Innate immunity based cancer immunotherapy: B16-F10 murine melanoma model

Abstract Background Using killed microorganisms or their parts to stimulate immunity for cancer treatment dates back to the end of 19th century. Since then, it undergone considerable development. Our novel approach binds ligands to the tumor cell surface, which stimulates tumor phagocytosis. The therapeutic effect is further amplified by simultaneous application of agonists of Toll-like receptors. We searched for ligands that induce both a strong therapeutic effect and are safe for humans. Methods B16-F10 murine melanoma model was used. For the stimulation of phagocytosis, mannan or N-formyl-methionyl-leucyl-phenylalanine, was covalently bound to tumor cells or attached using hydrophobic anchor. The following agonists of Toll-like receptors were studied: monophosphoryl lipid A (MPLA), imiquimod (R-837), resiquimod (R-848), poly(I:C), and heat killed Listeria monocytogenes. Results R-848 proved to be the most suitable Toll-like receptor agonist for our novel immunotherapeutic approach. In combination with covalently bound mannan, R-848 significantly reduced tumor growth. Adding poly(I:C) and L. monocytogenes resulted in complete recovery in 83% of mice and in their protection from the re-transplantation of melanoma cells. Conclusion An efficient cancer treatment results from the combination of Toll-like receptor agonists and phagocytosis stimulating ligands bound to the tumor cells.http://deepblue.lib.umich.edu/bitstream/2027.42/134739/1/12885_2016_Article_2982.pd

Elucidating the interaction of CF airway epithelial cells and rhinovirus: Using the host-pathogen relationship to identify future therapeutic strategies

© 2018 Ling, Garratt, Lassmann, Stick. Chronic lung disease remains the primary cause of mortality in cystic fibrosis (CF). Growing evidence suggests respiratory viral infections are often more severe in CF compared to healthy peers and contributes to pulmonary exacerbations (PEx) and deterioration of lung function. Rhinovirus is the most prevalent respiratory virus detected, particularly during exacerbations in children with CF < 5 years old. However, even though rhinoviral infections are likely to be one of the factors initiating the onset of CF lung disease, there is no effective targeted treatment. A better understanding of the innate immune responses by CF airway epithelial cells, the primary site of infection for viruses, is needed to identify why viral infections are more severe in CF. The aim of this review is to present the clinical impact of virus infection in both young children and adults with CF, focusing on rhinovirus infection. Previous in vitro and in vivo investigations looking at the mechanisms behind virus infection will also be summarized. The review will finish on the potential of transcriptomics to elucidate the host-pathogen responses by CF airway cells to viral infection and identify novel therapeutic targets

Redefining innovation processes: The digital designers at work

As design in digital innovation has become a thing, we highlight the inconclusive concepts that describe design activity in innovation processes. Proposing an alternative theoretical lens - a sociomaterial practice lens - we claim that this view can reveal the contribution of digital designers to the work of innovation. This paper draws on a research study with digital designers in the UK. At the same time as we begin to reconceptualise the ways digital design activity can be described, we also illustrate a theoretical framework based on 1) action and knowing as ordered by collectively produced objects, 2) sociomateriality and the configuration of human bodies and materials in action, 3) the co-emergence of objects and sociomaterial configurations where each is the condition of the other. This alternative way of looking at design activity may pose some challenges to the theoretical traditions in the field. We however believe that it contains immense potential too

Low-level regulatory T-cell activity is essential for functional type-2 effector immunity to expel gastrointestinal helminths

Helminth infection is frequently associated with the expansion of regulatory T cells (Tregs) and suppression of immune responses to bystander antigens. We show that infection of mice with the chronic gastrointestinal helminth Heligmosomoides polygyrus drives rapid polyclonal expansion of Foxp3(+)Helios(+)CD4(+) thymic (t)Tregs in the lamina propria and mesenteric lymph nodes while Foxp3(+)Helios(-)CD4(+) peripheral (p)Treg expand more slowly. Notably, in partially resistant BALB/c mice parasite survival positively correlates with Foxp3(+)Helios(+)CD4(+) tTreg numbers. Boosting of Foxp3(+)Helios(+)CD4(+) tTreg populations by administration of recombinant interleukin-2 (rIL-2):anti-IL-2 (IL-2C) complex increased worm persistence by diminishing type-2 responsiveness in vivo, including suppression of alternatively activated macrophage and granulomatous responses at the sites of infection. IL-2C also increased innate lymphoid cell (ILC) numbers, indicating that Treg functions dominate over ILC effects in this setting. Surprisingly, complete removal of Tregs in transgenic Foxp3-DTR mice also resulted in increased worm burdens, with "immunological chaos" evident in high levels of the pro-inflammatory cytokines IL-6 and interferon-γ. In contrast, worm clearance could be induced by anti-CD25 antibody-mediated partial depletion of early Treg, alongside increased T helper type 2 responses and without incurring pathology. These findings highlight the overarching importance of the early Treg response to infection and the non-linear association between inflammation and the prevailing Treg frequency

Regulatory T cells promote myelin regeneration in the central nervous system

Regeneration of CNS myelin involves differentiation of oligodendrocytes from oligodendrocyte progenitor cells. In multiple sclerosis, remyelination can fail despite abundant oligodendrocyte progenitor cells, suggesting impairment of oligodendrocyte differentiation. T cells infiltrate the CNS in multiple sclerosis, yet little is known about T cell functions in remyelination. We report that regulatory T cells (T$_{reg}$) promote oligodendrocyte differentiation and (re)myelination. T$_{reg}$-deficient mice exhibited substantially impaired remyelination and oligodendrocyte differentiation, which was rescued by adoptive transfer of T$_{reg}$. In brain slice cultures, T$_{reg}$ accelerated developmental myelination and remyelination, even in the absence of overt inflammation. T$_{reg}$ directly promoted oligodendrocyte progenitor cell differentiation and myelination in vitro. We identified CCN3 as a T$_{reg}$-derived mediator of oligodendrocyte differentiation and myelination in vitro. These findings reveal a new regenerative function of T$_{reg}$ in the CNS, distinct from immunomodulation. Although the cells were originally named 'T$_{reg}$' to reflect immunoregulatory roles, this also captures emerging, regenerative T$_{reg}$ functions.This work was supported by the Biotechnology and Biological Sciences Research Council (BB/J01026X/1 and BB/N003721/1, to D.C.F.), The Leverhulme Trust (ECF-2014-390, to Y.D.), QUB (QUB - Lucy McGuigan Bequest, to D.C.F.), The UK Multiple Sclerosis Society (941 and 50, to R.J.M.F. and C.Z.), MRC UK Regenerative Medicine platform (MR/KO26666/1, to A.C.W.), University of Edinburgh Wellcome Trust Multi User Equipment Grant (WT104915MA, to A.C.W.), by a core support grant from the Wellcome Trust and MRC to the Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute (097922/Z/11/Z to R.J.M.F.), studentship support from Dept. for the Economy (Northern Ireland) and British Pathological Society, US National Multiple Sclerosis Society (RG5203A4, to J.R.C.), NIH/NINDS (NS095889, to J.R.C.), NIH/NIGMS IRACDA Postdoctoral Fellowship (K12GM081266, to S.R.M.) and Wellcome Trust (110138/Z/15/Z, to D.C.F.)

Trace-strength and source-monitoring accounts of accuracy and metacognitive resolution in the misinformation paradigm

Two experiments are reported that investigate the impact of misinformation on memory accuracy and metacognitive resolution. In Experiment 1, participants viewed a series of photographs depicting a crime scene, were exposed to misinformation that contradicted details in the slides, and later took a recognition memory test. For each answer, participants were required to indicate whether they were willing to testify (report) their answer to the Court and to rate confidence. Misinformation impaired memory accuracy but it had no effect on resolution, regardless of whether resolution was indexed with confidence-rating measures (gamma correlation and mean confidence) or a report-option measure (type-2 discrimination: d’). In Experiment 2, a similar accuracy-confidence dissociation was found, and the misinformation effect occurred mostly with fine-grained responses, suggesting that responding was based on recollected details. We argue that the results support source-monitoring accounts of accuracy and resolution rather than accounts based on trace strength