Abstract Or307: Preferential Skewing of Cardiac iNKT1-mediated Response by α-GalCer/CD1d Treatment Without Exacerbating Doxorubicin-induced Cardiotoxicity
Bibliographic record
Abstract
Background: Invariant natural killer T (iNKT) cells are a unique subset of the innate immune system activated by T cell receptor (TCR) signaling through CD1d molecules presenting lipid antigens. Tissue-specific iNKT cells are critical in maintaining homeostasis and regulating pathophysiology. However, the potential roles of iNKT subsets in mitigating cardiac damage remain poorly understood. In this study, we examined the role of cardiac iNKT subsets and their response to TCR-directed αGalCer/CD1d complexes in a mouse model of Doxorubicin (Dox)-induced cardiotoxicity. Methods: A chronic model of Dox-induced cardiotoxicity was developed in C57BL/6J mice. After the fourth dose of Dox treatment, mice were randomly divided into two groups and intraperitoneally administered either CD1d-empty monomer (Dox+empty/CD1d) or αGalCer/CD1d (Dox+αGalCer/CD1d) (20 μg/mouse/week, dissolved in phosphate-buffered saline) for 7 weeks. The control mice were administered with PBS. iNKT cell expansion in the heart was analyzed by flow cytometry. Cardiac function was assessed by echocardiography, and histological analyses were used to evaluate cardiac remodeling. Results: Our findings reveal that the heart predominantly harbors the pro-inflammatory iNKT1 subset, with smaller populations of anti-inflammatory iNKT2 and iNKTR1 subsets. Under homeostatic conditions, treatment with αGalCer/CD1d complexes preferentially expanded the iNKT1 subset. In Dox-induced cardiotoxicity, αGalCer/CD1d treatment favored iNKT1-derived Ifng expression. These observations suggest that αGalCer/CD1d treatment skewed the cardiac iNKT cell population towards the iNKT1 subset, potentially altering the inflammatory balance within the heart. However, it did not exacerbate cardiac damage, likely due to compensatory IL-10 production by an unidentified regulatory subset. Overall, αGalCer/CD1d treatment promoted the expansion of iNKT1 cells and elevated IFN-γ levels with modest therapeutic effects on cardiac function. Conclusion: These findings highlight the importance of iNKT-mediated cardiac immune regulation in the heart and emphasize the potential of targeting iNKT cells for therapeutic benefit. Further studies are warranted to determine if TCR-directed immunotherapeutics could be modified to skew immune responses for effectively treating inflammatory cardiac diseases.
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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) | 0.000 | 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 | 0.001 |
| 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".