Uri Nevo

Autoimmune T cells as potential neuroprotective therapy for spinal cord injury

Autoimmune T cells against central nervous system myelin associated peptide reduce the spread of damage and promote recovery in injured rat spinal cord, findings that might lead to neuroprotective cell therapy without risk of autoimmune disease.

Posttraumatic therapeutic vaccination with modified myelin self-antigen prevents complete paralysis while avoiding autoimmune disease

Spinal cord injury results in a massive loss of neurons, and thus of function. We recently reported that passive transfer of autoimmune T cells directed against myelin-associated antigens provides acutely damaged spinal cords with effective neuroprotection. The therapeutic time window for the passive transfer of T cells was found to be at least 1 week. Here we show that posttraumatic T cell-based active vaccination is also neuroprotective. Immunization with myelin-associated antigens such as myelin basic protein (MBP) significantly promoted recovery after spinal cord contusion injury in the rat model. To reduce the risk of autoimmune disease while retaining the benefit of the immunization, we vaccinated the rats immediately after severe incomplete spinal cord injury with MBP-derived altered peptide ligands. Immunization with these peptides resulted in significant protection from neuronal loss and thus in a reduced extent of paralysis, assessed by an open-field behavioral test. Retrograde labeling of the rubrospinal tracts and magnetic resonance imaging supported the behavioral results. Further optimization of nonpathogenic myelin-derived peptides can be expected to lead the way to the development of an effective therapeutic vaccination protocol as a strategy for the prevention of total paralysis after incomplete spinal cord injury.

Diffusion anisotropy MRI for quantitative assessment of recovery in injured rat spinal cord.

Spinal cord injury and its devastating consequences are the subject of intensive research aimed at reversing or at least minimizing functional loss. Research efforts focus on either attenuating the post‐injury spread of damage (secondary degeneration) or inducing some regeneration. In most of these studies, as well as in clinical situations, evaluation of the state of the injured spinal cord poses a serious difficulty. To address this problem, we carried out a diffusion‐weighted MRI experiment and developed an objective routine for quantifying anisotropy in injured rat spinal cords. Rats were subjected to a contusive injury of the spinal cord caused by a controlled weight drop. Untreated control rats were compared with rats treated with T cells specific to the central nervous system self‐antigen myelin basic protein, a form of therapy recently shown to be neuroprotective. After the rats were killed their excised spinal cords were fixed in formalin and imaged by multislice spin echo MRI, using two orthogonal diffusion gradients. Apparent diffusion coefficient (ADC) values and anisotropy ratio (AI) maps were extracted on a pixel‐by‐pixel basis. The calculated sum of AI values (SAI) for each slice was defined as a parameter representing the total amount of anisotropy. The mean‐AI and SAI values increased gradually with the distance from the site of the lesion. At the site itself, the mean‐AI and SAI values were significantly higher in the spinal cords of the treated animals than in the controls (P = 0.047, P = 0.028, respectively). These values were consistent with the score of functional locomotion. The difference was also manifested in the AI maps, which revealed well‐organized neural structure in the treated rats but not in the controls. The SAI values, AI histograms, and AI maps proved to be useful parameters for quantifying injury and recovery in an injured spinal cord. These results encourage the development of diffusion anisotropy MRI as a helpful approach for quantifying the extent of secondary degeneration and measuring recovery after spinal cord injury. Magn Reson Med 45:1–9, 2001.

Vaccination with Dendritic Cells Pulsed with Peptides of Myelin Basic Protein Promotes Functional Recovery from Spinal Cord Injury

Injury-induced self-destructive processes cause significant functional loss after incomplete spinal cord injury (SCI). Cellular elements of both the innate (macrophage) and the adaptive (T-cell) immune response can, if properly activated and controlled, promote post-traumatic regrowth and protection after SCI. Dendritic cells (DCs) trigger activation of effector and regulatory T-cells, providing a link between the functions of the innate and the adaptive immune systems. They also initiate and control the bodys response to pathogenic agents and regulate immune responses to both foreign and self-antigens. Here we show that post-injury injection of bone marrow-derived DCs pulsed with encephalitogenic or nonencephalitogenic peptides derived from myelin basic protein, when administered (either systemically or locally by injection into the lesion site) up to 12 d after the injury, led to significant and pronounced recovery from severe incomplete SCI. No significant protection was seen in DC recipients deprived of mature T-cells. Flow cytometry, RT-PCR, and proliferation assays indicated that the DCs prepared and used here were mature and immunogenic. Taken together, the results suggest that the DC-mediated neuroprotection was achieved via the induction of a systemic T-cell-dependent immune response. Better preservation of neural tissue and diminished formation of cysts and scar tissue accompanied the improved functional recovery in DC-treated rats. The use of antigen-specific DCs may represent an effective way to obtain, via transient induction of an autoimmune response, the maximal benefit of immune-mediated repair and maintenance as well as protection against self-destructive compounds.

Therapeutic Vaccination for Closed Head Injury

Closed head injury often has a devastating outcome, partly because the insult, like other injuries to the central nervous system (CNS), triggers self-destructive processes. During studies of the response to other CNS insults, it was unexpectedly discovered that the immune system, if well controlled, provides protection against self-destructive activities. Here we show that in mice with closed head injury, the immune system plays a key role in the spontaneous recovery. Strain-related differences were observed in the ability to harness a T cell-dependent protective mechanism against the effects of the injury. We further show that the trauma-induced deficit could be reduced, both functionally and anatomically, by post-traumatic vaccination with Cop-1, a synthetic copolymer used to treat patients with multiple sclerosis and found (using a different treatment protocol) to effectively counteract the loss of neurons caused by axonal injury or glutamate-induced toxicity. We suggest that a compound such as Cop-1 can be safely developed as a therapeutic vaccine to boost the bodys immune repair mechanisms, thereby providing multifactorial protection against the consequences of brain trauma.

Autoimmunity as a special case of immunity: removing threats from within

The function of the adaptive immune response against exogenous (non-self) agents is to help the innate arm of the immune system (represented by phagocytic cells) to fight and eliminate these agents. We suggest that the body also protects itself against potentially harmful self components using mechanisms similar to those used for fighting and eliminating non-self agents, and that the protective immune activity against self-components competes with the activity of self-destructive compounds. Tolerance to self is thus not a lack of response to self, but the ability to tolerate an active defense response to self without developing an autoimmune disease.

The Elliptical Cone of Uncertainty and Its Normalized Measures in Diffusion Tensor Imaging

Diffusion tensor magnetic resonance imaging (DT-MRI) is capable of providing quantitative insights into tissue microstructure in the brain. An important piece of information offered by DT-MRI is the directional preference of diffusing water molecules within a voxel. Building upon this local directional information, DT-MRI tractography attempts to construct global connectivity of white matter tracts. The interplay between local directional information and global structural information is crucial in understanding changes in tissue microstructure as well as in white matter tracts. To this end, the right circular cone of uncertainty was proposed by Basser as a local measure of tract dispersion. Recent experimental observations by Jeong et al. and Lazar et al. that the cones of uncertainty in the brain are mostly elliptical motivate the present study to investigate analytical approaches to quantify their findings. Two analytical approaches for constructing the elliptical cone of uncertainty, based on the first-order matrix perturbation and the error propagation method via diffusion tensor representations, are presented and their theoretical equivalence is established. We propose two normalized measures, circumferential and areal, to quantify the uncertainty of the major eigenvector of the diffusion tensor. We also describe a new technique of visualizing the cone of uncertainty in 3-D.

Artificial Neural Networks Based Controller for Glucose Monitoring during Clamp Test

Insulin resistance (IR) is one of the most widespread health problems in modern times. The gold standard for quantification of IR is the hyperinsulinemic-euglycemic glucose clamp technique. During the test, a regulated glucose infusion is delivered intravenously to maintain a constant blood glucose concentration. Current control algorithms for regulating this glucose infusion are based on feedback control. These models require frequent sampling of blood, and can only partly capture the complexity associated with regulation of glucose. Here we present an improved clamp control algorithm which is motivated by the stochastic nature of glucose kinetics, while using the minimal need in blood samples required for evaluation of IR. A glucose pump control algorithm, based on artificial neural networks model was developed. The system was trained with a data base collected from 62 rat model experiments, using a back-propagation Levenberg-Marquardt optimization. Genetic algorithm was used to optimize network topology and learning features. The predictive value of the proposed algorithm during the temporal period of interest was significantly improved relative to a feedback control applied at an equivalent low sampling interval. Robustness to noise analysis demonstrates the applicability of the algorithm in realistic situations.

Optical phase nanoscopy in red blood cells using low-coherence spectroscopy

Abstract. We propose a low-coherence spectral-domain phase microscopy (SDPM) system for accurate quantitative phase measurements in red blood cells (RBCs) for the prognosis and monitoring of disease conditions that affect the visco-elastic properties of RBCs. Using the system, we performed time-recordings of cell membrane fluctuations, and compared the nano-scale fluctuation dynamics of healthy and glutaraldehyde-treated RBCs. Glutaraldehyde-treated RBCs possess lower amplitudes of fluctuations, reflecting an increased membrane stiffness. To demonstrate the ability of our system to measure fluctuations of lower amplitudes than those measured by the commonly used holographic phase microscopy techniques, we also constructed wide-field digital interferometry (WFDI) system and compared the performances of both systems. Due to its common-path geometry, the optical-path-delay stability of SDPM was found to be less than 0.3 nm in liquid environment, at least three times better than WFDI under the same conditions. In addition, due to the compactness of SDPM and its inexpensive and robust design, the system possesses a high potential for clinical applications.

Faster imaging with a portable unilateral NMR device.

Unilateral NMR devices are important tools in various applications such as non-destructive testing and well logging, but are not applied routinely for imaging, primarily because B0 inhomogeneity in these scanners leads to a relatively low signal and requires use of the slow single point imaging scan scheme. Enabling high quality, fast imaging could make this affordable and portable technology practical for various imaging applications as well as for new applications that are not yet feasible with MRI technology. The goal of this work was to improve imaging times in a portable unilateral NMR scanner. Both Compressed Sensing and Fast Spin Echo were modified and applied to fit the unique characteristics of a unilateral device. Two printed phantoms, allowing high resolution images, were scanned with both methods and compared to a standard scan and to a low pass scan to evaluate performance. Both methods were found to be feasible with a unilateral device, proving ways to accelerate single point imaging in such scanners. This outcome encourages us to explore how to further accelerate imaging times in unilateral NMR devices so that this technology might become clinically applicable in the future.