Molecular Events in Human T Cell-Mediated Rejection: The Relationship Between Innate Immunity and Cognate Recognition.
Bibliographic record
Abstract
The molecular events specific for biopsies with T cell-mediated rejection (TCMR) are of interest as a prototype for many T cell-mediated inflammatory diseases. The present study examined the secondary events that occur in TCMR - inflammasome activation, innate immunity, the parenchymal injury response, and their relative association with the cognate TCMR signal that reflects TCMR-APC synapse. In a discovery set of microarrays from 403 biopsies, we generated a hierarchy of TCMR-associated transcripts (defined by p-value) by comparing TCMR to all other biopsies, including antibody-mediated rejection, acute kidney injury, polyomavirus nephropathy, glomerulonephritis, and non-specific atrophy-fibrosis. Transcripts previously identified by a molecular classifier for TCMR, shown as black diamonds in Figure 1 - eg. CD8A, SH2D1A, IFNG, ADAMDEC1, CXCL13 (Reeve et al. Am J Transplant 13(3):2013) - had the greatest association with TCMR (p-values as low as 10-27). Other classes of transcripts, despite high fold increases, had moderate associations with TCMR (p-values >10-18). These included rejection biomarkers, shown as asterisks (eg. CXCL9/10/11, GZMA/B, PRF1); inflammasome-related transcripts, shown as grey squares (eg. PYCARD, CASP1, IL1B, IL18); toll-like receptors 7/8/9, shown as grey circles; IFNG-induced transcripts, shown as white triangles (eg. UBD and HLA-A/B/C); and kidney solute carrier (SLC) transcripts, shown as black crosses. These associations were confirmed in a validation set of 300 additional kidney transplant indication biopsies.Figure: No Caption available.TLR8 was moderately (p=10-15) associated with TCMR, but stronger than TLR7/9. Among inflammasome transcripts, CASP1 (six probesets) was moderately associated with TCMR (p=10-13), whereas IL1B (whose precursor is cleaved by CASP1), IL18, and CASP8 were much less associated, as was CD95 (Fas). All findings were confirmed in the validation set. The descending hierarchy of the TCMR classifier transcripts, inflammasome and TLR transcript associations with TCMR suggest that molecular events in TCMR are principally controlled by the cognate events, including those in macrophage-dendritic APCs as judged by the striking association of ADAMDEC1 and CXCL13 with TCMR. DISCLOSURES:Halloran, P.: Speaker's Bureau, Astellas, Novartis, OneLamba.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".