We and others have previously described signatures of tolerance in kidney transplantation showing the differential expression of B cell–related genes and the relative expansions of B cell subsets. ...However, in all of these studies, the index group—namely, the tolerant recipients—were not receiving immunosuppression (IS) treatment, unlike the rest of the comparator groups. We aimed to assess the confounding effect of these regimens and develop a novel IS‐independent signature of tolerance. Analyzing gene expression in three independent kidney transplant patient cohorts (232 recipients and 14 tolerant patients), we have established that the expression of the previously reported signature was biased by IS regimens, which also influenced transitional B cells. We have defined and validated a new gene expression signature that is independent of drug effects and also differentiates tolerant patients from healthy controls (cross‐validated area under the receiver operating characteristic curve AUC = 0.81). In a prospective cohort, we have demonstrated that the new signature remained stable before and after steroid withdrawal. In addition, we report on a validated and highly accurate gene expression signature that can be reliably used to identify patients suitable for IS reduction (approximately 12% of stable patients), irrespective of the IS drugs they are receiving. Only a similar approach will make the conduct of pilot clinical trials for IS minimization safe and hence allow critical improvements in kidney posttransplant management.
The relationship between B cell gene expression and transplantation tolerance is confounded by the effects of immunosuppressive drugs, and correcting for this effect on gene expression is possible, exposing an equally accurate signature of tolerance. See page 3320 for Markmann's editorial.
Allogeneic cell therapies derived from primary cell sources often have a finite specification for expansion before the cells become exhausted or their phenotype changes due to climatization to the ...culture process. Consequently, these products may require the generation of new master cells banks to maintain clinical and/or commercial supply. The use of new master cell banks requires in-depth product knowledge and a comprehensive comparability study to ensure that any differences in quality attributes have no adverse impact on the safety or efficacy of the drug product.
In this study we demonstrate an approach for product comparability testing of an allogenic therapy in Phase I/IIa clinical trials for the treatment of retinitis pigmentosa. The therapy is centred on the ability of foetal derived human retinal progenitor cells (hRPCs) to differentiate into mature photoreceptors while also establishing a neuroprotective microenvironment. Current strategies to maintain supply of the therapy for on-going clinical analysis include an increase in the passage level of the drug substance and the derivation of new master cell banks. Both approaches require comparability assessment as outlined in guidance documents such as ICH 5QE.
Three new GMP master cell banks from primary tissue sources were established for the hRP cells. We then performed an extensive omic characterisation of the product (cell surface markers, proteomics, RNA-sequencing), and identified a panel of markers that may be associated with function, maintenance and regenerative characteristics of the cells. This panel was used to assess changes in gene expression at higher cell passages and across different donors. Analysis with multiple independent replicates demonstrated that the expression of key markers remained similar up to 6 additional passages, while only minor changes were observed in the new master cell banks. This similarity was also assessed using single-cell RNA-sequencing, a method which could potentially be used as a predictor of product potency.
This omics-based approach provides a comprehensive characterisation of the current hRPC therapy product. It also allows an assessment of the impact of changes to both the manufacturing process and the cellular starting material. This work sets crucial groundwork for selecting critical quality attributes of the therapy and enables routine testing of new sources of hRPC material ensuring continued supply of the product through to commercialization.
Spintronics and quantum information science are two promising candidates for innovating information processing technologies. The combination of these two fields enables us to build solid-state ...platforms for studying quantum phenomena and for realizing multi-functional quantum tasks. For a long time, however, the intersection of these two fields was limited due to the distinct properties of the classical magnetization, that is manipulated in spintronics, and quantum bits, that are utilized in quantum information science. This situation has changed significantly over the last few years because of the remarkable progress in coding and processing information using magnons. On the other hand, significant advances in understanding the entanglement of quasi-particles and in designing high-quality qubits and photonic cavities for quantum information processing provide physical platforms to integrate magnons with quantum systems. From these endeavours, the highly interdisciplinary field of quantum magnonics emerges, which combines spintronics, quantum optics and quantum information science. Here, we give an overview of the recent developments concerning the quantum states of magnons and their hybridization with mature quantum platforms. First, we review the basic concepts of magnons and quantum entanglement and discuss the generation and manipulation of quantum states of magnons, such as single-magnon states, squeezed states and quantum many-body states including Bose–Einstein condensation and the resulting spin superfluidity. We discuss how magnonic systems can be integrated and entangled with quantum platforms including cavity photons, superconducting qubits, nitrogen-vacancy centers, and phonons for coherent information transfer and collaborative information processing. The implications of these hybrid quantum systems for non-Hermitian physics and parity-time symmetry are highlighted, together with applications in quantum memories and high-precision measurements. Finally, we present an outlook on some of the challenges and opportunities in quantum magnonics.
B cells emerge from the bone marrow as transitional (TS) B cells that differentiate through T1, T2, and T3 stages to become naive B cells. We have identified a bifurcation of human B cell maturation ...from the T1 stage forming IgMhi and IgMlo developmental trajectories. IgMhi T2 cells have higher expression of α4β7 integrin and lower expression of IL-4 receptor (IL4R) compared with the IgMlo branch and are selectively recruited into gut-associated lymphoid tissue. IgMhi T2 cells also share transcriptomic features with marginal zone B cells (MZBs). Lineage progression from T1 cells to MZBs via an IgMhi trajectory is identified by pseudotime analysis of scRNA-sequencing data. Reduced frequency of IgMhi gut-homing T2 cells is observed in severe SLE and is associated with reduction of MZBs and their putative IgMhi precursors. The collapse of the gut-associated MZB maturational axis in severe SLE affirms its existence in health.
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