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Understanding Therapeutic Concepts in Crohn's Disease.

ABSTRACT: For more than a decade, the therapeutic focus for Crohn's disease has remained fixed at temporary arrestment of symptomology. The Centers for Disease Control and Prevention (CDC) lists Crohn's disease as a disease entity without current cure. Biologics in combination with antibiotics can frequently achieve remissions. Without ongoing drug administration, these remissions tend to be of limited duration. Conceptual advancements in understanding the pathogenesis of Crohn's disease have identified treatment approaches, the focus of which goes beyond temporary remission. Concepts derived from Infectious Diseases Inc.'s 17?years of research with Mycobacterium avium subspecies paratuberculosis delineate how new knowledge can be integrated to achieve more sustained remissions.

SUBMITTER: Monif GR

PROVIDER: S-EPMC6287291 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Understanding Therapeutic Concepts in Crohn's Disease.

Monif Gilles Rg GR

Clinical medicine insights. Gastroenterology 20181203

For more than a decade, the therapeutic focus for Crohn's disease has remained fixed at temporary arrestment of symptomology. The Centers for Disease Control and Prevention (CDC) lists Crohn's disease as a disease entity without current cure. Biologics in combination with antibiotics can frequently achieve remissions. Without ongoing drug administration, these remissions tend to be of limited duration. Conceptual advancements in understanding the pathogenesis of Crohn's disease have identified t ...[more]

PMID: 30546265

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Project description:BackgroundNetwork concepts are increasingly used in biology and genetics. For example, the clustering coefficient has been used to understand network architecture; the connectivity (also known as degree) has been used to screen for cancer targets; and the topological overlap matrix has been used to define modules and to annotate genes. Dozens of potentially useful network concepts are known from graph theory.ResultsHere we study network concepts in special types of networks, which we refer to as approximately factorizable networks. In these networks, the pairwise connection strength (adjacency) between 2 network nodes can be factored into node specific contributions, named node 'conformity'. The node conformity turns out to be highly related to the connectivity. To provide a formalism for relating network concepts to each other, we define three types of network concepts: fundamental-, conformity-based-, and approximate conformity-based concepts. Fundamental concepts include the standard definitions of connectivity, density, centralization, heterogeneity, clustering coefficient, and topological overlap. The approximate conformity-based analogs of fundamental network concepts have several theoretical advantages. First, they allow one to derive simple relationships between seemingly disparate networks concepts. For example, we derive simple relationships between the clustering coefficient, the heterogeneity, the density, the centralization, and the topological overlap. The second advantage of approximate conformity-based network concepts is that they allow one to show that fundamental network concepts can be approximated by simple functions of the connectivity in module networks.ConclusionUsing protein-protein interaction, gene co-expression, and simulated data, we show that a) many networks comprised of module nodes are approximately factorizable and b) in these types of networks, simple relationships exist between seemingly disparate network concepts. Our results are implemented in freely available R software code, which can be downloaded from the following webpage: http://www.genetics.ucla.edu/labs/horvath/ModuleConformity/ModuleNetworks.

Project description:Background: Despite significant progress in the research of fibrosis in various organs, fibrosis remains a poorly understood complication of Crohn's disease (CD). We analyzed pathologic features of fibrosis and inflammation in CD and compared them with the normal bowel, aiming to clarify whether fibrosis in CD pathogenetically resembles fibrosis in other organs. Methods: Resection specimens from 30 patients with CD were included. Normal bowel from resection specimens of colorectal carcinoma was used for comparison. Trichrome Masson staining, immunohistochemistry for α-smooth muscle actin, fibroblast activation protein, CD34 and erg, in situ hybridization for TGF-β1 and analysis of selected fibrosis-related microRNAs were performed. Results: In normal bowel, CD34-positive fibroblasts/pericytes were detected in the submucosa and subserosa, particularly around blood vessels. In CD, fibrosis prevailed in the submucosa and subserosa, together with proliferation of myofibroblasts and disappearance of CD34-positive fibroblasts/pericytes. TGF-β1 was present in the lamina propria in normal bowel and CD, and in deeper parts of the bowel wall in CD. MicroRNAs miR-29c, miR-155 miR-150, and miR-155, which have been demonstrated to contribute to fibrosis in various organs, showed significant deregulation in CD. Conclusions: Distribution of fibroblasts/pericytes in the submucosa and subserosa of normal bowel, their disappearance in fibrosis in CD, together with the appearance of myofibroblasts, suggest that fibroblasts/pericytes are the most likely source of myofibroblasts in CD. Furthemore, fibrosis-related microRNAs showed deregulation in fibrotic areas. Pathogenesis of fibrosis in CD is thus comparable to fibrosis in other organs, in which myofibroblasts are the key effector cells, and pericytes have emerged as the main origin of myofibroblasts. Fibrosis in CD should be regarded as a result of (over)response of the bowel wall to the presence of inflammation in deep structures of the bowel wall, presenting another example of a common pathogenetic pathway of fibrosis development.

Project description:Background and Aim:Interleukin-21 (IL-21) is primarily a T cell-derived cytokine; it is upregulated in patients with Crohn's Disease (CD) and could be a potential new therapeutic target in CD. Methods:In human material, IL-21 and IL-21R expression was investigated by in situ hybridization (ISH) and immunohistochemistry (IHC) in noninflammatory bowel disease (non-IBD) controls and patients with CD. The pathologic role of IL-21 was examined in murine models of T cell-dependent and T cell-independent colitis, either with a neutralizing monoclonal antibody against IL-21 or with the transfer of CD4+CD45RBhighIL-21R-/- T cells. Colonic pathology was examined by endoscopy, histopathology, IHC, ELISA, and Luminex. Results:In the human intestine, IL-21 and IL-21R mRNA and protein-expressing cells were observed in the mucosa, in lymphoid aggregates of submucosa in non-IBD controls, and in lymphoid aggregates of muscularis externa in patients with CD. IL-21 expression was most abundant in germinal centers (GCs) of the lymphoid aggregates, and IL-21R expression assessed semiquantitatively, was significantly higher in patients with CD compared to non-IBD controls. Following prophylactic and interventive anti-IL-21 mAb treatment in the adoptive transfer (AdTr) model, clinical and pathological parameters were significantly reduced. The most persistent finding was a reduction in colonic infiltrating neutrophils. As well, Rag2-/- mice receiving CD4+CD45RBhighIL-21R-/- T cells developed less severe colitis compared to Rag2-/- mice receiving CD4+CD45RBhighIL-21R+/+ T cells. No effect of reduced IL-21 signalling was observed in T cell-independent colitis. Conclusion:Our study shows that patients with CD have significant expression of IL-21 and IL-21R in the gut. As well, we show that neutralization of IL-21 in experimental T cell-driven colitis is associated with a reduction in clinical and pathological findings. This amelioration seems to be associated with a reduction in colon-infiltrating neutrophils.

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Understanding Therapeutic Concepts in Crohn's Disease.

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Understanding Therapeutic Concepts in Crohn's Disease.

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