Regulatory T-cell therapy approaches.

Regulatory T cells (Tregs) have enormous therapeutic potential to treat a variety of immunopathologies characterized by aberrant immune activation. Adoptive transfer of ex vivo expanded autologous Tregs continues to progress through mid- to late-phase clinical trials in several disease spaces and has generated promising preliminary safety and efficacy signals to date. However, the practicalities of this strategy outside of the clinical trial setting remain challenging. Here, we review the current landscape of regulatory T-cell therapy, considering emergent approaches and technologies presenting novel ways to engage Tregs, and reflect on the progress necessary to deliver their therapeutic potential to patients.

Freezing Medium Containing 5% DMSO Enhances the Cell Viability and Recovery Rate After Cryopreservation of Regulatory T Cell Products ex vivo and in vivo.

Cell therapies have significant therapeutic potential in diverse fields including regenerative medicine, transplantation tolerance, and autoimmunity. Within these fields, regulatory T cells (Treg) have been deployed to ameliorate aberrant immune responses with great success. However, translation of the cryopreservation strategies employed for other cell therapy products, such as effector T cell therapies, to Treg therapies has been challenging. The lack of an optimized cryopreservation strategy for Treg products presents a substantial obstacle to their broader application, particularly as administration of fresh cells limits the window available for sterility and functional assessment. In this study, we aimed to develop an optimized cryopreservation strategy for our CD4+CD25+Foxp3+ Treg clinical product. We investigate the effect of synthetic or organic cryoprotectants including different concentrations of DMSO on Treg recovery, viability, phenotype, cytokine production, suppressive capacity, and in vivo survival following GMP-compliant manufacture. We additionally assess the effect of adding the extracellular cryoprotectant polyethylene glycol (PEG), or priming cellular expression of heat shock proteins as strategies to improve viability. We find that cryopreservation in serum-free freezing medium supplemented with 10% human serum albumin and 5% DMSO facilitates improved Treg recovery and functionality and supports a reduced DMSO concentration in Treg cryopreservation protocols. This strategy may be easily incorporated into clinical manufacture protocols for future studies.

Distinct metabolic pathways mediate regulatory T cell differentiation and function.

Investigation of the cellular metabolic pathways of immune cells, or immunometabolism, is a field of increasing interest. An understanding of immunometabolism provides routes to modifying T cell function for therapeutic purposes. Here, we review immunometabolism with a specific focus on regulatory T cells (Tregs). While T cells are known to switch their metabolic profile from oxidative phosphorylation to aerobic glycolysis upon activation, in vitro-induced Tregs display alternate metabolic characteristics which may be related to their specialised suppressive function. Recent data suggest that the preferential pathways employed by Tregs differ in vivo and ex vivo. Metabolic 'harshness', particularly the deterioration of glycolysis, positively affects Treg differentiation and function, while negatively correlating with Treg clonal expansion and migratory capacity. These context-dependent findings provide new insights into the behaviour of Tregs with implications for both tumour immunology and autoimmunity. This review examines the field in detail, offering an overview of our current understanding of Treg immunometabolism.

The functional neuroanatomy of musical memory in Alzheimer's disease.

BACKGROUND: Memory for music has attracted much recent interest in Alzheimer's disease but the underlying brain mechanisms have not been defined in patients directly. Here we addressed this issue in an Alzheimer's disease cohort using activation fMRI of two core musical memory systems. METHODS: We studied 34 patients with younger onset Alzheimer's disease led either by episodic memory decline (typical Alzheimer's disease) or by visuospatial impairment (posterior cortical atrophy) in relation to 19 age-matched healthy individuals. We designed a novel fMRI paradigm based on passive listening to melodies that were either previously familiar or unfamiliar (musical semantic memory) and either presented singly or repeated (incidental musical episodic memory). RESULTS: Both syndromic groups showed significant functional neuroanatomical alterations relative to the healthy control group. For musical semantic memory, disease-associated activation group differences were localised to right inferior frontal cortex (reduced activation in the group with memory-led Alzheimer's disease); while for incidental musical episodic memory, disease-associated activation group differences were localised to precuneus and posterior cingulate cortex (abnormally enhanced activation in the syndromic groups). In post-scan behavioural testing, both patient groups had a deficit of musical episodic memory relative to healthy controls whereas musical semantic memory was unimpaired. CONCLUSIONS: Our findings define functional neuroanatomical substrates for the differential involvement of musical semantic and incidental episodic memory in major phenotypes of Alzheimer's disease. The complex dynamic profile of brain activation group differences observed suggests that musical memory may be an informative probe of neural network function in Alzheimer's disease. These findings may guide the development of future musical interventions in dementia.

Deciphering the Contribution of γδ T Cells to Outcomes in Transplantation.

γδ T cells are a subpopulation of lymphocytes expressing heterodimeric T-cell receptors composed of γ and δ chains. They are morphologically and functionally heterogeneous, innate yet also adaptive in behavior, and exhibit diverse activities spanning immunosurveillance, immunomodulation, and direct cytotoxicity. The specific responses of γδ T cells to allografts are yet to be fully elucidated with evidence of both detrimental and tolerogenic roles in different settings. Here we present an overview of γδ T-cell literature, consider ways in which their functional heterogeneity contributes to the outcomes after transplantation, and reflect on methods to harness their beneficial properties.

Music models aberrant rule decoding and reward valuation in dementia.

Aberrant rule- and reward-based processes underpin abnormalities of socio-emotional behaviour in major dementias. However, these processes remain poorly characterized. Here we used music to probe rule decoding and reward valuation in patients with frontotemporal dementia (FTD) syndromes and Alzheimer's disease (AD) relative to healthy age-matched individuals. We created short melodies that were either harmonically resolved ('finished') or unresolved ('unfinished'); the task was to classify each melody as finished or unfinished (rule processing) and rate its subjective pleasantness (reward valuation). Results were adjusted for elementary pitch and executive processing; neuroanatomical correlates were assessed using voxel-based morphometry. Relative to healthy older controls, patients with behavioural variant FTD showed impairments of both musical rule decoding and reward valuation, while patients with semantic dementia showed impaired reward valuation but intact rule decoding, patients with AD showed impaired rule decoding but intact reward valuation and patients with progressive non-fluent aphasia performed comparably to healthy controls. Grey matter associations with task performance were identified in anterior temporal, medial and lateral orbitofrontal cortices, previously implicated in computing diverse biological and non-biological rules and rewards. The processing of musical rules and reward distils cognitive and neuroanatomical mechanisms relevant to complex socio-emotional dysfunction in major dementias.

Intrauterine fetal death and risk of shoulder dystocia at delivery.

INTRODUCTION: Vaginal delivery is recommended after intrauterine fetal death. However, little is known about the risk of shoulder dystocia in these deliveries. We studied whether intrauterine fetal death increases the risk of shoulder dystocia at delivery. MATERIAL AND METHODS: In this population-based register study using the Medical Birth Registry of Norway, we included all singleton pregnancies with vaginal delivery of offspring in cephalic presentation in Norway during the period 1967-2012 (n = 2 266 118). Risk of shoulder dystocia was estimated as absolute risk (%) and odds ratio with 95% confidence interval. Adjustment was made for offspring birthweight (in grams). We performed sub-analyses within categories of birthweight (<4000 and ≥4000 g) and in pregnancies with maternal diabetes. RESULTS: Shoulder dystocia occurred in 1.1% of pregnancies with intrauterine fetal death and in 0.8% of pregnancies without intrauterine fetal death (p < 0.0001) (crude odds ratio 1.5, 95% confidence interval 1.2-4.9). After adjustment for birthweight, the odds ratio was 5.9 (95% confidence interval 4.7-7.4). In pregnancies with birthweight ≥4000 g, shoulder dystocia occurred in 14.6% of pregnancies with intrauterine fetal death and in 2.8% of pregnancies without intrauterine fetal death (p < 0.001) (crude odds ratio 5.9, 95% confidence interval 4.5-7.9). In pregnancies with birthweight ≥4000 g and concurrent maternal diabetes, shoulder dystocia occurred in 57.1% of pregnancies with intrauterine fetal death and 9.6% of pregnancies without intrauterine fetal death (p < 0.001) (crude odds ratio 12.6, 95% confidence interval 5.9-26.9). CONCLUSIONS: Intrauterine fetal death increased the risk of shoulder dystocia at delivery, and the absolute risk of shoulder dystocia was particularly high if offspring birthweight was high and the mother had diabetes.