Immunomodulatory peptides attenuate local and systemic inflammation in a murine DSS-colitis model
Bibliographic record
Abstract
Innate defence regulator (IDR) peptides are synthetic derivatives of endogenous host defence peptides (HDPs), under investigation as novel anti-infective agents. IDRs lack effective antimicrobial activity; rather, they enhance bacterial clearance by increasing leukocyte recruitment to infection sites while simultaneously suppressing harmful inflammation. We hypothesized that IDRs might be efficacious in attenuating inflammation in a murine DSS colitis model, given that dysfunctional innate immune responses to gut microflora are believed to drive the etiopathogenesis of IBD. Two peptides, IDR-1002 and IDR-1018, were selected for their ability to modulate PBMC cytokine production in vitro, and enhance clearance of Staphylococcus aureus and Escherichia coli in murine infection models. Using a standard model of DSS-colitis, colonic inflammation was induced by addition of 2.75% DSS (w/v) to the drinking water (day 0) of 6-week old male C57BL/6 mice. Mice were randomized to receive 2 doses of IDR-1002 or IDR-1018, 3 doses of IDR-1018, or 3 doses of the endogenous human HDP LL-37. Peptides (200 ug) were administered intraperitoneally on day 1, 3, and 6 (3-dose regime), or on day 4 and 7 (2-dose regime), and mice were euthanized on day 9. Weights were recorded daily, and serum was collected on day 1, 7, and 9, for ELISA quantification of Serum Amyloid A. Colons were excised from cecum to rectum and homogenized for quantification of IL-12p70, IL-10, TNF-a, IL-6, and IFN-g. Colonic myeloperoxidase (MPO) was quantified as a measure of neutrophil infiltration. Sections of the cecum and proximal, mid, and distal colons were formalin fixed, and used to prepare H&E slides for histopathological scoring. Mice administered DSS showed progressive weight loss beginning on day 4 or 5. Both IDR-1002 and IDR-1018 slowed the weight loss trajectory as revealed by linear regression analysis. Relative to healthy controls, colitic animals showed a 4-fold reduction in tissue IL-10, however treatment with IDR-1018 restored IL-10 to healthy levels. Serum amyloid A, a systemic correlate of inflammation, was reduced by 3-4 fold in IDR-1002 and IDR-1018 treated mice. In contrast, tissue levels of MPO, a marker of PMN infiltration, was increased by both IDR-1002 and IDR-1018. Of the HDPs tested, only IDR-1018 improved the histological appearance of colitis, predominately in the cecum and distal colon. When taken together, these data provide the first evidence that IDR peptides being developed as anti-infective agents might one day be used in the treatment of auto-inflammatory diseases. Further research is needed to determine if the effects of IDRs in DSS-colitis are due to enhanced immune killing of intestinal microbiota, attenuation of the inflammatory process, or both.
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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 | 0.000 |
| 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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".