MHC-Matched A-Expressing Blood Cells Induce ABO Tolerance in Infant and Adult Mice
Bibliographic record
Abstract
Purpose ABO-incompatible heart transplantation (ABOi HTx) is safe during infancy and allows increased donor access. Post-ABOi HTx B cell tolerance develops to donor blood group antigen(s) by mechanisms not fully defined. We developed A-transgenic mice (A-Tg) that express A-antigen on vascular endothelium and erythrocytes and demonstrated A-antigen specific tolerance induced by HTx into 4 wk-old, MHC-identical, wild-type (WT) mice. Herein, we explored intentional tolerance induction in infant and adult WT mice using A-Tg blood cells. Methods WT BALB/c mice were injected ip (weekly×3) with intact A-Tg BALB/c blood cells (±40Gy irradiated), beginning at 7 days (neonates) or 5 months of age (adults; see Table). Two weeks after treatment, all mice were injected ip (weekly×5) with human A-erythrocytes (‘A-sensitized’) in an attempt to elicit anti-A antibody (Ab) production. Serum anti-A and 3rd-party (non-A anti-human) Ab were assessed by hemagglutination assay. Results In response to A-sensitization, high levels of anti-A Ab were produced in untreated mice (group 1, Table). In contrast, anti-A remained undetectable in A-sensitized mice previously treated as neonates with A-Tg blood cells ±irradiation (groups 2&3). Treatment of adult mice (groups 4&5) with A-Tg blood cells resulted in reduced anti-A production in response to A-sensitization compared with untreated mice (group 1). Adult mice with undetectable natural anti-A (group 4) produced less anti-A vs those with pre-existing natural anti-A (group 5). Third-party antibody responses were high for all groups. Conclusions Our results suggest that the erythrocyte component of A-Tg blood cells can induce robust A-antigen-specific tolerance in WT mice. Importantly, our findings suggest that tolerance to A-antigen is not limited to the neonatal period but can also be induced in adults, especially in mice without previously detectable natural anti-A antibody. Intentional induction of tolerance to A/B-antigen(s) may allow subsequent ABOi HTx. Supported by Heart and Stroke Foundation of Canada; Women and Children’s Health Research Institute, University of Alberta; Alberta Innovates Health Solutions; and the Canadian Institutes of Health Research (CIHR) through the Canadian National Transplant Research Program (CNTRP).
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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 | 0.001 | 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) | 0.002 | 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".