A1 TARGETING IL-4 AND IL-13 TO TREAT 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 for intestinal fibrosis are needed as currently, there are no treatment that target intestinal fibrosis directly. 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 PI3Kp110d activity, leading to induction of the enzyme arginase I (argI). Genetic ablation or pharmacologic inhibition of PI3Kp110δ or inhibition of arginase activity block the development of intestinal fibrosis in SHIP-/- mice. IL-4 and IL-13 can activate PI3Kp110δ and IL-4 concentrations are elevated systemically in SHIP-/- mice. Thus, we hypothesize that SHIP-/- mice develop CD-like intestinal fibrosis due to increased IL-4 and/or IL-13 signalling. Purpose Aim 1: To determine whether genetic ablation of IL-4 prevents ileal fibrosis in SHIP-/- mice Aim 2: To determine whether a blocking antibody directed against IL-4 or IL-13 Method SHIP-/- mice were crossed with IL-4 deficient mice (IL-4-/-) to generate wild type, SHIP+/+IL-4-/- SHIP-/-IL-4+/+, and SHIP-/-IL4-/- mice. SHIP-/- mice (6-week-old) were treated with an anti-IL-4 antibody or an anti-IL-13 antibody, IgG isotype control, or PBS (injection control), for 2 weeks. Ileal fibrosis was assessed in SHIP-/- mice comparing mice treated with anti-IL-4 antibody or anti-IL-13 antibody to IgG controls. Measurements of ileal fibrosis included gross and histopathology, muscle thickening, and collagen accumulation (Masson’s trichrome staining for fibrosis). Result(s) SHIP-/-IL-4-/- mice did not have less ileal fibrosis than their SHIP-/- littermates and blocking IL-4 in SHIP-/- mice did not reduce ileal fibrosis. However, blocking IL-13 in SHIP-/- mice reduced ileal fibrosis. Conclusion(s) Blocking IL-4 genetically or with a blocking antibody is insufficient to reduce ileal fibrosis in SHIP-/- mice. Blocking IL-13 with a blocking antibody is sufficient to block the development of ileal fibrosis in SHIP-/- mice. In future experiments, we will cross SHIP-/- mice with IL-13-/- mice to determine whether targeting IL-13 genetically also reduces fibrosis in SHIP-/- mice. We will also determine which receptor IL-13 is signalling through to indue fibrotic pathology in SHIP deficient mice. 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. Disclosure of Interest None Declared
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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 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".