Novel Photodepletion Strategy to Preserve and Expand Tregs While Eliminating CD4+ Effector T Cells From Patients with Chronic Graft-Versus-Host Disease
Notice bibliographique
Résumé
Abstract Abstract 353 Even the most potent immunosuppressive drugs often fail to control graft-versus-host disease (GVHD), the most frequent and deleterious post-transplantation adverse condition. The development of a strategy to eliminate alloreactive T cells and spare regulatory T cells (Tregs) would provide a direly needed therapeutic option for patients with refractory GVHD. We previously reported that photodepletion using dibromorhodamine (TH9402) eliminates T cells from healthy donors activated against major histocompatibility complex (MHC)-incompatible cells and spares resting T cells. In the present study, we identified novel photodepletion conditions (1.32 μM TH9402, 45 minutes incubation, and 5 J/cm2 light delivery at 514 nm) selectively eradicating 60–90% of endogenous proliferating host T cells as measured by 3H-thymidine incorporation, and CD4+CD25+FOXP3- effector memory phenotype cells (p<0.001) from chronic GVHD patient cells, with concomitant sparing of the majority of CD4+CD25+FOXP3+ Tregs. All GVHD patients tested (n=10) had severe extensive chronic disease and were refractory to at least 2 immunosuppressive agents. Preservation of Treg function after photodepletion was confirmed by demonstrating reduction in the proliferation of GVHD T lymphocytes by 66.6±7.1% to 75.8±7.0% (mean±SEM; p<0.001, n=6) after their exposure to photodepletion lymphocytes at ratios of 8:1 to 1:1, respectively. The fact that immunomagnetic depletion of CD4+CD25+ T cells from lymphocytes exposed to photodepletion abrogated the inhibitory activity of both GVHD patient and healthy donor cells indicated that these Tregs harbored a CD4+CD25+ phenotype. Moreover, Treg activity was recovered upon CD4+CD25+ cell repletion. Treg survival to photodepletion relied on P-glycoprotein induced efflux of TH9402 since inhibition of this membrane transporter by verapamil (50 μM) induced TH9402 accumulation and Treg demise upon illumination. We found that IL-10 secretion increased when photodepletion cells were cultured with GVHD untreated cells (p<0.01) and anti-IL-10 monoclonal antibodies (mAbs) blocked their suppressive activity. TGF-β was not found to be implicated in the suppression of proliferation. Allowing cell-cell contact between photodepletion exposed lymphocytes and cGVHD cells in 3- to 6-day cultures led to doubling of Treg numbers (p<0.01, n=5) while separating photodepletion treated and untreated GVHD cells abrogated both IL-10 secretion and Treg suppressive activity. Additionally, blocking CTLA-4 ligation with anti-CTLA-4 mAbs abrogated Treg function and prevented the generation of Tregs ex vivo (p<0.05), thus identifying CTLA-4-mediated cell-cell contact as a crucial priming event for Treg function. This increase in Tregs was not caused by increased proliferation as measured by EdU labelling. Exposing isolated CD4+CD25- cells to TH9402 photodepletion itself also failed to increase the number of FOXP3 expressing cells. However Treg numbers increased when CD4+CD25- cells were incubated with CD4+CD25+ cells previously exposed to photodepletion, suggesting that photodepletion cells promote the acquisition of Treg features in CD4+CD25- T cells. This photodepletion strategy was then evaluated in 5 patients suffering from refractory chronic GVHD. The patients had their cells collected by lymphopheresis, exposed to photodepletion and reinfused back into them on a weekly basis. Interestingly, the frequency of circulating Tregs in cGVHD patients undergoing TH9402 photodepletion increased in comparison to healthy donors (p<0.05), with a doubling in their numbers in comparison to pre-treatment levels (p<0.05) as early as 2 weeks after initiating treatment and these patients' conditions improved. In conclusion, these results identify a new approach to both preserve and expand Tregs while selectively eliminating CD4+ effector T cells. They also uncover effector pathways that could be used advantageously for the treatment of patients with refractory GVHD. Disclosures: Egeler: Kiadis Pharma: Employment. Roy:Kiadis Pharma: Research Funding.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 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) | 0,001 | 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 source (Gemma direct ou Codex distillé), 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 ».