Dissecting the Cognate Event in Human Kidney Transplants With T Cell-Mediated Rejection.
Bibliographic record
Abstract
We hypothesized that the molecular changes most associated with TCMR would reveal the cognate event - T cell-APC engagement in the graft - and distinguish this from the inflammatory response (IFNG effects, innate immunity) and the injury response. We analyzed microarray data from indication kidney transplant biopsies: 403 as a discovery set and 300 as an independent validation set. In the discovery set we generated the top 300 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; then analyzed these transcripts for overrepresentation in the curated IPA Canonical Pathways (Ingenuity Systems). The top pathways were associated with proximal signals of T cell activation - signal 1 pathways T Cell Receptor Signaling (p=2.0x10-12) and PKC-theta Signaling (p=3.0x10-10) - and signal 2 pathways iCOS-iCOSL (p=7.9x10-14), CD28 (p=2.0x10-12), and CTLA4 Signaling (p=3.0x10-10). Shown in Figure 1, the signal 2 pathways shared many transcripts (eg CD3D, LCK, ZAP70, LAT, ITK) with signal 1. Reasoning that the TCMR-associated transcripts must reflect T cell receptor triggering, we removed the transcripts used in the T Cell Receptor Signaling Pathway and reran pathway analysis - Step 2 of Figure 1. Top pathways no longer included proximal signals of T cell activation, but rather T Helper Cell Differentiation (p=4.0x10-8) and Antigen Presentation (p=9.1x10-6), which included HLA-DMA/B, -DOA, IFNG, IL12RB1, IL21R, and STAT1. Subsequent removal of these transcripts and re-analysis of the TCMR-associated transcripts left weak pathway associations representing innate immunity - Step 3 of Figure 1. All findings were confirmed in the validation set.Figure: No Caption available.The minimal model that accounts for the pathway ontology is that the cognate event in TCMR activates both the effector T cell and various APCs (dendritic cells, macrophages, and B cells), triggering antigen presentation (HLA-DMA/B, DOA/DOB) and specific cytokine crosstalk (IL21 and IL12), including IFNG. This method of stratifying pathway analysis into distinct layers could be applied to other well phenotyped diseases. DISCLOSURES:Halloran, P.: Speaker's Bureau, Astellas, Novartis, OneLamba.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 | 0.001 |
| 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) | 0.001 | 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".