TISSUE-SPECIFIC, BUT NOT STRAIN-SPECIFIC, ACCEPTANCE OF CARDIAC ALLOGRAFTS IN NEONATALLY-TOLERIZED MICE IS MEDIATED BY TRANSFERABLE CD4+CD45RBLOWCD25+ T CELLS
Bibliographic record
Abstract
P954 Aims: Non-donor-specific cardiac allograft acceptance is induced in C3H/He (C3H; H-2k) recipients injected as neonates with fully allogeneic BALB/c (BALB; H-2d) fetal liver cells (FLC). This occurs despite intact reactivity to donor-type and third-party alloantigens in in vitro assays and skin transplants. As we could not find evidence for deletional or anergic mechanisms, we hypothesized that active suppression of allograft rejection by regulatory T cells could be responsible for this unusual phenomenon. To determine the role of regulatory T cells we performed adoptive transfer studies and specifically assessed CD4+ and CD8+ T cells. Methods: 6 populations of cells (30x106 erythrocyte-free splenocytes; 5x106 positive-selected CD4+, 10x106 CD4- [CD8, NK], 1.5x105 CD4+CD45RBlowCD25+, 1x106 CD4+CD45RBlowCD25- and 2x106CD4-CD45RBhighCD25-) from neonatally-treated C3H mice with accepted C57BL/6 (B6; H-2b) third-party cardiac grafts were adoptively transferred by iv injection into sublethally irradiated (6.5 Gy) C3H mice. All inocula were assessed by flow cytometry. Reconstituted mice were challenged 14 days later with B6 cardiac grafts, B6 skin grafts or unrelated (NZW, BALB) cardiac grafts. Separated cell populations were assessed in cocultured proliferative assays and cytokine ELISA. Results: Acceptance of B6 cardiac grafts occurs in 90% of BALB-FLC treated mice and was successfully transferred by unfractionated cells (n=11, 75% graft survival >100d), CD4+ cells (n=6, 85% graft survival >100d) and CD4+CD45RBlowCD25+ cells (n=4, 100% graft survival >60d). Acceptance of unrelated NZW and BALB cardiac grafts was achieved in mice reconstituted with unfractionated splenocytes (n=5, 60% graft survival >60d). C3H reconstituted with CD4- cells (n=5), unfractionated cells from naïve C3H (n=5) or only irradiated C3H mice (n=5) rejected B6 grafts within 32 days. C3H reconstituted with unfractionated cells from neonatally-treated untransplanted C3H mice (n=5) rejected BALB or B6 grafts within 35 days. None of the inocula was able to induce skin graft acceptance. The in vivo suppressive function of CD4+CD45RBlowCD25+ cells was abrogated by anti-CD25 monoclonal antibody PC61, which blocks IL-2 binding to CD25. Cocultured proliferative assays confirmed the suppressive function of CD4+CD45RBlowCD25+cells in vitro, associated with reduced IL-2 and IFN-γ production. Conclusions: These experiments demonstrate that cardiac allograft acceptance in our model is regulated by CD4+ cells expressing the regulatory phenotype CD45RBlowCD25+. The regulatory cell population in this setting is induced by the cardiac graft itself and appears to mediate in vivo acceptance of cardiac grafts specifically. These cells show effective suppression of cardiac allograft rejection even in small numbers and their function is dependent upon ability to bind IL-2. Investigations are ongoing to establish the impact of the initial neonatal FLC treatment.
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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 | 0.002 |
| 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".