A36 HUMAN INTERLEUKIN-4 EDUCATED MACROPHAGES SUPPRESS DNBS-INDUCED COLITIS IN MICE
Why this work is in the frame
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Bibliographic record
Abstract
We have shown that adoptive transfer of IL-4 stimulated alternatively activated macrophages (AAM) (i.e. M(IL4)) into wild-type mice can inhibit colitis. Mouse models of inflammation have shown that the AAM is important for wound healing: deletion of this type of macrophage can exacerbate disease by impairing wound repair. Translating this to humans, ongoing studies in our laboratory show that human M(IL4)s promote epithelial wound repair in vitro and this process is partially TGFβ dependent. Therefore, we tested the possibility that human M(IL4)s injected into Rag1-/- mice could suppress enteric inflammation. To assess the ability of human M(IL4)s to protect against DNBS-induced colitis in Rag1-/- mice. Human blood-derived macrophages from healthy volunteer donors were exposed to IL-4 (10 ng/ml; 48h) and expression of the M(IL4) markers CD206, CD14, CCL18 was assessed by qPCR. Human M(IL4)s (1x106) or mouse bone marrow-derived M(IL4)s (10 ng/ml; 48h; 1x106), as a positive control, were injected into male Rag1-/- mice (~8 weeks old) in 250 ml PBS ip., 48h before intra-rectal administration of DNBS (3mg in 100 ml 50% ethanol) to elicit colitis (100 ml PBS for controls). Necropsies were performed three days-post DNBS and disease assessed by measuring the colon and calculating macroscopic and histologic damage scores. Macrophages from healthy donors responded to IL-4, converting to M(IL4)s as defined by increased mRNA for CD206 and CCL18 (and protein), and reduced CD14 mRNA. As before, murine M(IL4)s significantly blocked DNBS-induced colitis in Rag1-/- mice (Leung et al., Mol. Med. 2016). Moreover, systemic delivery of human M(IL4)s from 7 of 8 donors resulted in significantly less severe DNBS-induced disease. Compared to DNBS-only treated mice, those given human M(IL4s) had longer colons, reduced macroscopic disease, lower levels of conA-stimulated TNFa production by splenocytes. While average colonic histopathology scores were lower in human M(IL4)-treated mice this was not a statistically different finding. Cellular immunotherapy has the potential to be a component of personalized medicine. Here using a semi-humanized mouse model of colitis we show that treatment with human M(IL4)s substantially reduces disease severity. These data are presented as proof-of-concept support for autologous M(IL4) transfer to treat IBD. CCCNSERC CREATE
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| 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) | 0.000 | 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 it