Anti-Chronic Graft Versus Host Disease Activity Though a Regulatory T Cell Dependent Mechanism after Photodynamic Therapy.
Notice bibliographique
Résumé
Abstract Graft-versus-host disease (GVHD) is the principal cause of morbidity and mortality after hematopoietic stem cell transplantation. Even the most potent immunosuppressive agents often fail to control GVHD. Because of its unique cell-mediated approach, photopheresis represents an appealing alternative for the treatment of GVHD, particularly in its chronic form. Photodynamic therapy (PDT) using TH9402 (4,5-dibromorhodamine methyl ester), a photosensitizer, which upon activation with visible light, exhibits specific toxicity against activated T lymphocytes, while preserving resting T cells, has emerged as a potentially interesting alternative treatment modality for GVHD patients. However, the immunologic mechanisms involved in GVHD modulation by PDT still remain obscure. Since CD4+CD25+FoxP3+ regulatory T cells (Tregs) have an inhibitory effect on GVHD, we sought to determine the role of Tregs in the context of photopheresis using TH9402 for GVHD modulation. We first evaluated, using flow cytometry, the impact of PDT on activated T cells and Tregs obtained from steroid-refractory chronic GVHD patients. High (10 uM) and low (1,32 uM) TH9402 concentrations were compared to measure their ability preserve Tregs. Interestingly, low intensity TH9402 treatment demontrated particularly interesting features, resulting in the elimination of more than 90% of activated CD4+CD25+FoxP3- and CD4+CD44high T cells, while preserving 95% of CD4+CD25+ FoxP3+ cells (p<0.001; n=5 pts). The proportion of live CD4+CD25+ FoxP3+ cells increased from 51.8±5.2% to 89.0±5.9% (mean±SD; pre and post PDT, respectively; p<0.01) thus enriching the graft in Tregs. Next, we evaluated the ability of PDT treated mononuclear cells to inhibit the proliferation of untreated MNCs from cGVHD pts. The addition of PDT cells reduced the proliferation of cGVHD T lymphocytes by 41–76% (p<0.001, n=6 pts). This inhibitory effect disappeared following inhibition of Pgp-171 by verapamil, which promoted TH9402 intracellular retention and effector cell elimination upon light exposure, indicating that Tregs must not only be present but viable to exert their suppressive activity. In addition, higher levels of IL-10, but not TGF-β, were secreted when cGVHD cells were exposed to PDT-treated cells (34.7±5.1ng/mL) than when exposed to untreated cells (20.3±3.2ng/mL, p<0.05). Furthermore, the inhibitory effect decreased 5-fold when cGVHD cells were co-cultured for 6 days with CD4+CD25+ depleted PDT cells (p<0.001). Addition of anti-IL-10 monoclonal antibody (mAb) to the co-culture (PDT-treated cells with cGVHD cells) resulted in a 3-fold decrease in the inhibition of cGVHD cell proliferation mediated by PDT-treated cells (p<0.01) and a 1.5-fold decrease when anti-TGF-β mAb was added to the co-culture (p<0.05). In conclusion, our results demonstrate that TH9402 PDT not only eliminates activated T cells, but preserves Tregs, with the functional ability to inhibit residual alloreactive cGVHD cells. This inhibitory effect requires live effector Tregs, secretion of IL-10 and TGF-β expression. With such dual effector mechanisms, photopheresis using TH9402 should translate into improved treatment efficacy and enhanced quality of life for patients with chronic GVHD.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».