Effect of Ivig On Human T Cells: Interference with Activation Rather Than Suppression of Activated Cell Functions.
Notice bibliographique
Résumé
Abstract Abstract 4738 Introduction IVIg is known to have immunosuppressive effects in a variety of inflammatory and autoimmune diseases, which may be caused by modulations of T cell functions in treated patients. The mechanisms responsible for these modulations have been mostly investigated using in vitro stimulated T cells. These studies revealed that IVIg inhibited the proliferation of activated T cells possibly by interfering with the secretion of cytokines important for T cell proliferation, such as IL-2. In the present study, we sought to determine the precise mechanism by which IVIg inhibited cytokine secretion by stimulated T cells. Methods Human PBMC and Jurkat T cells were stimulated with PHA. Human T cells purified from PBMC were stimulated with CD3/CD28 T cell expander beads. Cells were cultured in presence or not of 10 mg/ml of IVIg for 24 hours. IL-2 secretion was measured in the culture supernatants by ELISA. IVIg was depleted of PHA-reactive IgG by passage on a PHA-Sepharose column. The extent of depletion was evaluated by ELISA using PHA as capture antigen. The role of F(ab')2 fragments in the inhibitory effect of IVIg on IL-2 secretion was determined using pepsin-generated fragments. Results IVIg inhibited IL-2 secretion by PHA-stimulated T cells, as previously reported. However, the use of increasing concentrations of PHA for T cell stimulation led to a decreased ability of IVIg to inhibit IL-2 production, suggesting that IVIg acted by neutralizing PHA or by competition for receptor occupancy on the cell surface. Pre-incubation of T cells with IVIg followed by washing and addition of PHA did not result in inhibition of IL-2 secretion, indicating that competition for receptor was not involved in this IVIg-mediated inhibition. In contrast, inhibition of IL-2 production by IVIg was completely abrogated using IVIg depleted from PHA-reactive IgG, indicating that IVIg-mediated inhibition of IL-2 secretion was the consequence PHA neutralization. Testing of F(ab')2 fragments of IVIg showed that these fragments bound to PHA and inhibited IL-2 secretion as efficiently as IVIg. Using another activation strategy, we showed that IVIg could also decrease IL-2 secretion by purified human T cells following anti-CD3/CD28 stimulation. Preliminary data using light microscopy indicated that IVIg interfered with the binding of CD3/CD28 beads on T cells, therefore reducing cell activation as evaluated by IL-2 secretion. Conclusion Altogether, our results suggest that the inhibition of T cell responses by IVIg occurs during the cell activation step, by preventing the binding of mitogens or antibody-coated beads on the cell surface. These observations emphasize the importance of ruling out the possible interactions of IVIg with culture medium additives, mitogens or activating agents before deriving strong conclusions on the mechanisms of action of IVIg based on their apparent immunomodulatory effects observed in vitro assays. Disclosures: No relevant conflicts of interest to declare.
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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 | 0,000 | 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) | 0,000 | 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 ».