A195 IL-13 DRIVES CROHN’S DISEASE ASSOCIATED-INTESTINAL FIBROSIS IN SHIP DEFICIENT MICE
Bibliographic record
Abstract
Abstract Background Crohn’s disease (CD) is an immune-mediated disease characterized by chronic, relapsing and remitting, or progressive inflammation of the digestive tract. One in 3 people with CD will develop intestinal fibrosis requiring surgery within 10 years of diagnosis. Biological therapy is effective at reducing inflammation in CD and early and aggressive treatment with biologics will reduce the incidence of fibrosis. However, in children, for whom a step-up approach to therapy is used, and populations that are refractory to biological therapy; fibrosis remains a serious concern. Treatments are urgently needed as currently there are no treatments that target intestinal fibrosis directly in CD. Mice deficient in the Src homology 2 domain-containing inositolpolyphosphate 5’-phosphatase (SHIP-/-) develop spontaneous CD-like ileal inflammation and fibrosis. Fibrosis is dependent on PI3Kp110δ activity. IL-4 and IL-13 lead to downstream activation of PI3Kp110δ. Recent work in our lab has shown through pharmacological inhibition that the development of fibrosis in SHIP-/- mice is dependenet on IL-13 signaling, but not IL-4. Aims Aim 1: To determine whether genetic ablation of IL-13 prevents ileal fibrosis in SHIP-/- mice Aim 2: To determine the cellular source of IL-13 in the distal ileum of SHIP-/- mice Aim 3: To determine the cellular source of IL-13 in the distal ileum of individuals with CD Methods SHIP-/- mice were crossed with IL-13 deficient mice (IL13-/-) to generate SHIP+/+IL13+/+, SHIP+/+IL13-/-, SHIP-/-IL13+/+, and SHIP-/-IL13-/- mice. Measurements of ileal fibrosis included gross and histopathology, muscle thickening, and collagen accumulation (Masson’s trichrome staining for fibrosis). Single cell RNA sequencing (snRNA-seq) was performed on the distal ileum of SHIP-/- mice to determine the cellular source of IL-13. Previously published scRNA-seq data were analyzed to determine the cellular source of IL-13 in individuals with CD. Results Genetic ablation of IL-13 in SHIP-/- mice (SHIP-/-IL13-/-) reduced the development of ileal fibrosis. Analysis of single cell RNA sequencing data (scRNA seq) has revealed mast cells as the cellular source of IL-13 in the distal ileum of people with CD. Conclusions Mast cell derived IL-13 may be driving the development of intestinal fibrosis in CD. Our data suggest that an antibody-based biologic targeting IL-13 may be an effective strategy to prevent fibrosis in people with Crohn’s Disease. Funding Agencies CAG, CIHR
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.007 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".