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Improving T Cell Expansion with a Soft Touch.

ABSTRACT: Protein-coated microbeads provide a consistent approach for activating and expanding populations of T cells for immunotherapy but do not fully capture the properties of antigen presenting cells. In this report, we enhance T cell expansion by replacing the conventional, rigid bead with a mechanically soft elastomer. Polydimethylsiloxane (PDMS) was prepared in a microbead format and modified with activating antibodies to CD3 and CD28. A total of three different formulations of PDMS provided an extended proliferative phase in both CD4+-only and mixed CD4+-CD8+ T cell preparations. CD8+ T cells retained cytotoxic function, as measured by a set of biomarkers (perforin production, LAMP2 mobilization, and IFN-? secretion) and an in vivo assay of targeted cell killing. Notably, PDMS beads presented a nanoscale polymer structure and higher rigidity than that associated with conventional bulk material. These data suggest T cells respond to this higher rigidity, indicating an unexpected effect of curing conditions. Together, these studies demonstrate that adopting mechanobiology ideas into the bead platform can provide new tools for T cell based immunotherapy.

SUBMITTER: Lambert LH

PROVIDER: S-EPMC5504474 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Improving T Cell Expansion with a Soft Touch.

Lambert Lester H LH Goebrecht Geraldine K E GK De Leo Sarah E SE O'Connor Roddy S RS Nunez-Cruz Selene S Li Tai-De TD Yuan Jinglun J Milone Michael C MC Kam Lance C LC

Nano letters 20170130 2

Protein-coated microbeads provide a consistent approach for activating and expanding populations of T cells for immunotherapy but do not fully capture the properties of antigen presenting cells. In this report, we enhance T cell expansion by replacing the conventional, rigid bead with a mechanically soft elastomer. Polydimethylsiloxane (PDMS) was prepared in a microbead format and modified with activating antibodies to CD3 and CD28. A total of three different formulations of PDMS provided an ext ...[more]

PMID: 28122453

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Project description:Highlights • Patients with skin-picking disorder (SPD) display reduced neural sensitivity to affective/soft self-touch.• Neurobiological evaluation of a new Soft Touch Training (STT) for SPD patients.• STT increased the pleasantness ratings for (slow/soft) touch administered during fMRI.• STT changed activity/ connectivity in the secondary somatosensory cortex. Background Individuals with skin-picking disorder (SPD) display reduced neural sensitivity to slow/soft touch. This functional magnetic resonance imaging (fMRI) study investigated the effects of Soft Touch Training (STT) on neural correlates of touch processing and SPD symptoms. Method Females with a primary diagnosis of SPD (n = 57) were randomly assigned to receive either four weeks of STT (guided soft brushing of selected skin regions) or Progressive Muscle Relaxation (PMR) training (guided tensing and relaxing of selected muscle regions). The app-assisted intervention consisted of 15-minute daily training sessions at home. Before and after the four-week intervention, the two groups participated in a standardized tactile stimulation procedure during fMRI (affective vs nonaffective touch of the forearm). Intervention-based changes in subjective and neural responses to the tactile stimulation as well as SPD severity were compared between the groups. Results STT increased the pleasantness ratings for (affective) touch administered during fMRI, which was accompanied by decreased activation in the parietal operculum (PO) and supramarginal gyrus (SMG), as well as increased PO-SMG connectivity. These findings possibly reflect normalized affective touch processing due to STT. Both interventions (STT and PMR) reduced SPD severity. Conclusions This study demonstrated that a brief app-assisted touch training can change the experience of receiving touch from others and the associated brain activity and connectivity. Adaptations of the training relating to duration/ frequency of sessions might enhance its effectiveness.

Project description:High proliferative and differentiation capacity renders embryonic stem cells (ESCs) a promising cell source for tissue engineering and cell-based therapies. Harnessing their potential, however, requires well-designed, efficient and reproducible expansion and differentiation protocols as well as avoiding hazardous by-products, such as teratoma formation. Traditional, standard culture methodologies are fragmented and limited in their fed-batch feeding strategies that afford a sub-optimal environment for cellular metabolism. Herein, we investigate the impact of metabolic stress as a result of inefficient feeding utilizing a novel perfusion bioreactor and a mathematical model to achieve bioprocess improvement.To characterize nutritional requirements, the expansion of undifferentiated murine ESCs (mESCs) encapsulated in hydrogels was performed in batch and perfusion cultures using bioreactors. Despite sufficient nutrient and growth factor provision, the accumulation of inhibitory metabolites resulted in the unscheduled differentiation of mESCs and a decline in their cell numbers in the batch cultures. In contrast, perfusion cultures maintained metabolite concentration below toxic levels, resulting in the robust expansion (>16-fold) of high quality 'naïve' mESCs within 4 days. A multi-scale mathematical model describing population segregated growth kinetics, metabolism and the expression of selected pluripotency ('stemness') genes was implemented to maximize information from available experimental data. A global sensitivity analysis (GSA) was employed that identified significant (6/29) model parameters and enabled model validation. Predicting the preferential propagation of undifferentiated ESCs in perfusion culture conditions demonstrates synchrony between theory and experiment.The limitations of batch culture highlight the importance of cellular metabolism in maintaining pluripotency, which necessitates the design of suitable ESC bioprocesses. We propose a novel investigational framework that integrates a novel perfusion culture platform (controlled metabolic conditions) with mathematical modeling (information maximization) to enhance ESC bioprocess productivity and facilitate bioprocess optimization.

Dataset Information

Improving T Cell Expansion with a Soft Touch.

Publications

Improving T Cell Expansion with a Soft Touch.

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