Neonatal Follicular Th Cell Responses Are Impaired and Modulated by IL-4.

Newborns are characterized by poor responses to vaccines. Defective B cell responses and a Th2-type polarization can account for this impaired protection in early life. We in this study investigated the generation of follicular Th (TFH) cells, involved in the development of Ab response and germinal center reaction, upon vaccination in neonates. We showed that, compared with adults, Ab production, affinity maturation, and germinal center formation were reduced in neonates immunized with OVA-aluminum hydroxide. Although this vaccination induced CD4(+) CXCR5(+) PD-1(+) TFH cells in newborns, their frequency, as well as their Bcl6 expression and IL-21 and IL-4 mRNA induction, was decreased in early life. Moreover, neonatal TFH cells were mainly localized in interfollicular regions of lymphoid tissues. The prototypic Th2 cytokine IL-4 was found to promote the emergence and the localization in germinal centers of neonatal TFH cells, as well as the neonatal germinal center reaction itself. In addition, IL-4 dampened expression of Th17-related molecules in neonatal TFH cells, as TFH cells from immunized IL-4-deficient neonates displayed enhanced expression of RORγt and IL-17. This Th17-like profile correlated with an increased secretion of OVA-specific IgG2a. Our study thus suggests that defective humoral immunity in early life is associated with limited and IL-4-modulated TFH cell responses.JOURNAL ARTICLESCOPUS: ar.jinfo:eu-repo/semantics/publishe

[18F]-JK-PSMA-7 and [18F]-FDG tumour PET uptake in treated xenograft human prostate cancer model in mice

Purpose This preclinical study aims to evaluate the extent to which a change in prostate-specific membrane antigen (PSMA) expression of castration-resistant prostate cancer (CRPC) following standard treatment is reflected in [18F]JK-PSMA-7 PET/CT. Methods Castrated mice supplemented with testosterone implant were xenografted with human LNCaP CRPC. After appropriate tumour growth, androgen deprivation therapy (ADT) was carried out by the removal of the implant followed by a single injection of docetaxel (400 μg/20-g mouse) 2 weeks later. [18F]JK-PSMA-7 PET/CT were performed before ADT, then before and at days 12, 26, 47 and 69 after docetaxel administration. The [18F]JK-PSMA-7 PET data were compared to corresponding unspecific metabolic [18F]FDG PET/CT and ex vivo quantification of PSMA expression estimated by flow cytometry on repeated tumour biopsies. Results ADT alone had no early effect on LNCaP tumours that pursued their progression. Until day 12 post-docetaxel, the [18F]JK- PSMA7 uptake was significantly higher than that of [18F]FDG, indicating the persistence of PSMA expression at those time points. From day 26 onwards when the tumours were rapidly expanding, both [18F]JK-PSMA7 and [18F]FDG uptake continuously decreased although the decrease in [18F]JK-PSMA uptake was markedly faster. The fraction of PSMA-positive cells in tumour biopsies decreased similarly over time to reach a non-specific level after the same time period.Conclusion Applying PSMA-based imaging for therapy monitoring in patients with CRPC should be considered with caution since a reduction in [18F]JK-PSMA-7 PET uptake after successive ADT and chemotherapy may be related to downregulation of PSMA expression in dedifferentiated and rapidly proliferating tumour cells.info:eu-repo/semantics/publishe

Fibroblast Activation Protein Inhibitor, a Promising Radiotracer inFibrogenesis

Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic and irreversible interstitial lung diseasefor which biomarker of the fibrotic activity of the disease are lacking. Fibroblast activation protein-α(FAP) is a marker of activated fibroblasts. The development of quinoline-based PET tracers that actas FAP inhibitors (FAPIs) demonstrated promising results in oncology with a high and selectivetumor uptake. In the present study, we evaluated the potential role of FAPI as a biomarker of lungfibrogenesis. Methods: The lung uptake of FAPI and its kinetic was assessed in a mouse model ofpulmonary fibrosis. Thus, intratracheal instillation of bleomycin (0.02U/mouse) was performed onC56BL/6 mice. Control mice received an intratracheal instillation of NaCl 0.9%. FAPI was providedby SOFIE (Totowa, USA) and the radiotracer 18F-FAPI was produced in the department of NuclearMedicine of Erasme Hospital. PET/CT imaging were determined at different timepoints (days 3, 10,16 and 28) after the instillation of bleomycin. A time course of uptake of the radiotracer wasevaluated. The results are presented as the mean standardized uptake value (SUV mean) in thelungs and the calculation of a lung-to-muscle ratio (LMR). To correlate with the PET scan results, theextent of fibrosis was assessed by measuring lung content of hydroxyproline and by evaluating theAshcroft modified scale. Results: The optimal imaging window was determined between 40 and 90minutes after radiotracer injection. Bleomycin-treated mice presented a significantly higher uptakeof 18F-FAPI (both SUV mean and LMR) at days 10 and 16 after instillation as compared to controlmice (p < 0.01). No significant statistical difference was observed at day 3 and day 28 afterinstillation. At day 10 and day 16, a strong correlation between 18F-FAPI uptake and hydroxyprolinelung content was observed, as well as a moderate correlation with the Ashcroft modified score.Conclusions: Our results suggest that FAPI constitutes a promising marker of fibrogenesis whoseexpression can be assessed by PET/CT imaging in a mouse model of lung fibrosis. Interestingly, nosignificant increase of lung FAPI uptake was observed during the initial inflammatory phase afterbleomycin instillation as well as at the later stage when fibrotic changes are established and nolonger grow. 18F-FAPi PET/CT could be a useful tool for preclinical evaluation of antifibrotic drugsand further studies should assess its value in patients with IPF.info:eu-repo/semantics/publishe

Usefulness of FAPα assessment in bronchoalveolar lavage as a marker of fibrogenesis: results of a preclinical study and first report in patients with idiopathic pulmonary fibrosis

Background: Fibroblast activation protein-α (FAPα) is a marker of activated fibroblasts that can be selectively targeted by an inhibitor (FAPI) and visualised by PET/CT imaging. We evaluated whether the measurement of FAPα in bronchoalveolar lavage fluids (BALF) and the uptake of FAPI by PET/CT could be used as biomarkers of fibrogenesis. Methods: The dynamics of lung uptake of 18F-labeled FAPI ([18F]FAPI-74) was assessed in the bleomycin mouse model at various time points and using different concentrations of bleomycin by PET/CT. FAPα was measured in BALFs from these bleomycin-treated and control mice. FAPα levels were also assessed in BALFs from controls and patients with idiopathic pulmonary fibrosis (IPF). Results: Bleomycin-treated mice presented a significantly higher uptake of [18F]FAPI-74 during lung fibrinogenesis (days 10 and 16 after instillation) compared to control mice. No significant difference was observed at initial inflammatory phase (3 days) and when fibrosis was already established (28 days). [18F]FAPI-74 tracer was unable to show a dose-response to bleomycin treatment. On the other hand, BALF FAPα levels were steeply higher in bleomycin-treated mice at day 10 and a significant dose-response effect was observed. Moreover, FAPα levels were strongly correlated with lung fibrosis as measured by the modified Aschroft histological analysis, hydroxyproline and the percentage of weight loss. Importantly, higher levels of FAPα were observed in IPF patients where the disease was progressing as compared to stable patients and controls. Moreover, patients with FAPα BALF levels higher than 192.5 pg/mL presented a higher risk of progression, transplantation or death compared to patients with lower levels. Conclusions: Our preclinical data highlight a specific increase of [18F]FAPI-74 lung uptake during the fibrotic phase of the bleomycin murine model. The measurement of FAPα in BALF appears to be a promising marker of the fibrotic activity in preclinical models of lung fibrosis and in IPF patients. Further studies are required to confirm the role of FAPα in BALF as biomarker of IPF activity and assess the relationship between FAPα levels in BALF and [18F]FAPI-74 uptake on PET/CT in patients with fibrotic lung disease

Usefulness of FAPα assessment in bronchoalveolar lavage as a marker of fibrogenesis: results of a preclinical study and first report in patients with idiopathic pulmonary fibrosis.

Fibroblast activation protein-α (FAPα) is a marker of activated fibroblasts that can be selectively targeted by an inhibitor (FAPI) and visualised by PET/CT imaging. We evaluated whether the measurement of FAPα in bronchoalveolar lavage fluids (BALF) and the uptake of FAPI by PET/CT could be used as biomarkers of fibrogenesis.info:eu-repo/semantics/publishe