Follicular helper T cell profiles predict response to costimulation blockade in type 1 diabetes

Follicular helper T (TFH) cells are implicated in type 1 diabetes (T1D), and their development has been linked to CD28 costimulation. We tested whether TFH cells were decreased by costimulation blockade using the CTLA-4–immunoglobulin (Ig) fusion protein (abatacept) in a mouse model of diabetes and in individuals with new-onset T1D. Unbiased bioinformatics analysis identified that inducible costimulatory molecule (ICOS)+ TFH cells and other ICOS+ populations, including peripheral helper T cells, were highly sensitive to costimulation blockade. We used pretreatment TFH profiles to derive a model that could predict clinical response to abatacept in individuals with T1D. Using two independent approaches, we demonstrated that higher frequencies of ICOS+ TFH cells at baseline were associated with a poor clinical response following abatacept administration. Therefore, TFH analysis may represent a new stratification tool, permitting the identification of individuals most likely to benefit from costimulation blockade

Stratification of PD-1 blockade response in melanoma using pre- and post-treatment immunophenotyping of peripheral blood

Efficacy of checkpoint inhibitor therapies in cancer varies greatly, with some patients showing complete responses while others do not respond and experience progressive disease. We aimed to identify correlates of response and progression following PD-1-directed therapy by immunophenotyping peripheral blood samples from 20 patients with advanced malignant melanoma before and after treatment with the PD-1 blocking antibody pembrolizumab. Our data reveal that individuals responding to PD-1 blockade were characterised by increased CD8 T cell proliferation following treatment, while progression was associated with an increase in CTLA-4-expressing Treg. Remarkably, unsupervised clustering analysis of pre-treatment T cell subsets revealed differences in individuals that went on to respond to PD-1 blockade compared to individuals that did not. These differences mapped to expression of the proliferation marker Ki67 and the costimulatory receptor CD28 as well as the inhibitory molecules 2B4 and KLRG1. While these results require validation in larger patient cohorts, they suggest that flow cytometric analysis of a relatively small number of T cell markers in peripheral blood could potentially allow stratification of PD-1 blockade treatment response prior to therapy initiation

NEDA—NEutron Detector Array

The NEutron Detector Array, NEDA, will form the next generation neutron detection system that has been designed to be operated in conjunction with γ-ray arrays, such as the tracking-array AGATA, to aid nuclear spectroscopy studies. NEDA has been designed to be a versatile device, with high-detection efficiency, excellent neutron-γ discrimination, and high rate capabilities. It will be employed in physics campaigns in order to maximise the scientific output, making use of the different stable and radioactive ion beams available in Europe. The first implementation of the neutron detector array NEDA with AGATA 1π was realised at GANIL. This manuscript reviews the various aspects of NEDA

Follicular helper T cell signature in type 1 diabetes

The strong genetic association between particular HLA alleles and type 1 diabetes (T1D) indicates a key role for CD4+ T cells in disease; however, the differentiation state of the responsible T cells is unclear. T cell differentiation originally was considered a dichotomy between Th1 and Th2 cells, with Th1 cells deemed culpable for autoimmune islet destruction. Now, multiple additional T cell differentiation fates are recognized with distinct roles. Here, we used a transgenic mouse model of diabetes to probe the gene expression profile of islet-specific T cells by microarray and identified a clear follicular helper T (Tfh) cell differentiation signature. Introduction of T cells with a Tfh cell phenotype from diabetic animals efficiently transferred diabetes to recipient animals. Furthermore, memory T cells from patients with T1D expressed elevated levels of Tfh cell markers, including CXCR5, ICOS, PDCD1, BCL6, and IL21. Defects in the IL-2 pathway are associated with T1D, and IL-2 inhibits Tfh cell differentiation in mice. Consistent with these previous observations, we found that IL-2 inhibited human Tfh cell differentiation and identified a relationship between IL-2 sensitivity in T cells from patients with T1D and acquisition of a Tfh cell phenotype. Together, these findings identify a Tfh cell signature in autoimmune diabetes and suggest that this population could be used as a biomarker and potentially targeted for T1D interventions.This work was funded by an MRC Senior Fellowship (to L.S.K. Walker), a project grant from JDRF (to L.S.K. Walker and P. Narendran), and a studentship from Diabetes UK (to L.S.K. Walker and P. Narendran). L. Wardzinski and A. Kogimtzis were supported by a Wellcome Trust project grant (to L.S.K. Walker). M. Ono is a BBSRC David Philips fellow.Published versio

Commissioning of the BRIKEN beta-delayed neutron detector for the study of exotic neutron-rich nuclei

published_or_final_versio

The Advanced Implantation Detector Array (AIDA)

The Advanced Implantation Detector Array (AIDA) is a state-of-the-art detector system for the measurement of the decay properties of exotic nuclei at fragmentation/fission facilities. Built around stacks of up to eight 8cm×8cm, 128 × 128 strip (16384 pixels) or up to four 24cm×8cm, 384 × 128 strip (49152 pixels) double sided silicon strip detectors, the positions of both implanted ions and their subsequent decay products can be measured to sub-mm precision. The large number of pixels per detector provide implant-decay correlations at implantation rates ∼kHz. To process signals from the large number of strips application specific integrated circuits provide low and high gain signal processing per strip (20 GeV and 20 MeV full scale range) with a dynamic range of 1000:1, or better. A summary of the system and the analysis methodologies used are presented

Nuclear astrophysics with radioactive ions at FAIR

The nucleosynthesis of elements beyond iron is dominated by neutron captures in the s and r processes. However, 32 stable, proton-rich isotopes cannot be formed during those processes, because they are shielded from the s-process flow and r-process, β-decay chains. These nuclei are attributed to the p and rp process. For all those processes, current research in nuclear astrophysics addresses the need for more precise reaction data involving radioactive isotopes. Depending on the particular reaction, direct or inverse kinematics, forward or time-reversed direction are investigated to determine or at least to constrain the desired reaction cross sections. The Facility for Antiproton and Ion Research (FAIR) will offer unique, unprecedented opportunities to investigate many of the important reactions. The high yield of radioactive isotopes, even far away from the valley of stability, allows the investigation of isotopes involved in processes as exotic as the r or rp processes

The new neutron multiplicity filter NEDA and its first physics campaign with AGATA

A new neutron multiplicity filter NEDA, after a decade of design, R&D and construction, was employed in its first physics campaign with the AGATA spectrometer. Properties and performance of the array are discussed

Conceptual design of a hybrid neutron-gamma detector for study of beta-delayed neutrons at the RIB facility of RIKEN

The conceptual design of the BRIKEN neutron detector at the radioactive ion beam factory (RIBF) of the RIKEN Nishina Center is reported. The BRIKEN setup is a complex system aimed at detecting heavy-ion implants, β particles, γ rays and β-delayed neutrons. The whole setup includes the Advanced Implantation Detection Array (AIDA), two HPGe Clover detectors and up to 166 3He-filled counters embedded in a high-density polyethylene moderator. The design is quite complex due to the large number and different types of 3He-tubes involved and the additional constraints introduced by the ancillary detectors for charged particles and γ rays. This article reports on a novel methodology developed for the conceptual design and optimisation of the 3He-counter array, aiming for the best possible performance in terms of neutron detection. The algorithm is based on a geometric representation of two selected detector parameters of merit, namely, the average neutron detection efficiency and the efficiency flatness as a function of a reduced number of geometric variables. The response of the neutron detector is obtained from a systematic Monte Carlo simulation implemented in Geant4. The robustness of the algorithm allowed us to design a versatile detection system, which operated in hybrid mode includes the full neutron counter and two clover detectors for high-precision gamma spectroscopy. In addition, the system can be reconfigured into a compact mode by removing the clover detectors and re-arranging the 3He tubes in order to maximize the neutron detection performance. Both operation modes shows a rather flat and high average efficiency. In summary, we have designed a system which shows an average efficiency for hybrid mode (3He tubes + clovers) of 68.6% and 64% for neutron energies up to 1 and 5 MeV, respectively. For compact mode (only 3He tubes), the average efficiency is 75.7% and 71% for neutron energies up to 1 and 5 MeV, respectively. The performance of the BRIKEN detection system has been also quantified by means of Monte Carlo simulations with different neutron energy distributions

THE BRIKEN PROJECT: EXTENSIVE MEASUREMENTS OF beta-DELAYED NEUTRON EMITTERS FOR THE ASTROPHYSICAL r PROCESS

An ambitious program to measure decay properties, primarily β-delayed neutron emission probabilities and half-lives, for a significant number of nuclei near or on the path of the rapid neutron capture process, has been launched at the RIKEN Nishina Center. We give here an overview of the status of the project