Abstract 4952: Transplant Vasculopathy Response in CCR2 and NDST-1 Deficient Mice Aortic Transplant Model After Viral Anti-Inflammatory Chemokine Modulating Protein, M-T7, Treatment
Bibliographic record
Abstract
Background: Transplant vasculopathy impedes long-term organ transplant survival. Chemokines direct inflammatory cell migration, through binding to glycosaminoglycans (GAGs) on the surface of endothelial cells and in connective tissues. Chemokines bind GAGs via the C terminus and receptors via the N terminus. Both chemokine receptor and chemokine GAG interactions are important to inflammatory responses. Chemokines and chemokine receptors have been demonstrated to have important roles in transplant rejection. The relative roles of receptor and GAG interaction in transplant vasculopathy are not defined. Myxoma viral chemokine modulating protein (CMP) M-T7 interrupts C terminal GAG binding of C, CC and CXC chemokines. In prior work M-T7 reduced transplant vasculopathy in aortic and renal transplant models. We examine here the effects of CCR2 and GAG deficiency as well as M-T7 treatment in CCR2 and heparan sulfate (HS-GAG) deficient mouse aortic allograft transplant models. Methods: CCR2 −/− or CCR2 +/+ donor Balb/C aorta was transplanted to C57BL/6 recipients HS-GAG +/+ and HS-GAG −/− aorta was transplanted to Balb/C. WT to CCR2 −/− or NDST-1 −/− reverse aortic transplant was also examined. All aortic transplant group were assessed with and without M-T7 treatment. Plaque growth and macrophage/T cell invasion were measured at 28 days. Results: Plaque growth was significantly decreased in both CCR2 −/− and HS-GAG −/− transplants when compared to CCR2 +/+ (P = .021) or HS-GAG +/+ (P = .032), respectively. Immunostaining demonstrated reduced CD3 T-cell and macrophage invasion. Plaque was reduced in WT HS-GAG +/+ when compared to WT Balb/C aortic transplant (P = .306). Reverse Transplant of WT C57Bl/6 or Balb/C donor aorta to CCR2 −/− or HS-GAG −/− mice, respectively, did not reduce plaque growth. M-T7 treatment reduced plaque growth in both CCR2 +/+ (P < .047) and CCR2 −/− (P = .017) aortic transplant, but had reduced inhibitory activity in HS-GAG −/− aortic transplants when compared to HS-GAG +/+ . Conclusion: Heparan sulfate GAG is an important mediator in transplant vasculopathy development. Interruption of chemokine: GAG binding provides a new therapeutic target for prevention of transplant vasculopathy.
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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) | 0.001 | 0.001 |
| 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 | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 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".