A Novel RORγt Inverse Agonist to Target Th17 in Sensitized Skin Allograft Mouse Model
Bibliographic record
Abstract
🧾 AbstractPurpose: Th17 and IL-17 play a critical role in acute and chronic antibody-mediated allograft rejection and accelerated graft loss. We have recently designed novel inverse agonists against the retinoic acid receptor-related orphan receptor gamma t (RORγt) and demonstrated in-vitro activity against IL-17 expression in a Th17 lymphocyte polarization assay. We sought to determine whether this approach would delay skin allograft rejection in a sensitized mouse model. Methods: C57BL/6 mice were sensitized by administration of 10⁷ Balb/c splenocytes intraperitoneally on days 0, 7, and 14, and transplanted with Balb/c skin grafts on day 15. Mice were treated daily with the RORγt inhibitor TF-S14 (1 mg/kg, IP), tacrolimus (0.5 mg/kg, IP), or their combination. Modified ASEPSIS score was used to assess graft inflammation, and survival was monitored until 100% necrosis. Skin grafts were sampled at day 5 for histology and immunohistochemistry (CD3⁺, CD4⁺, CD8⁺). Results: The RORγt inhibitor (TF-S14) prolonged median graft survival from 6 to 13.5 days and from 7 to 23 days when combined with tacrolimus. Wound scores were reduced fourfold at day 7 compared to controls (p < 0.05). Neutrophilic and lymphocytic infiltrations were markedly reduced in TF-S14 and combination groups compared to vehicle or tacrolimus alone. Conclusions: The novel RORγt inhibitor TF-S14, especially in combination with tacrolimus, significantly prolongs graft survival in sensitized mouse models. These results highlight RORγt as a promising target for Th17-mediated rejection and potential therapy for highly sensitized transplant patients.📁 File DescriptionThe file represents the official published abstract from the American Transplant Congress (ATC 2023) Poster Abstracts section (Abstract B28, AJT Volume 23, Issue 6, Supplement 1).📍 Conference and MetadataPresented at: American Transplant Congress (ATC 2023) Abstract ID: B28 Presentation Date: 7 June 2023 Location: San Diego, CA, USA Abstract Category: Immunosuppression & Tolerance – Preclinical & Translational Studies Presentation Type: Poster Presentation Authors: Ahmed Fouda, Mohamed Taoubane Maallah, Sarita Negi, Steven Paraskevas, Jean Tchervenkov Affiliation: Experimental Surgery and McGill University Health Centre, McGill University, Montreal, QC, Canada 📚 Full Citation📘 Fouda, A.; Maallah, M.; Negi, S.; Paraskevas, S.; Tchervenkov, J. A Novel RORγt Inverse Agonist to Target Th17 in Sensitized Skin Allograft Mouse Model. In Proc. Am. Transplant Congr. 2023; Am. J. Transplant., Vol. 23, Issue 6 (Suppl. 1), Abstract B28. American Transplant Congress (ATC 2023), San Diego, CA, USA, 3–7 June 2023. DOI: 10.6084/m9.figshare.30422875 © 2023, Ahmed Fouda.
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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) | 0.001 | 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".