CD20 B Cell Depleting Therapy Is Associated with up-Regulation of CD8+CD25highFoxp3+ T Regulatory Cells in a Murine Model of Immune Thrombocytopenia (ITP)
Notice bibliographique
Résumé
Abstract Primary immune thrombocytopenia (ITP) is an autoimmune disease characterized by increased platelet destruction and/or impaired megakaryocyte production, mediated by autoreactive B cells and T cells. B cell depletion therapy by rituximab, a monoclonal human anti-CD20 antibody, has been shown effective in both anti-platelet antibody positive (B cell mediated) and negative (T cell mediated) ITP patients. Those patients responsive to rituximab therapy showed normalized CD4+ and CD8+ T cell responses (Stasi et al. Blood. 2007), however, the mechanism of T cell regulation by B cell depletion is not clear. One possibility is through normalization of CD4+ T helper cells or up-regulation of CD4+ regulatory T cells (Tregs) (Stasi et al. Blood. 2008). Another possibility is by suppression of activated conventional CD8+ T cells or the up-regulation of CD8+ Tregs. We examined the changes of both CD4+ and CD8+ T cells and Tregs (CD25highFoxp3+) after B cell depletion in vivo in our ITP mouse model. Briefly, BALB/c GPIIIa (CD61) KO mice were either given PBS (ND) or mouse monoclonal anti-CD20 antibody (B-dep, Biogen) at day -1 and day 13 (250ug/mouse, ip). Residual CD19+ B cells in peripheral blood were less than 0.1% within 24hours in the latter group. All mice were immunized by transfusions of wildtype (WT) platelets at day 0, 7, 14, and 21 (1×108/mouse, iv). At day 28, we examined the percentages of T cell subsets in the spleens of the immunized mice. B cell-depleted immune CD61 KO mice showed significantly higher percentages of both CD3+CD8+ T cells and CD8+CD25highFoxp3+ T cells (Table 1). There was no significant difference in the CD3+CD4+ and CD4+CD25highFoxp3+ T cell populations. Both ND and B-dep immune CD61 KO splenocytes showed increased cytotoxicity activity against CD61+ PU5-1.8 target cells in vitro compared with naïve CD61 KO splenocytes, indicating the activation of CD8+ T cells. To test their in vivo effect on ITP development, splenocytes were engrafted from immune mice into irradiated and AsialoGM-1 treated severe combined immunodeficient (SCID) mice at a dose of 2.5×104/mouse and the mice were monitored for weekly platelet counts. ND and in vitro B cell depleted splenocytes from immune KO mice induced persistent ITP during 3 weeks observation whereas splenocytes from B-dep immune mice did not. To further confirm the role of B cell depletion on CD8+ T cell responses, CD8+ T cells from either ND or B-dep immune CD61 KO splenocytes were purified and transferred into SCID mice at 3×104/mouse. CD4+ T cells from ND immune CD61 KO splenocytes were added at 3×104/mouse to all the SCID mice to support the CD8+ T cell survival in vivo. SCID mice received CD8+ T cells from B-dep group showed higher platelet count at Day 14. Overall, our results indicate a protective role of CD8+CD25highFoxp3+ T cells against the development of cell mediated ITP that is enhanced by B cell depleting therapy in vivo. Table 1. CD61 KO MouseSpleens CD3+CD8+(%) CD8+CD25highFoxp3+ (%) Naïve Control 9.12±0.37 0.12±0.08 Immune, ND 6.78±2.37 0.0925±0.03 Immune, B-dep 14.15±5.1 0.2367±0.11 P value (ND vs B-dep) 0.0007 0.0064 Disclosures No relevant conflicts of interest to declare.
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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) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,001 | 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 | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,001 |
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 ».