or when administered in vivo , while those defined as 'immunogenic' are able to specifically stimulate HLA-DQ2-or DQ8-restricted T cell clones isolated from jejunal mucosa or peripheral blood of coeliac patients. These peptides are able to trigger two immunological pathways: one is thought to be a rapid effect on the epithelium that involves the innate immune response and the other represents the adaptive immune response involving CD4 + + + + T cells in the lamina propria that recognize gluten epitopes processed and presented by antigen presenting cells. These findings are the subject of the present review. Keywords: coeliac disease, gluten, innate immunity, adaptive immunity Definition and clinical description of coeliac diseaseCoeliac disease (CD) may be considered the most common chronic inflammatory condition since the estimated prevalence in Western Countries is near to one per cent [1,2]. CD is an autoimmune enteropathy caused by an abnormal immune response to dietary gluten that occurs in genetically susceptible individuals [3]. The unique well established genetic factor is the HLA-DQ region at 6p21.3 [4] which, however, contributes no more than 40% of the risk, the non-HLA genes being the stronger determinant of CD susceptibility [5]. The broad spectrum of gluten-sensitive intestinal mucosal changes that are characteristic, albeit not pathognomonic of this condition, ranges from a complete disruption of the mucosal architecture with villous flattening and crypt hyperplasia, to a slight increase of inflammatory infiltrate in both the epithelium and lamina propria [6]. Furthermore, from in vivo and ex vivo challenges it has been shown that all the lesions comprise a dynamically interrelated series of events that, however, do not necessarily occur in the same patient [7][8][9]. The wide spectrum of clinical manifestations comprises the classical features of intestinal malabsorption to atypical or asyntomatic cases that now are believed to represent the majority of patients [10]. The only treatment currently available is a lifelong strict adherence to a gluten-free diet that is followed by an amelioration or a normalization of the histological lesions [3,6].As far as pathogenesis is concerned, CD represents a unique and privileged model sinc...