The engagement of the aryl hydrocarbon receptor by tryptophan derivatives can prevent the development of anti-FVIII antibodies in an experimental model of hemophilia A
Bibliographic record
Abstract
Abstract Patients affected by haemophilia A require treatment with factor VIII (FVIII) protein. The most relevant complication is the development of neutralizing FVIII-specific antibodies or "inihibitors". We reported that the inhibitor-positive status was associated with reduced activity of the immune-regulatory enzyme indoleamine 2,3-dioxygenase 1 (IDO1), that promotes regulatory effects via the production of tryptophan catabolites, known as kynurenines. Some of those tryptophan derivatives are endogenous ligands for the Aryl hydrocarbon receptor (AhR). In this study we tested the potential of tryptophan-related AhR ligands for inhibiting the development of anti-FVIII antibodies in hemophilic (F8 KO) mice. To this aim, F8 KO mice were treated with recombinant human FVIII (rhFVIII) alone or in combination with selected AhR ligands once weekly for four weeks. Antibody titers were tested by specific ELISA and Bethesda test. All mice treated with rhFVIII developed high-titer anti-FVIII antibodies after 4 weeks of treatment. Administration of a specific tryptophan metabolite prevented the generation of anti-FVIII antibodies in almost 80% of F8 KO mice. The protective effect of these AhR ligands was negated by co-administration of the AhR antagonist CH-223191 or in AhR KO mice. Similar results were obtained by administration of engineered gold nanoparticles loaded with the same tryptophan metabolite and rhFVIII. These results suggest that the engagement of AhR, by specific tryptophan derivatives, may be a possible new strategy to control the immune response to rhFVIII. Our findings might lead to the development of novel immunomodulatory interventions for preventing or eradicating inhibitors in hemophilia A patients.
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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) | 0.000 | 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 | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 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".