Chronic Tumor Necrosis Factor Alters T Cell Responses by Attenuating T Cell Receptor Signaling

Repeated injections of adult mice with recombinant murine TNF prolong the survival of NZB/W F1 mice, and suppress type I insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice. To determine whether repeated TNF injections suppress T cell function in adult mice, we studied the responses of influenza hemagglutinin-specific T cells derived from T cell receptor (HNT-TCR) transgenic mice. Treatment of adult mice with murine TNF for 3 wk suppressed a broad range of T cell responses, including proliferation and cytokine production. Furthermore, T cell responses of HNT-TCR transgenic mice also expressing the human TNF-globin transgene were markedly reduced compared to HNT-TCR single transgenic littermates, indicating that sustained p55 TNF-R signaling is sufficient to suppress T cell function in vivo. Using a model of chronic TNF exposure in vitro, we demonstrate that (a) chronic TNF effects are dose and time dependent, (b) TNF suppresses the responses of both Th1 and Th2 T helper subsets, (c) the suppressive effects of endogenous TNF produced in T cell cultures could be reversed with neutralizing monoclonal antibodies to TNF, and (d) prolonged TNF exposure attenuates T cell receptor signaling. The finding that anti-TNF treatment in vivo enhances T cell proliferative responses and cytokine production provides evidence for a novel regulatory effect of TNF on T cells in healthy laboratory mice. These effects are more pronounced in chronic inflammatory disease. In addition, our data provide a mechanism through which prolonged TNF exposure suppresses disease in animal models of autoimmunity.     

Differential force scaling of fine‐graded power grip force in the sensorimotor network

Force scaling in the sensorimotor network during generation and control of static or dynamic grip force has been the subject of many investigations in monkeys and human subjects. In human, the relationship between BOLD signal in cortical and subcortical regions and force still remains controversial. With respect to grip force, the modulation of the BOLD signal has been mostly studied for forces often reaching high levels while little attention has been given to the low range for which electrophysiological neuronal correlates have been demonstrated. We thus conducted a whole‐brain fMRI study on the control of fine‐graded force in the low range, using a power grip and three force conditions in a block design. Participants generated on a dynamometer visually guided repetitive force pulses (ca. 0.5 Hz), reaching target forces of 10%, 20%, and 30% of maximum voluntary contraction. Regions of interest analysis disclosed activation in the entire cortical and subcortical sensorimotor network and significant force‐related modulation in several regions, including primary motor (M1) and somatosensory cortex, ventral premotor and inferior parietal areas, and cerebellum. The BOLD signal, however, increased monotonically with force only in contralateral M1 and ipsilateral anterior cerebellum. The remaining regions were activated with force in various nonlinear manners, suggesting that other factors such as visual input, attention, and muscle recruitment also modulate the BOLD signal in this visuomotor task. These findings demonstrate that various regions of the sensorimotor network participate differentially in the production and control of fine‐graded grip forces. Hum Brain Mapp 2009. © 2009 Wiley‐Liss, Inc.     

Investigating the stabilising and mobilising features of footedness

This study investigated lower limb laterality for stabilising and mobilising actions in 10 right- and 10 mixed-footed participants by determining, via the Waterloo Footedness Questionnaire--Revised (WFQ-R), the preferred foot in carrying out a range of stabilising and mobilising activities and by recording foot performance on standing balance and ball juggling. The log odds ratio (lambda score) was used to quantify the degree of laterality in task performance. Differences between the stability and mobility scores and the two groups were analyzed using a 2 (Group) x 2 (Task) ANOVA model with repeated measures on Task. Right- and mixed-footed participants differed significantly in the stability but not in the mobility items of the WFQ-R. No significant between-group differences were noted in either ball-juggling or standing balance performance. Mixed-footed participants had a significant right-left foot difference in standing balance, whereas both groups had a significant right-left foot difference in ball juggling. It is concluded that preference is not a steady attribute across the mobility and stability items of the WFQ-R and appears to be dependent on the behavioural context of a particular task. Results further indicated a lack of concordance between questionnaire and performance-based measures suggesting that these two methods of measuring laterality may be indicators of different underlying factors.     

Insulin-like growth factor-I ameliorates demyelination induced by tumor necrosis factor-alpha in transgenic mice

Our groups have reported that tumor necrosis factor-alpha (TNF-alpha) causes myelin damage and apoptosis of oligodendrocytes and their precursors in vitro and in vivo. We also have reported that insulin-like growth factor-I (IGF-I) can protect cultured oligodendrocytes and their precursors from TNF-alpha-induced damage. In this study, we investigated whether IGF-I can protect oligodendrocytes and myelination from TNF-alpha-induced damage in vivo by cross-breeding TNF-alpha transgenic (Tg) mice with IGF-I Tg mice that overexpress IGF-I exclusively in brain. At 8 weeks of age, compared with those of wild-type (WT) mice, the brain weights of TNF-alpha Tg mice were decreased by approximately 20%, and those of IGF-I Tg mice were increased by approximately 20%. The brain weights of mice that carry both TNF-alpha and IGF-I transgenes (TNF-alpha/IGF-I Tg mice) did not differ from those of WT mice. As judged by histochemical staining and immunostaining, myelin content in the cerebellum of TNF-alpha/IGF-I Tg mice was similar to that in WT mice and much more than that in TNF-alpha Tg mice. Consistently, Western immunoblot analysis showed that myelin basic protein (MBP) abundance in the cerebellum of TNF-alpha/IGF-I Tg mice was double that in TNF-alpha Tg mice. In comparison with WT mice, the number of oligodendrocytes was decreased by approximately 36% in TNF-alpha Tg mice, whereas it was increased in IGF-I Tg mice by approximately 40%. Oligodendrocyte number in TNF-alpha/IGF-I Tg mice was almost twice that in TNF-alpha Tg mice. Furthermore, IGF-I overexpression significantly reduced TNF-alpha-induced increases in apoptotic cell number, active caspase-3 abundance, and degradaion of MBP. Our results indicate that IGF-I is capable of protecting myelin and oligodendrocytes from TNF-alpha-induced damage in vivo.     

Electrophysiological and hemodynamic evidence for late maturation of hand power grip and force control under visual feedback

Several human imaging studies have described the neural network involved in power grip under visual control and the subset of cortical areas within this network that are sensitive to force modulation. As there is behavioral evidence for late maturation in even simple hand motor tasks involving visual feedback, we aimed at identifying the neural correlates of these developmental changes. Subjects from three developmental age groups (9-11, 15-17, and adults) performed the same power grip task in both a functional magnetic resonance imaging and an event-related potential (ERP) session. Trials started with a visual target indicating whether to squeeze at 20%, 40%, or 75% of their maximum and online visual feedback on the actual amount of force was provided. Longer reaction times and more shallow slopes of the force curve characterized the behavior of the younger age groups, especially the children. Both neurophysiological methods detected both general as well as force modulation-specific maturational changes. General development was characterized by decreasing ERP amplitudes and increasing deactivation of an extended network, closely resembling the so-called "default" network. The most pronounced developmental changes specific for force control were observed in an ERP component and brain regions involved in feedback processing. In contrast to adult subjects, we found evidence for a stronger dependency on visual feedback information in the younger age groups. Our results also suggest that the ability to deactivate task-irrelevant networks might be a late developmental achievement.     

Diffusion-weighted imaging of the entire spinal cord

In spite of their diagnostic potential, the poor quality of available diffusion-weighted spinal cord images often restricts clinical application to cervical regions, and improved spatial resolution is highly desirable. To address these needs, a novel technique based on the combination of two recently presented reduced field-of-view approaches is proposed, enabling high-resolution acquisition over the entire spinal cord. Field-of-view reduction is achieved by the application of non-coplanar excitation and refocusing pulses combined with outer volume suppression for removal of unwanted transition zones. The non-coplanar excitation is performed such that a gap-less volume is acquired in a dedicated interleaved slice order within two repetition times. The resulting inner volume selectivity was evaluated in vitro. In vivo diffusion tensor imaging data on the cervical, thoracic and lumbar spinal cord were acquired in transverse orientation in each of four healthy subjects. An in-plane resolution of 0.7 x 0.7 mm(2) was achieved without notable aliasing, motion or susceptibility artifacts. The measured mean +/- SD fractional anisotropy was 0.69 +/- 0.11 in the thoracic spinal cord and 0.75 +/- 0.07 and 0.63 +/- 0.08 in cervical and lumbar white matter, respectively.     

Actin cytoskeleton dynamics linked to synovial fibroblast activation as a novel pathogenic principle in TNF-driven arthritis

Rheumatoid arthritis is a chronic inflammatory disorder whose origin of defect has been the subject of extensive research during the past few decades. While a number of immune and non-immune cell types participate in the development of chronic destructive inflammation in the arthritic joint, synovial fibroblasts have emerged as key effector cells capable of modulating both joint destruction and propagation of inflammation. Ample evidence of aberrant changes in the morphology and biochemical behaviour of rheumatoid arthritis synovial fibroblasts have established the tissue evading and "transformed" character of this cell type. We have recently demonstrated that actin cytoskeletal rearrangements determine the pathogenic activation of synovial fibroblasts in modelled TNF-mediated arthritis, a finding correlating with similar gene expression changes which we observed in human rheumatoid arthritis synovial fibroblasts. Here, we show that pharmacological inhibition of actin cytoskeleton dynamics alters potential pathogenic properties of the arthritogenic synovial fibroblast, such as proliferation, migration and resistance to apoptosis, indicating novel opportunities for therapeutic intervention in arthritis. Recent advances in this field of research are reviewed and discussed.     

Proton magnetic resonance spectroscopy characteristics of a focal cortical dysgenesis during status epilepticus and in the interictal state.

We report the magnetic resonance imaging and proton magnetic resonance spectroscopic findings ((1)HMRS) in a patient with a focal cortical dysgenesis in the right superior frontal gyrus during intermittent frontal status epilepticus (IFSE) with simple partial seizures, and after she had become seizure free. During the status epilepticus, demonstrated by simultaneous behavioural and electroencephalographic telemetric long-term monitoring with scalp electrodes and ictal SPECT, we performed a single voxel spectroscopy of the dysgenic cortex. The(1)HMRS was repeated after 20 days when the patient's seizures were controlled.The N-acetyl-aspartate concentration in the focal dysgenic cortex was decreased in the interictal state but more during IFSE. The creatine/phosphocreatine concentration was normal in both instances. There was a clear lactate signal during IFSE, which was no longer visible in the interictal state.To our knowledge this is the first report of a(1)HMRS study of a focal cortical dysgenesis during an intermittent status epilepticus. We interpret the observed changes as signs of histopathological changes inherent to a cortical malformation and of an impaired energy metabolism due to the partial status epilepticus.     

Protection of zinc against tumor necrosis factor induced lethal inflammation depends on heat shock protein 70 and allows safe antitumor therapy

Tumor necrosis factor (TNF)-induced inflammation prevents its broad application as an antitumor agent. We here report that addition of ZnSO(4) to the drinking water of mice induces expression of heat shock protein 70 (HSP70) in several organs, notably the gastrointestinal track. Zinc conferred dose-responsive protection against TNF-induced hypothermia, systemic induction of interleukin-6 and NO(x), as well as against TNF-induced bowel cell death and death of the organism. The protective effect of zinc was completely absent in mice deficient in the major HSP70-inducible gene, hsp70.1, whereas transgenic mice constitutively expressing the human HSP70.A gene, under control of a beta-actin promoter, was also protected against TNF, indicating that an increase in HSP70 is necessary and sufficient to confer protection. The therapeutic potential of the protection induced by ZnSO(4) was clearly shown in a TNF/IFNgamma-based antitumor therapy using three different tumor models. In hsp70.1 wild-type mice, but not in hsp70.1-deficient mice, zinc very significantly protected against lethality but left the antitumor effect intact. We conclude that zinc protects against TNF in a HSP70-dependent way and that protection by zinc could be helpful in developing a safer anticancer therapy with TNF/IFNgamma.