P0876 DIFFERENTIAL POTENCY IN THE RECRUITMENT OF IBD PATIENT NEUTROPHILS ACROSS A MODEL EPITHELIUM BY THE CXC CHEMOKINES, IL‐8 AND ENA‐78
Bibliographic record
Abstract
Introduction: Neutrophils feature prominently in the mucosal cellular landscape of inflammatory bowel disease (IBD), including in the lumen as crypt abscesses. Considering the presumed role of these cells in perpetuating the inflammation, blocking neutrophil infiltration of the epithelium may be an effective means of controlling inflammation. In this study we report that different CXC chemokines associated with IBD show different potencies at recruiting neutrophils across a model epithelium. Methods: Peripheral blood neutrophils of first presentation adolescent Crohn’s disease and ulcerative colitis patients, or healthy donor cells were used with the T84 colonocyte line in Transwell filters. We used the CXC chemoattractants, IL-8, ENA-78 and Gro-alpha and receptor blocking antibodies. IL-8 binds to the receptors CXCR1 and CXCR2 while ENA-78 and Gro-alpha both only bind to CXCR2. Results: IL-8 recruited roughly 50% of the 105 neutrophils added onto bare Transwell filters and across T84 monolayers growing on Transwell filters. In contrast, ENA-78 and Gro-alpha recruited about 25% of the neutrophils across bare filters but only 13% across T84 monolayers. A similar low level of recruitment was observed when IL-8 was used in the presence of anti-CXCR1 antibodies, indicating that recruitment through CXCR2 was significantly less potent than via CXCR1 across epithelial monolayers. Neutrophils stimulated through CXCR1 reportedly increase superoxide radical production and metalloproteinase secretion, which might facilitate epithelial transmigration. However, incubation of patient cells in superoxide dismutase had no effect on migration and neutrophils from a chronic granulomatous patient migrated similar to IBD patient neutrophils, ruling-out any effect of superoxide radicals. Metalloproteinases were ruled-out with pharmacological inhibitors. On the other hand, migration of healthy donor neutrophils to IL-8 was reduced by 35% in the presence of 100muM adenosine and by greater than 50% in response to ENA-78 or Gro-alpha, and migration to ENA-78 and Gro-alpha was almost doubled in the presence of 1 U/ml adenosine deaminase. We are testing whether patient neutrophils show similar CXCR2-dependent responses to adenosine. Conclusion: We conclude that neutrophils stimulated through CXCR2 show reduced migration across epithelial monolayers compared to cells stimulated through CXCR1 and that generation of adenosine by CXCR2 ligands may be responsible for this difference in potency. Supported by grants from the Nova Scotia Health Research Foundation and Crohn’s and Colitis Foundation of Canada.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".