Targeting PI3K signaling to ameliorate chronic graft versus host disease.
Bibliographic record
Abstract
Abstract The phosphoinositide 3-kinase (PI3K) pathway is a key signaling pathway necessary for T cell activation, differentiation and metabolism. T effector cells rely on increased PI3K signaling to fuel glycolysis for their metabolic needs, while T regulatory cells downregulate PI3K and favor lipid oxidation. The metabolic processes of lymphocytes modulating chronic graft versus host disease (cGVHD) have remained largely unexamined and represent a novel therapeutic strategy for this disease. Here, we investigated the role of PI3K signaling in a murine model of cGVHD that is etiologically linked to up regulated germinal centers (GCs) and characterized by multisystem organ disease; including fibrosis of the lung, which results in pulmonary dysfunction. We hypothesized that inhibition of PI3K signaling would alter the activation and/or function of GC-facilitating T follicular helper (TFH) cells resulting in lessened disease. The findings in this study are that mice treated with a PI3Kd inhibitor had decreased pulmonary dysfunction similar to that of the control, non-cGVHD mice. The frequencies of splenic TFH cells as well as GC B cells were decreased by a PI3K delta inhibitor compared to non-treated cGVHD controls. In a similar manner, mice that received PI3K kinase delta dead Tregs also had decreased TFH frequency as well as reduced pulmonary dysfunction. Our results indicate the differential requirement for signaling through PI3K delta and suggest that targeting this pathway may be a potential new therapy for treatment of cGVHD. Additional studies are required to validate the potential therapeutic use.
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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 | 0.000 | 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".