Selected articles April 2015
Collaborative effort to investigate IgE and its receptors in seasonal allergic rhinitis
Variability of Total and Free IgE Levels and IgE Receptor Expression in Allergic Subjects in and Out of Pollen Season
M. Carlsson, L. Thorell, A. Sjölander and S. Larsson-Faria
In a study by Swedish researchers on seasonal allergic rhinitis subjects a small seasonal variation of IgE-related biomarkers studies was found, suggesting that allergen exposure affects expression of these biomarkers only to a minor degree. The objective of the study was to assess the inter- and intra-individual variability and seasonal variation of the level of IgE, high- and low-affinity receptor expression and receptor occupation in blood from seasonal allergic rhinitis subjects, both before and during a birch pollen season.
Mats Carlsson was, at the time of the study, a member of a project team developing a fully human anti-IgE monoclonal antibody, MEDI4212. The project team consisted of members in Lund and MedImmune Cambridge, UK.
– At the time I had a position as Senior Scientist at the Department of Clinical Discovery Medicine, AstraZeneca R&D Lund, Sweden, Mats Carlsson says. My main responsibility was early clinical planning and leading the biomarker program in the project. I was the main project contact for Thermo Fisher Scientific (Phadia AB), Uppsala, Sweden. Together with Anders Sjölander we lead the work on free-IgE assay development. After the completion of the study I took on the role as main author of the publication.
Mats Carlsson says that robustness for most of the assay was very good.
– As an example, the free-IgE assay was verified with results for discriminatory ability, precision, linearity and stability in comparison to the commercial total IgE assay.
Biomarkers can serve as indicators in early clinical development of efficacy and increase the confidence in the program for further development. Furthermore, robust biomarkers may be used in early clinical testing for dose selection and not at least as markers for patient stratification.
– In the perspective of developing a drug, as in this case the anti-IgE mAb MEDI4212, it is advantageous to have robust biomarkers, Mats Carlsson says.
This study was a big collaborative effort, which Mats Carlsson says was very fruitful and fun.
– First we had the collaboration with our MedImmune Cambridge colleagues to develop MEDI4212. Secondly, the work in Lund between several departments, such as Clinical Discovery Medicine, Discovery Translational Sciences and the Clinical Pharmacology Unit that took care of the subjects, was very inspiring. It is also worth mentioning Susanne Larsson-Faria and the Biomarker Team in Lund and their dedicated work with developing the flow cytometry assays and the planning of the clinical study. We also had a very fruitful collaboration with Thermo Fisher Scientific and acknowledging of the excellent work of Lisa Thorell developing the free-IgE assay on the ImmunoCap platform.
On the function of human Foxp3
C-Terminal Cleavage of Human Foxp3 at a Proprotein Convertase Motif Abrogates its Suppressive Function
R. Elhage, M. Cheraï, B. Levacher, G. Darrasse-Jeze, C. Baillou, X. Zhao, A.-M. Khatib, E. Piaggio and D. Klatzmann
Regulatory T cells (Tregs) have been shown to play a major role in the control of many autoimmune and inflammatory diseases. Yet, little is known about the molecular mechanisms that control the properties of human Tregs. In the present study, the researchers from Paris investigated the transcription factor Foxp3 that is central for the development and function of Tregs.
Human Foxp3 exists as four isoforms generated by alternative splicing. Mouse Foxp3 only exists as one isoform, but can be proteolytically cleaved by N-terminal and/or C-terminal proprotein convertase subtilisin/kexins (PCSKs).
Here, the researchers show by transcriptome analysis that the proprotein convertases PCSK7, PCSK5 and Furin are present in human CD4-positive T cells with different expression patterns.
In addition, human CD4+ cells where transduced with Foxp3-expressing lentiviral vectors and generation of proteolytically cleaved Foxp3 was detected by Western blot. Three different Foxp3 forms were detected, indicating that human Foxp3 can also be subjected to proteolytic cleavage at the N-terminal and C-terminal ends.
Thereafter, the suppressive activity associated with these three splice forms was assessed, showing that C-cleaved of N&C-cleaved Foxp3 had almost no suppressive function, indicating a crucial role of the human Foxp3 C-terminal region in the suppressive activity of T regulatory cells.