Role of Carbon Monoxide Releasing Molecules(CORMs) in Toll-Like Receptor Mediated Immune Responses in Renal Transplantation.
Bibliographic record
Abstract
Introduction: In spite of recent advances in early renal transplant survival, chronic allograft damage remains a serious obstacle to the long term success of kidney transplantation. Dendritic cells (DCs) and macrophages play a crucial role in both innate and adaptive immune responses provoked by Toll-like receptors (TLRs) that lead to sterile inflammation in ischemia-reperfusion injury. Based on our novel findings of the anti-inflammatory action of CORMs, we studied TLR mediated immune activation in allograft damage to unveil possible TLR/CORMs based therapeutic intervention in renal transplantation. Method: TLR expression in DCs, Macrophage, and human monocytes by RT-PCR, Western Blot and immunostaining. TLR manipulation by over-expressing dominant negative form of specific TLR; blocking by inhibitory peptides; knocking down by siRNA, shRNA; Inhibition with TLR antagonist or inhibitors; Stimulation of TLR with natural ligands or DAMPs; Treatment of cells with CORM401 & inactive CORM401. Detection of IL6, TNFα, IL10, IL12 etc by ELISA. Characterization of the DCs by TLR4, 9, MHCclassII, CD83, CD80, CD86, IL12, IL10 by flow cytometry. Result: When CORM-3 was infused directly into the donor kidney, an improvement in survival, function and histology vs. controls (p<0.05) was observed. In addition, Brown Norway rats were pre-treated with CORM-2 6hr prior to procurement and transplantation into allogeneic Lewis rats. Histologic examination (day10) showed lymphocytic infiltrate, glomerular congestion, and acute tubular necrosis in control animals whereas CORM-2 treated animals had completely normal histology. TLRs were differentially expressed by bone marrow DCs, macrophages and human monocyte-derived cells. Gene expression analysis of 43,000 mRNAs demonstrated that CORM-401 modulated many genes which include markers of DC maturation (CD80, CD83, CD86), diverse immune responses (TLR9, NFkB, TNFa, IL6, IL1b, IL10) and pro-to-anti-inflammatory conversion (Regnase1, TRIB1). Random Forest algorithm analysis on immune functions also concluded wide spectrum of intervention of CORM-401 from immune activation to leukocyte activation.Conclusion: TLRs on DCs and macrophages promote inflammation subsequent to kidney IRI, the leading cause of rejection. CORMs have potential to protect kidney allograft function and survival.
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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) | 0.000 | 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) | 0.002 | 0.000 |
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".