CD8+ T LYMPHOCYTES MEDIATE ALLOGRAFT VASCULOPATHY BY DIRECT CYTOLYSIS AND AN INTERFERON-Г-DEPENDENT INDIRECT EFFECTOR PATHWAY
Bibliographic record
Abstract
P1023 Aims: Allograft vasculopathy (AV) has emerged as the major obstacle to long-term survival in clinical heart transplantation. Although immune events are implicated in the development of AV, the cellular and molecular mechanisms involved remain unclear. In this study we examined the role of CD8+ T lymphocyte effector mechanisms in the development of AV. Methods and Results: The transfer of allo-primed CD8+ T lymphocytes into immunodeficient recombinase activating gene-1 knockout (RAG-1−/−) mouse recipients of fully histo-incompatible aortic allografts results in the development of AV, confirming that CD8+ effector T cells are sufficient to induce AV. We also used CD8+ T cells with targeted deletions of effector molecules necessary for the granule-exocytosis and the Fas-Fas ligand (FasL) pathways to demonstrate that CD8+ T cell-mediated AV occurs, at least in part, through direct cytolysis. We confirmed that non-cytotoxic T lymphocyte (CTL) effector mechanisms contribute to AV by adoptive transfer of allo-primed CD8+ T cells into RAG-1−/− recipients of MHC class I-deficient allografts. In these latter experiments primed CD8+ T cells from wildtype mice induced AV, whereas CD8+ T cells from interferon-γ deficient mice did not, confirming the existence of non-CTL effectors and suggesting an important role for interferon-γ. Furthermore, AV mediated by CD8+ T cells, but not CD4+ T cells, is refractory to cyclosporine A (50 mg/kg/d) treatment. Conclusions: These data indicate that CD8+ T cells mediate AV through direct cytolysis and a distinct interferon-γ-dependent indirect effector pathway. This study demonstrates the impact of CD8+ T cells on the development of AV. Given the resistance of this cell type to conventional immunosuppression these results may have important therapeutic implications.
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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 | 0.001 | 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".