Abstract 13988: Class II Major Histocompatibility Complex Transactivator (CIITA) Knockdown Prevents Immune Rejection of Allogeneic Bone Marrow Stem Cells in Cardiac Regeneration
Bibliographic record
Abstract
Introduction: Allogeneic young mesenchymal stem cells (MSCs) are excellent candidates for cardiac repair due to their great regenerative potential and immunoprivilege. However, their differentiation increases major histocompatibity complex II (MHC II) expression which induces transition from an immunoprivileged to an immunogenic state. The expression of MHC II is transcriptionally regulated by the class II MHC transactivator (CIITA). We assayed the effects of blocking MHC II upregulation using CIITA gene knockdown (CIITA − ) on survival of allogeneic MSCs in vitro and in vivo . Methods: In vitro, wild-type (WT) or CIITA knockout (CIITA − ) mouse MSCs were induced to differentiate using 5-azacytidine or cytokines. A co-culture system with allogeneic leukocytes was used to evaluate cytotoxicity (LDH release and leukocyte proliferation). Human MSCs (hMSCs) were treated with interferon-γ (INF-γ) to induce MHC II expression. siRNA was used to knockdown CIITA and evaluate immunoprivilege. In vivo, WT or CIITA − MSCs were allogeneically implanted into infarcted myocardium. Allo-antibody formation in the recipients, cell survival, and cardiac function were assessed for the duration of the 5 week experiment. Results: Mouse data - MSC differentiation induced MHC II expression in WT cells whereas CIITA knockout completely prevented MHC II upregulation in differentiated MSCs. When these cells were co-cultured with allogeneic leukocytes, immune rejection was observed in differentiated WT-MSCs but immune tolerance was achieved with differentiated CIITA (-) -MSCs. In vivo : knocking out CIITA in MSCs alleviated allogeneic immune response after cell therapy and prevented the rejection of transplanted cells, improving post-infarction cardiac function when compared to WT MSCs ( P Human data - MHC II upregulation by INF-γ exposure was associated with increased immunogenicity of hMSCs. Knocking down CIITA restored the immunoprivilege in the in vitro co-culture system. Conclusions: CIITA is a key factor which regulates the switch of allogeneic MSCs from an immunoprivileged to an immunogenic phenotype in vitro and in vivo . CIITA knockdown rescued MSC immunoprivilege and prolonged the beneficial effect of allogeneic MSC therapy for cardiac repair.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.002 |
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".