Protective Effects Of A Peroxisome Proliferator-Activated Receptor-beta/delta Agonist In Experimental Autoimmune Encephalomyelitis
Polak PE, Kalinin S, Dello Russo C, Gavrilyuk V, Sharp A, Peters JM, Richardson J, Willson TM, Weinberg G, Feinstein DL
J NeuroImmunol 2005 Aug 9
University of Illinois, & Jesse Brown Veteran's Affairs Research Division, Department of Anesthesiology, Chicago, IL, 60612, United States
Agonists of the Peroxisome Proliferator-Activated Receptor gamma (PPAR-gamma) exert anti-inflammatory and anti-proliferative effects which led to testing of these drugs in Experimental Autoimmune Encephalomyelitis (EAE), a model for Multiple Sclerosis.
In contrast, the effect of PPAR-delta (PPAR-delta) agonists in EAE is not yet known.
We show that oral administration of the selective PPAR-delta agonist GW0742 reduced clinical symptoms in C57BL/6 mice that had been immunized with Encephalitogenic Myelin Oligodendrocyte Glycoprotein (MOG) peptide.
In contrast to previous results with PPAR-gamma agonists, GW0742 only modestly attenuated clinical symptoms when the drug was provided simultaneously with immunization, but a greater reduction was observed if administered during disease progression.
Reduced clinical symptoms were accompanied by a reduction in the appearance of new Cortical lesions, however Cerebellar lesion load was not reduced.
Treatment of T-Cells with GW0742 either in vivo or in vitro did not reduce IFN-γ production; however GW0742 reduced Astroglial and Microglial inflammatory activation and IL-1-beta levels in EAE Brain.
RTPCR analysis showed that GW0742 increased expression of some Myelin genes. These data demonstrate that PPAR-delta agonists, like other PPAR ligands, can exert protective actions in an AutoImmune model of DeMyelinating Disease.
Predictors Of Long-Term Clinical Response To Interferon-beta Therapy In Relapsing Multiple Sclerosis
Tomassini V, Paolillo A, Russo P, Giugni E, Prosperini L, Gasperini C, Antonelli G, Bastianello S, Pozzilli C
J Neurol 2005 Sep 14
La Sapienza University, Dept. of Neurological Sciences, viale dell'Universita, 30, 00185, Rome, Italy
The aim of this study was to identify clinical, Magnetic Resonance Imaging (MRI) and biological markers predictive of long-term clinical response to Interferon-beta (IFN-ß) therapy in patients with Relapsing/Remitting Multiple Sclerosis (RRMS).
Sixty-eight patients treated with IFN-ß were followed over a 6-year period. Relapse rate and disability progression were evaluated throughout the study.
We considered suboptimal clinical response to be either the presence of sustained disability progression, or more than two relapses.
Baseline and 12-month demographic, clinical and MRI findings, as well as the development of Neutralizing AntiBodies (NABs) against IFN-ß during the first year of therapy were analyzed as predictors of long-term clinical outcome.
"Black holes" on MRI were the best baseline predictor of disability progression (odds ratio [OR] 6.8; p < 0.001).At 1 year, both male gender (OR 4.9; p = 0.009) and NABs (OR 7.3; p = 0.003) were independently associated with a high risk of developing subsequent disability.
The presence of Gadolinium enhancement, both at baseline (OR 4.7; p = 0.005) and on the 1-year MRI scan (OR 7.9; p = 0.002), was the unique variable associated with the number of relapses over the study period.
Variables assessable within the first year of treatment significantly influence relapse rate and disability progression in patients with RRMS treated with IFN-ß.
These findings may help clinicians to make decisions regarding therapy regimen over time, and highlight the need for a prognostic algorithm.
DeMyelinated NeoCortical Lesions In Marmoset Autoimmune Encephalomyelitis Mimic Those In Multiple Sclerosis
Pomeroy IM, Matthews PM, Frank JA, Jordan EK, Esiri MM
Brain 2005 Sep 8
University of Oxford, Department of Clinical Neurology, Oxford, UK
The use of ImmunoHistoChemical methods has led to a new understanding of the prevalence and significance of Cortical lesions in Multiple Sclerosis but these lesions have not yet been formally described in an animal model.
In this study we have set out to use ImmunoHistoChemical techniques to identify and describe Cortical lesions in marmosets with Experimental Autoimmune Encephalomyelitis (EAE).
Using AntiBodies to ProteoLipid Protein (PLP), we found a total of 70 Cortical lesions in 11 tissue blocks from 6 animals. These lesions were subdivided into LeucoCortical (40), IntraCortical (12) and SubPial lesions (18).
We quantified the density of inflammatory cells within lesions using a double labelling protocol which employed Anti-PLP in addition to AntiBodies against markers of B-Lymphocytes (CD20), T-Lymphocytes (CD3), Macrophages (MAC387) and MHC-II expressing cells (CR3/43).
This analysis revealed that the large SubPial lesions accounted for the majority of DeMyelinated Cortex (88%) despite possessing the lowest density of inflammatory cells.
This study has shown that lesions in this model share many of the major features of Cortical lesions in Multiple Sclerosis both in terms of morphology and inflammatory cell content.
We believe that this tool can be exploited in future studies to investigate the Etiology, development and clinical significance of Cortical lesions in DeMyelinating Disease.
Vitamin D3 Confers Protection From Autoimmune Encephalomyelitis Only In Female Mice
Spach KM, Hayes CE
J Immunol 2005 Sep 15;175(6):4119-26
Department of Nutritional Sciences
The prevalence of Multiple Sclerosis (MS) increases significantly with decreasing UV B light exposure, possibly reflecting a protective effect of Vitamin D(3).
Consistent with this theory, previous research has shown a strong protective effect 1,25-DihydroxyVitamin D3 in Experimental Autoimmune Encephalomyelitis (EAE), an MS model.
However, it is not known whether the hormone precursor, Vitamin D3, has protective effects in EAE.
To address this question, B10.PL mice were fed a diet with or without Vitamin D3, immunized with Myelin Basic Protein, and studied for signs of EAE and for metabolites and transcripts of the Vitamin D3 Endocrine System.
The intact, Vitamin D3-fed female mice had significantly less clinical, HistoPathological, and Immunological signs of EAE than ovariectomized females or intact or castrated males.
Correlating with reduced EAE, the intact, Vitamin D3-fed female mice had significantly more 1,25-DihydroxyVitamin D3 and fewer CYP24A1 transcripts, encoding the 1,25-DihydroxyVitamin D3-inactivating enzyme, in the Spinal Cord than the other groups of mice.
Thus, there was an unexpected synergy between Vitamin D3 and Ovarian tissue with regard to EAE inhibition.
We hypothesize that an ovarian hormone inhibited CYP24A1 gene expression in the Spinal Cord, so the locally-produced 1,25-DihydroxyVitamin D3 accumulated and resolved the inflammation before severe EAE developed.
If humans have a similar gender difference in Vitamin D3 metabolism in the CNS, then sunlight deprivation would increase the MS risk more significantly in women than in men, which may contribute to the unexplained higher MS incidence in women than in men.
Glial Grafting For DeMyelinating Disease
Tepavcevic V, Blakemore WF
Philos Trans R Soc Lond B Biol Sci 2005 Sep 29;360(1461):1775-95
MS Society Cambridge Centre for Myelin Repair, Cambridge Centre for Brain Repair Department of Veterinary Medicine Madingley Road, Cambridge CB3 OES, UK
ReMyelination of DeMyelinated Central Nervous System (CNS) Axons is considered as a potential treatment for Multiple Sclerosis, and it has been achieved in experimental models of DeMyelination by transplantation of Pro-Myelinating Cells.
However, the experiments undertaken have not addressed the need for tissue-type matching in order to achieve graft-mediated ReMyelination since they were performed in conditions in which the chance for graft rejection was minimized.
This article focuses on the factors determining survival of allogeneic Oligodendrocyte lineage cells and their contribution to the ReMyelination of DeMyelinating CNS lesions.
The Immune status of the CNS as well as the suitability of different models of DeMyelination for graft rejection studies are discussed, and ways of enhancing allogeneic Oligodendrocyte-mediated ReMyelination are presented.
Finally, the effects of Glial graft rejection on host ReMyelination are described, highlighting the potential benefits of the acute CNS inflammatory response for Myelin repair.
Effects Of Pregnancy And Child Birth On Urinary Symptoms And Urodynamics In Women With Multiple Sclerosis
Durufle A, Petrilli S, Nicolas B, Robineau S, Guille F, Edan G, Gallien P
Int Urogynecol J Pelvic Floor Dysfunct 2005 Oct 5;:1-4
Centre Hospitalier Universitaire, Department of Physical Medicine and Rehabilitation, Rue Henri Le Guillou, 35 033, Rennes Cedex, France
Our objective was to study the impact of pregnancy and delivery on VesicoUrethral Disorders in patients with Multiple Sclerosis (MS).
Design And Setting
We performed a retrospective chart review of records of women diagnosed with MS who were referred to the clinic.
A total of 102 women with MS (mean age of 44.7+/-11.4 years at the time of the study and mean age of 30.0+/-9.6 years at the onset of MS) participated in the study.
The mean duration of disease was 15+/-10 years. The mean Expanded Disability Status Scale score was 5.4+/-1.8.
Main Outcome Measures
For each patient, demographic data, disease characteristics, Urological and Obstetrical history and Urodynamic data were collected.
Urinary Disorders were classified as irritative (Urinary urgency and frequency) or as obstructive (hesitancy of micturition, reduced or interrupted urinary stream and sensation of incomplete Bladder emptying).
Urodynamic study consisted of Cystometry with continuous recording of Urethral Sphincter Electromyography in 77 (76%) cases.
IntraVesical and IntraUrethral pressures were recorded. Bladder dysfunctions were classified into Neurogenic Detrusor overactivity or Detrusor underactivity.
Pregnancies and deliveries did not influence symptoms. Moreover, the only statistical difference from a Urodynamic point of view was a decrease in maximal Urethral closure pressure.
No interaction between pregnancy, delivery and urinary symptoms was found in this study.
The effects of pregnancy and delivery seemed to be the same in women with MS and in healthy women, with a tendency towards a decrease in Urethral pressure in women with MS.
SimvaStatin Affects Cell Motility And Actin CytoSkeleton Distribution Of Microglia
Kuipers HF, Rappert AA, Mommaas AM, Van Haastert ES, Van Der Valk P, Boddeke HW, Biber KP, Van Den Elsen PJ
Glia 2005 Oct 3
Leiden University Medical Center, Department of ImmunoHematology and Blood Transfusion, Leiden, The Netherlands
Statin treatment is proposed to be a new potential therapy for Multiple Sclerosis (MS), an Inflammatory DeMyelinating Disease of the Central Nervous System. The effects of Statin treatment on Brain cells, however, are hardly understood.
We therefore evaluated the effects of SimvaStatin treatment on the migratory capacity of Brain Microglial Cells, key elements in the pathogenesis of MS.
It is shown that exposure of human and murine Microglial Cells to SimvaStatin reduced cell surface expression of the Chemokine Receptors CCR5 and CXCR3.
In addition, SimvaStatin treatment specifically abolished Chemokine-induced Microglial Cell motility, altered Actin CytoSkeleton distribution, and led to changes in IntraCellular Vesicles.
These data clearly show that SimvaStatin inhibits several Immunological properties of Microglia, which may provide a rationale for Statin treatment in MS.
(c) 2005 Wiley-Liss, Inc.