•Immunodeficient mice have a suppressed glial response after facial nerve axotomy.•Neuroprotective WT CD4+ T cells regulate the glial microenvironment.•Intrinsic motoneuron regeneration response is ...independent of immune status.•mSOD1 whole splenocytes induce cell death pathways after axotomy.•New role proposed for the immune system in neurodegenerative diseases.
When facial nerve axotomy (FNA) is performed on immunodeficient recombinase activating gene-2 knockout (RAG-2−/−) mice, there is greater facial motoneuron (FMN) death relative to wild type (WT) mice. Reconstituting RAG-2−/− mice with whole splenocytes rescues FMN survival after FNA, and CD4+ T cells specifically drive immune-mediated neuroprotection. Evidence suggests that immunodysregulation may contribute to motoneuron death in amyotrophic lateral sclerosis (ALS). Immunoreconstitution of RAG-2−/− mice with lymphocytes from the mutant superoxide dismutase (mSOD1) mouse model of ALS revealed that the mSOD1 whole splenocyte environment suppresses mSOD1 CD4+ T cell-mediated neuroprotection after FNA. The objective of the current study was to characterize the effect of CD4+ T cells on the central molecular response to FNA and then identify if mSOD1 whole splenocytes blocked these regulatory pathways.
Gene expression profiles of the axotomized facial motor nucleus were assessed from RAG-2−/− mice immunoreconstituted with either CD4+ T cells or whole splenocytes from WT or mSOD1 donors. The findings indicate that immunodeficient mice have suppressed glial activation after axotomy, and cell transfer of WT CD4+ T cells rescues microenvironment responses. Additionally, mSOD1 whole splenocyte recipients exhibit an increased astrocyte activation response to FNA. In RAG-2−/− + mSOD1 whole splenocyte mice, an elevation of motoneuron-specific Fas cell death pathways is also observed. Altogether, these findings suggest that mSOD1 whole splenocytes do not suppress mSOD1 CD4+ T cell regulation of the microenvironment, and instead, mSOD1 whole splenocytes may promote motoneuron death by either promoting a neurotoxic astrocyte phenotype or inducing Fas-mediated cell death pathways. This study demonstrates that peripheral immune status significantly affects central responses to nerve injury. Future studies will elucidate the mechanisms by which mSOD1 whole splenocytes promote cell death and if inhibiting this mechanism can preserve motoneuron survival in injury and disease.
Current immunization protocols in cancer patients involve CTL-defined tumor peptides. Mature dendritic cells (DC) are the most potent APCs for the priming of naive CD8(+) T cells, eventually leading ...to tumor eradication. Because DC can secrete MHC class I-bearing exosomes, we addressed whether exosomes pulsed with synthetic peptides could subserve the DC function consisting in MHC class I-restricted, peptide-specific CTL priming in vitro and in vivo. The priming of CTL restricted by HLA-A2 molecules and specific for melanoma peptides was performed: 1) using in vitro stimulations of total blood lymphocytes with autologous DC pulsed with GMP-manufactured autologous exosomes in a series of normal volunteers; 2) in HLA-A2 transgenic mice (HHD2) using exosomes harboring functional HLA-A2/Mart1 peptide complexes. In this study, we show that: 1). DC release abundant MHC class I/peptide complexes transferred within exosomes to other naive DC for efficient CD8(+) T cell priming in vitro; 2). exosomes require nature's adjuvants (mature DC) to efficiently promote the differentiation of melanoma-specific effector T lymphocytes producing IFN-gamma (Tc1) effector lymphocytes in HLA-A2 transgenic mice (HHD2). These data imply that exosomes might be a transfer mechanism of functional MHC class I/peptide complexes to DC for efficient CTL activation in vivo.
We tested whether satisfaction of search (SOS) effects that occur in computed tomography (CT) examination of the chest on detection of native abnormalities are produced by the addition of simulated ...pulmonary nodules.
Two experiments were conducted. In the first experiment, 70 CT examinations, half that demonstrated diverse, subtle abnormalities and half that demonstrated no native lesions, were read by 18 radiology residents and fellows under two experimental conditions: presented with and without pulmonary nodules. In a second experiment, many of the examinations were replaced to include more salient native abnormalities. This set was read by 14 additional radiology residents and fellows. In both experiments, detection of the natural abnormalities was studied. Receiver operating characteristic (ROC) curve areas for each reader-treatment combination were estimated using empirical and proper ROC models. Additional analyses focused on decision thresholds and visual search time on abnormality-free CT slice ranges. Institutional review board approval and informed consent from 32 participants were obtained.
Observers more often missed diverse native abnormalities when pulmonary nodules were added, but also made fewer false-positive responses. There was no change in ROC area, but decision criteria grew more conservative. The SOS effect on decision thresholds was accompanied by a reduction in search time on abnormality-free CT slice ranges.
The SOS effect in CT examination of the chest is similar to that found in contrast examination of the abdomen, involving induced visual neglect.
The efficacy of combined aspiration catheter and stent retriever compared with stent retriever alone for the treatment of large-vessel occlusion acute ischemic stroke is unclear.
Our aim was to ...conduct a systematic literature review and meta-analysis on several metrics of efficacy comparing aspiration catheter and stent retriever with stent retriever alone.
MEDLINE and the Cochrane Library Databases were searched. Randomized controlled trials and case-control and cohort studies were included.
Ten comparative studies were included detailing a combined 1495 patients with aspiration catheter and stent retriever and 1864 with stent retrievers alone.
Data on first pass effect (TICI 2b/2c/3 after first pass), final successful reperfusion (modified TICI ≥2b), and 90-day functional independence (mRS ≤ 2) were collected. Meta-analysis was performed using a random-effects model.
There was a pooled composite first pass effect of 40.8% (611/1495) versus 32.6% (608/1864) for aspiration catheter and stent retriever and stent retriever alone, respectively (
< .0001). Similarly, on a meta-analysis, aspiration catheter and stent retriever were associated with a higher first pass effect compared with stent retriever alone (OR = 1.63; 95% CI, 1.20-2.21;
= .002; I
= 72%). There was no significant difference in composite rates of successful reperfusion between aspiration catheter and stent retriever (72.8%, 867/1190) and stent retriever alone (70.8%, 931/1314) (
= .27) or on meta-analysis (OR = 1.31; CI, 0.81-2.12;
= .27; I
= 82%). No difference was found between aspiration catheter and stent retriever and stent retriever alone on 90-day functional independence (OR = 1.02; 95% CI, 0.77-1.36;
= .88; I
= 40%).
This study is limited by high interstudy heterogeneity.
On meta-analysis, aspiration catheter and stent retriever are associated with a superior first pass effect compared with stent retriever alone, but they are not associated with statistically different final reperfusion or functional independence.
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