Evaluation of [¹²³I]-CLINDE as a potent SPECT radiotracer to assess the degree of astroglia activation in cuprizone-induced neuroinflammation.

Purpose: The purpose of this study was to assess the feasibility and sensitivity of the high-affinity translocator protein (TSPO) ligand [(123)I]-CLINDE in imaging TSPO changes in vivo and characterise and compare astroglial and TSPO changes in the cuprizone model of demyelination and remyelination in C57BL/6 mice.

Methods: C57BL/6 mice were fed with cuprizone for 4 weeks to induce demyelination followed by 2-4 weeks of standard diet (remyelination). Groups of mice were followed by in vivo single photon emission computed tomography (SPECT)/CT imaging using [(123)I]-CLINDE and uptake correlated with biodistribution, autoradiography, immunohistochemistry, immunofluorescence and real-time polymerase chain reaction (RT-PCR).

Demyelination caused by the copper chelator cuprizone halts T cell mediated autoimmune neuroinflammation.

Myelin reactive T cells are central in the development of the autoimmune response leading to CNS destruction in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis (EAE). Investigations on the mechanisms underlying the activation and expansion of myelin reactive T have stressed the importance of non-autoimmune conditions impinging the autoimmune repertoire potentially involved in the disease. Here, we show that CNS injury caused by the toxic cuprizone results in the generation of immunoreactivity towards several myelin components.

The innate immune response to adjuvants dictates the adaptive immune response to autoantigens.

To elucidate the role of innate immunity in susceptibility to the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), we induced EAE by immunization with spinal cord homogenate (SCH) plus complete Freund adjuvant or carbonyl iron in 3 inbred rat strains. Lewis are considered "susceptible," PVG/c-Rt7a (PVG) as "semisusceptible," and Brown Norway (BN) as "resistant" to EAE. Immunization with SCH-carbonyl iron resulted in clinical disease in all 3 strains, but the pathologic features of EAE in the resistant BN and the semisusceptible PVG rats differed from those in the Lewis and PVG model of EAE induced with SCH-complete Freund adjuvant.

Expression of the heparan sulfate-degrading enzyme heparanase is induced in infiltrating CD4 T cells in experimental autoimmune encephalomyelitis and regulated at the level of transcription by early growth response gene.

The heparan sulfate-cleaving enzyme heparanase (HPSE) plays an important role in remodeling of the basement membrane and extracellular matrix during inflammation. Inducible HPSE enzymatic activity has been reported in leukocytes; however, little is known of the molecular mechanisms that regulate HPSE gene expression during inflammatory disease. In this study, HPSE expression and regulation in the T cell-mediated disease model, experimental autoimmune encephalomyelitis (EAE), were investigated.

The contribution of nitric oxide and interferon gamma to the regulation of the neuro-inflammation in experimental autoimmune encephalomyelitis.

Nitric oxide (NO) is a key messenger involved in physiological functions including endothelium-dependent vascular relaxation, inhibition of platelet adhesion and aggregation and regulation of inflammatory and immune responses. Here we briefly introduce NO and its functions and then describe our work over the past several years examining the role of NO in EAE in both the rat and the mouse. We show that NO plays a significant role in determining the resistance or susceptibility to EAE in various strains and or sexes of animals.

Expression of the heparan sulfate-degrading enzyme heparanase is induced in infiltrating CD4+ T cells in experimental autoimmune encephalomyelitis and regulated at the level of transcription by early growth response gene 1.

The heparan sulfate-cleaving enzyme heparanase (HPSE) plays an important role in remodeling of the basement membrane and extracellular matrix during inflammation. Inducible HPSE enzymatic activity has been reported in leukocytes; however, little is known of the molecular mechanisms that regulate HPSE gene expression during inflammatory disease. In this study, HPSE expression and regulation in the T cell-mediated disease model, experimental autoimmune encephalomyelitis (EAE), were investigated.

Neuronal nitric oxide synthase plays a key role in CNS demyelination.

Nitric oxide (NO) is a small, short-lived molecule released from a variety of cells that is implicated in a multitude of biological processes. In pathological conditions, overproduction of NO may lead to the generation of highly reactive species, such as peroxynitrite and stable nitrosothiols, that may cause irreversible cell damage. Accordingly, several studies have suggested that NO may be involved in the pathogenesis of various neuroinflammatory/degenerative diseases.

Nitric oxide contributes to the resistance of young SJL/J mice to experimental autoimmune encephalomyelitis.

EAE development in SJL/J mice is age and sex dependent: young males are EAE resistant; females and adult males are EAE susceptible. By studying splenocytes' IFNgamma and NO production and the induction or the suppression of actively induced EAE by manipulating NO systemic levels, we provide evidence that the failure of young male SJL/J mice to develop EAE lies in the activation of the innate immune system by the immunising stimulus.

Nitric oxide contributes to resistance of the Brown Norway rat to experimental autoimmune encephalomyelitis.

The Brown Norway (BN) rat is reported to be resistant to the induction of experimental autoimmune encephalomyelitis (EAE) and a number of mechanisms have been suggested to explain this resistance. In work reported here we provide evidence that such resistance in the BN rat can be accounted for, at least in part, by their ability to produce higher levels of nitric oxide (NO) than susceptible strains of rats. Spleen cells from the BN rat make significantly more NO following in vitro stimulation than do cells from the Lewis or PVG rat and following in vivo immunization using complete Freund's adjuvant (CFA) the BN rat makes substantially more NO than either susceptible strain.

Expression of rat I-TAC/CXCL11/SCYA11 during central nervous system inflammation: comparison with other CXCR3 ligands.

The chemokines are a large gene superfamily with critical roles in development and immunity. The chemokine receptor CXCR3 appears to play a major role in the trafficking of activated Th1 lymphocytes. There are at least three major ligands for CXCR3: mig/CXCL9, IP-10/CXCL10 and I-TAC/CXCL11, and of these three ligands, CXCL11 is the least well-characterized.

A role for macrophage inflammatory protein-3 alpha/CC chemokine ligand 20 in immune priming during T cell-mediated inflammation of the central nervous system.

Chemokines are a family of cytokines that exhibit selective chemoattractant properties for target leukocytes and play a significant role in leukocyte migration. In this study, we have investigated the role of the C-C chemokine, macrophage inflammatory protein (MIP)-3alpha/CC chemokine ligand 20, in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a model of T cell-dependent inflammation. Expression in the CNS of MIP-3alpha, as determined by RT-PCR, increased in a time-dependent manner such that peak expression correlated with peak clinical disease.

Nitric oxide induces polarization of actin in encephalitogenic T cells and inhibits their in vitro trans-endothelial migration in a p70S6 kinase-independent manner.

Nitric oxide (NO) inhibits both actively induced and transferred autoimmune encephalomyelitis. To explore potential mechanisms, we examined the ability of NO to inhibit migration of T lymphoblasts through both collagen matrices and monolayers of rat brain endothelial cells. The NO donor 1-hydroxy-2-oxo-3, 3-bis (2-aminoethyl)-1-triazene (HOBAT) inhibited migration in a concentration-dependent manner.

Macrophages and nitric oxide as the possible cellular and molecular basis for strain and gender differences in susceptibility to autoimmune central nervous system inflammation.

PVG rats are resistant to actively induced experimental autoimmune encephalomyelitis (EAE) and this appears to be directly related to high and sustained systemic levels of reactive nitrogen intermediates(RNI) following sensitization for EAE when compared to the highly susceptible Lewis rat. An apparent cellular basis for the different EAE susceptibility between the two rat strains is described. Spleens of PVG rats have increased monocyte/macrophage numbers(NO producing cells) and lower erythrocyte (NO scavengers) to nucleated spleen cell ratios compared with Lewis rats.