Innate Immune Cell Expression of Pattern Recognition Receptors From β-Thalassemia Patients During Intensive Combination Chelation Therapy
Notice bibliographique
Résumé
Abstract Abstract 1025 Introduction: Thalassemia major patients endure chronic RBC transfusions, high levels of tissue iron, iron chelation and organ injury. Patients with thalassemia also have reduced immune function and are at risk for infection. Infection is in fact the second most common cause of death in thalassemia. The innate immune system provides the first line of defense against infection and it specificity depends on pattern recognition receptors (PRRs) specific to microbial pathogens. One class of PRR called the toll-like receptors (TLRs) interact with CD14 on innate immune cells transducing the signal for bacterial Lipopolysaccharide (LPS), resulting in cytokine production. The role iron plays in thalassemia in determining expression level of PRRs is unknown. Thus, the goal in these studies is to investigate the relationship of iron overload and its chelation to innate immune cell expression of PRRs in thalassemia. Patients and Methods: Eighteen transfusion dependent thalassemia patients (11 – 29 yrs old) participating in the combination trial of deferasirox and deferoxamine (Novartis sponsored CICL670AUS24T) were enrolled in a substudy investigating innate immunology (Novartis sponsored CICL670AUS42T). Fasting blood samples were obtained i) at baseline after a 72 hr. washout of chelator, and ii) at 6 and 12 months on study. Fourteen healthy controls (10 – 35 yrs old) were also enrolled. Peripheral blood mononuclear cells (PBMCs) were isolated from blood samples and then from these cells monocytes and granulocytes were purified using antibody-linked magnetic microbeads (Miltenyi Biotec Inc). Highly enriched populations of CD14+ monocytes and CD15+ granulocytes were verified by flow cytometry. The expression level of CD14 and CD15 in PBMCs and TLR4 in purified cells were determined and reported as the median fluorescent intensity (MFI). Liver iron concentration (LIC) was determined by biomagnetic susceptibility (“SQUID”, Ferritometer®) in patients with thalassemia; healthy controls were shown to have normal ferritin. Results: In PBMCs from thalassemia patients at baseline, the expression of monocyte CD14 and TLR4 were significantly increased 22% and 6.5% respectively compared to healthy controls (p < 0.05). Granulocytes from patients with thalassemia at baseline were also found to have a 50% higher expression of TLR4 compared to controls. Markers of iron burden, such as LIC and ferritin also significantly correlated with the expression of monocyte TLR4. In longitudinal analysis markers of iron burden, the expression of TLR4 on monocytes and granulocytes all significantly decreased in the follow-up period in thalassemia patients receiving intensive combination chelator therapy (p<0.05). Conclusions: These studies support the hypothesis that iron burden influences the innate immune response in thalassemia as demonstrated by the increased monocyte expression of both CD14 and TLR4 at baseline, both of which likely contribute to the commonly observed susceptibility to infection. After intensive chelation, the levels of CD14 and TLR4 decreased, indicating that decreased iron overload with chelation may improve innate immune responsiveness. These changes in CD14 and TLR4 may be able to restore proper innate immune function in thalassemia patients. Disclosures: Walter: Novartis: Research Funding. Harmatz:Novartis: Research Funding; FerroKin BioSciences: Research Funding. Porter:Novartis: Consultancy, Research Funding. Vichinsky:ARUP Research Lab: Research Funding; ApoPharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.
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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) | 0,000 | 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 ».