A New Model of Pure Acute Antibody-Mediated Rejection Shows Concurrent Complement-Mediated Injurious and Anti-Inflammatory Effects of High Titer Anti-MHC IgG DSA.
Bibliographic record
Abstract
We developed a new mouse model of acute antibody-mediated rejection (ABMR) in the absence of T and B cells, in which full MHC-mismatched wild type kidneys (CBA) were transplanted into Rag1 knock-out (B6) mice, that were adoptively transferred with high titer (3mg/day) donor specific anti-class 1 antibodies (IgG2a, IgG2b, IgG1) between day 5 to 40 after transplantation. Controls included baseline kidneys and allografts with non-immune IgG or PBS injections.Table: No Caption available.Figure: No Caption available.Allograft recipients with DSA (G4, G6) showed reduced renal function, increased serum levels of C5a and C5b-9, intragraft C4d deposition along peritubular capillaries (PTC) and glomerular capillaries, intragraft antibody deposition, and pathology consistent with Banff type I acute ABMR (acute tubular injury, PTC endothelial swelling, PTC dilatation, focal microthrombi, mild Cd68+ macrophage and Ly49G2+ NK cell infiltrates).Figure: No Caption available.Multiplexed gene expression profiling of kidney allografts with DSA (fdr<0.05) showed significant increases in endothelial activation genes and surprisingly, decreases in MHC class 1 and class 2, Th1-type chemoattractants and their receptor (Cxcl9,10,11, Cxcr3), and NK cell-associated cytolytic granules, in comparison to control allografts with non-immune IgG and/or PBS injections. The presence of anti-inflammatory state in allografts with DSA was associated with upregulation of inhibitory receptor for IgG Fc portion (Fcgr2b). Immunostaining studies to determine intrarenal cellular source of Fcgr2b are ongoing. In conclusion, high titer donor specific IgG antibodies caused concurrent complement-mediated graft damage and a transcriptionally regulated antiinflammatory state. This model may give clues to understand why human ABMR sometimes presents with only ATN-like histology and why some patients with DSA do not develop rejection.
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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) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| 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".