IFN-ß-1b Inhibits IL-12 Production In Peripheral Blood MonoNuclear Cells In An IL-10-Dependent Mechanism
Relevance To IFN-ß-1b Therapeutic Effects In Multiple Sclerosis
Wang X, Chen M, Wandinger KP, Williams G, Dhib-Jalbut S
J Immunol 2000 Jul 1;165(1):548-557
Baltimore Veterans Affairs Medical Center,
Univ of Maryland, Dept of Neurology, Baltimore, MD 21201;
National Institutes of Health, NeuroImmunology Branch, National Institute of Neurologic Disease and Stroke, Bethesda, MD 20892; and
Berlex Laboratories, Richmond, CA 94806
PMID# 10861095; UI# 20318759
IL-12 is a ProInflammatory Cytokine secreted by Dendritic Cells in response to Microbial Ags and mitogens. IL-12 is thought to contribute to the PathoGenesis of AutoImmune Diseases such as Multiple Sclerosis (MS).
This is based on studies in Experimental Allergic EncephaloMyelitis and the demonstration that PBMC IL-12 production correlates with disease progression in MS. IFN-ß-1b is an effective treatment for MS, which is thought to involve in part inhibition of ProInflammatory Cytokines.
In this study we examined the effect of in vitro treatment with IFN-ß-1b, on mitogen-induced IL-12 production in human PBMC and Myelin Basic Protein-specific T-Cell lines obtained from healthy donors and MS patients.
We demonstrate that IFN-ß-1b significantly inhibits inducible IL-12 p40 up to 80% and biologically active IL-12 p70 up to 70% beginning at a dose of 10 IU/ml.
This inhibition is IL-10 dependent, as it could be blocked by Anti-IL-10 but not Anti-IL-4 or control Abs. Thus, endogenously produced IL-10 is a required cofactor for the IFN-ß-1b inhibitory effect on IL-12 to occur.
We conclude that IFN-ß-1b has a profound inhibitory effect on PBMC IL-12 production in vitro, and that this effect is IL-10 dependent.
These findings are potentially relevant to the therapeutic mechanism of IFN-ß-1b in MS.
Neuhaus O, Farina C, Yassouridis A, Wiendl H, Then Bergh F, Dose T, Wekerle H, Hohlfeld R
Proc Natl Acad Sci USA 2000 Jun 20;97(13):7452-7457
Max Planck Institute of NeuroBiology, Dept of NeuroImmunology, Am Klopferspitz 18A, 82152 Martinsried, Germany;
Max Planck Institute of Psychiatry, Dept of Statistics, Kraepelinstrasse 2-10, 80804 Munich, Germany; and
Institute for Clinical NeuroImmunology, and
Ludwig Maximilians University, Dept of Neurology, Klinikum Grosshadern, Marchioninistrasse 15, 81366 Munich, Germany
PMID# 10861011; UI# 20319047
Copolymer-1 (Cop), a standardized mixture of synthetic PolyPeptides consisting of l-Glutamic Acid, L-Lysine, L-Alanine, and L-Tyrosine, has beneficial effects in Multiple Sclerosis and Experimental AutoImmune EncephaloMyelitis.
We selected a panel of 721 COP-reactive T-Cell lines (TCL) from the blood of COP-treated and untreated Multiple Sclerosis patients and from healthy donors by using the split-well cloning technique.
All TCL selected with COP proliferated in response to COP but not to Myelin Basic Protein (MBP). Conversely, 31 control TCL selected with MBP proliferated in response to MBP but not to COP.
We used IntraCellular double-immunofluorescence flow cytometry for quantitative analysis of Cytokine production (IL-4, IFN-) by the TCL.
The majority of the COP-reactive TCL from untreated Multiple Sclerosis patients and normal donors predominantly produced IFN- and, accordingly, were classified as Helper 1 T-Cells (Th1).
In contrast, the majority of the COP-reactive TCL from COP-treated patients predominantly (but not exclusively) produced IL-4-i.e., were Th2 (P < 0.05 as assessed by using a suitable preference intensity index).
Longitudinal analyzes revealed that the Cytokine profile of COP-reactive TCL tends to shift from Th1 to Th2 during treatment.
Interestingly, although there was no proliferative cross-reaction, about 10% of the COP-reactive TCL responded to MBP by secretion of small amounts of IL-4 or IFN-, depending on the Cytokine profile of the TCL.
These results are consistent with a protective effect of Cop-reactive Th2 Cells.
It is hypothesized that these cells are activated by COP in the periphery, migrate into the Central Nervous System, and produce ImmunoModulatory Cytokines after local recognition of MBP.
Urinary And Sexual Alterations
In Multiple Sclerosis
Martin C, Salinas J, Fernandez-Duran A, Fernandez-Gomez J, Jimenez N, Gangoiti L
Rev Neurol 2000 Apr 1-15;30(7):643-8
Hospital de Valdepenas, Servicio de Urologia, Ciudad Real, Espana
PMID# 10859743; UI# 20317324
In this study we have evaluated the Urinary and Sexual alterations of patients with Multiple Sclerosis (MS) by means of NeuroUrological and NeuroAndrological studies.
Patients And Methods
In 41 patients with MS we took a clinical history and made a NeuroUrological Physical Examination.
We also did a full Urodynamic study including measurement of Flow and Postmictional Residue, Cystomanometry and test of the Detrusor Pressure/Mictional Flow.
Selective ElectroMyography of the Periurethral Sphincter and a Cystourethrographic study were also done.
In patients complaining of Erection Dysfunction this was also studied by means of an erection test with IntraCavernosal Vasoactive drugs and special NeuroPhysiological techniques including the obtention of S2-S4 Evoked Potentials in the Bulbo-Cavernosal Muscle and the SomatoSensorial Potentials of the Pudendal Nerve.
In patients with MS there is a predominance of Mixed and Irritative Urinary Symptoms rather than Obstructive Symptoms.
The Vesico-Urethral Dysfunction of Upper Motor Neuron type was the most frequent Urodynamic diagnosis.
There were no statistically significant differences between the Urinary symptoms of the different Urodynamic diagnoses.
Ninety percent of the patients with Erectile Dysfunction had associated Vesico-Urethral Dysfunction of Upper Motor Neuron type and 100% of the patient with Erectile Dysfunction had dysfunction of the Sphincter of the Urinary Bladder.
In patients with MS there is no correlation between the clinical symptoms and Urodynamic diagnosis.
Therefore Urodynamic diagnosis is essential not only for diagnosis but also for development of suitable treatment.
The Urodynamic diagnosis of dysfunction of the Bladder Sphincter is a risk factor in patients with MS. In our series 100% of the cases with Erectile Dysfunction also had dysfunction of the Bladder Sphincter.
Plasma ImmunoAdsortion Treatments In Severe Relapses Of Multiple Sclerosis
de Andres C, Anaya F, Gimenez-Roldan S
Rev Neurol 2000 Apr 1-15;30(7):601-5
Hospital General Universitario Gregorio Maranon, Servicio de Neurologia, Madrid, Espana
PMID# 10859735; UI# 20317316
The treatment of prolonged, severe relapses in Multiple Sclerosis (MS) patients who respond poorly to high-dose IntraVenous CorticoSteroids is not yet established.
Plasma ImmunoAdsortion (IA) removes ImmunoGlobulins (IgG), Immune complexes, and Complement from Plasma.
It may bear some advantages compared to Plasmapheresis, a nonselective procedure that requires substitution of patient Plasma by Colloids solutions or Plasma, which may carry a potential risk for Viral infections.
Patients And Methods
Three Relapsing/Remitting MS patients with a malignant course received IA. They were all experiencing a prolonged relapse unresponsive to high-dose IntraVenous CorticoSteroids, causing a locked-in state in two of the patients and severe PseudoBulbar Impairment in the third one.
Five to six IA consecutive sessions were administered along a 7-10 days course.
IA was followed by a prompt and unequivocal clinical response in all three patients, which paralleled a decrease in IgG, Fibrinogen, and C3 Complement Serum levels.
IA administration was followed by ImmunoSuppressor therapy, either with Cyclophosphamide and IntraVenous ACTH (2 cases) or Mitoxantrone (1 case).
Improvement has been sustained along a mean follow-up of 7.6 years (range: 7-8.5 years), only one of the patients suffering two mild clinical relapses.
We believe that IA may be useful, either as a co-adyuvant or alternative treatment in severe relapses in MS patients that do not respond to high-dose IntraVenous CorticoSteroid therapy.
HLA-DQ PolyMorphism Influences Progression Of DeMyelination And Neurologic Deficits In A Viral Model Of Multiple Sclerosis
Pavelko KD, Drescher KM, McGavern DB, David CS, Rodriguez M
Mol Cell NeuroSci 2000 Jun;15(6):495-509
Mayo Clinic and Mayo Foundation, Dept of Immunology, Rochester, Minnesota, 55905
PMID# 10860577; UI# 20319124
The importance of Genetic susceptibility in determining the progression of DeMyelination and Neurologic deficits is a major focus in NeuroScience.
We studied the influence of Human Leukocyte Antigen (HLA)-DQ PolyMorphisms on disease course and Neurologic Impairment in Virus-induced DeMyelination.
HLA-DQ6 or DQ8 was inserted as a transgene into mice lacking endogenous expression of MHC Class I (ß(2)m) and Class II (H2-Aß) molecules.
Following Theiler's Murine EncephaloMyelitis Virus (TMEV) infection, we assessed survival, Virus persistence, DeMyelination, and clinical disease.
Mice lacking expression of endogenous Class I and Class II molecules (ß(2)m degrees Aß degrees mice) died 3 to 4 weeks postinfection (p.i.) due to overwhelming Virus replication in Neurons.
ß(2)m degrees Aß degrees DQ6 and ß2)m degrees Aß degrees DQ8 mice had increased survival and decreased Gray Matter Disease and Virus replication compared to NonTransGenic littermate controls.
Both ß(2)m degrees Aß degrees DQ6 and ß(2)m degrees Aß degrees DQ8 mice developed chronic Virus persistence in Glial Cells of the White Matter of the Spinal Cord, with greater numbers of Virus Antigen-positive cells in ß(2)m degrees Aß degrees DQ8 than in ß(2)m degrees Aß degrees DQ6 mice.
At day 45 p.i., the DeMyelinating Lesions in the Spinal Cord of ß(2)m degrees Aß degrees DQ8 were larger than those in the ß(2)m degrees Aß degrees DQ6 mice.
Earlier and more profound Neurologic deficits were observed in ß(2)m degrees Aß degrees DQ8 mice compared to ß(2)m degrees Aß degrees DQ6 mice.
Although by 120 days p.i. both strains of mice showed similar extent of DeMyelination and Neurologic deficits. Delayed-type hypersensitivity and AntiBody responses to TMEV demonstrated that the mice mounted Class II-mediated Cellular and Humoral Immune Responses.
The results are consistent with the hypothesis that rates of progression of DeMyelination and Neurologic deficits are related to the differential ability of DQ6 and DQ8 transgenes to modulate the Immune Response and control Virus.
Copyright 2000 Academic Press.
Lesion Pattern In Patients With Multiple Sclerosis And Depression
Berg D, Supprian T, Thomae J, Warmuth-Metz M, Horowski A, Zeiler B, Magnus T, Rieckmann P, Becker G
Mult Scler 2000 Jun;6(3):156-62
Bayerische Julius-Maximilians-Universitat Wurzburg, Dept of Neurology, 97080 Wurzburg, Germany
PMID# 10871826; UI# 20332493
To assess if a specific lesion pattern or changes of the Basal Limbic System as seen in Primary Depression and Depression associated with NeuroDegenerative Disorders might be identified in depressive Multiple Sclerosis (MS) patients.
We submitted 78 MS patients to a MRI examination consisting of a quantitative measurement of lesions and of HyperIntense signals from the PontoMesenCephalic Midline (Raphe).
Furthermore Relaxometry of the PontoMesenCephalic midline, a TransCranial Ultrasound Examination rating its Echogenicity semiquantitatively and a standardized Neurological, NeuroPsychiatric and NeuroPsychological assessment were obtained.
Thirty-one patients fulfilled the DSM-IV criteria for Depression. Depressed MS patients had a significantly larger Temporal lesion load than Non-Depressed MS patients, especially on the right side.
A trend of difference was detected for lesions of the Right Parietal Lobe, the Right Frontal Lobe, the Cerebellum and the total lesion load.
Neither HyperIntense signals or Relaxometry nor Echogenicity of the region at the level of the PontoMesenCephalic Midline were significantly different between the groups.
We conclude that Depression in MS patients is not associated with an alteration of the Basal Limbic System at the BrainStem as seen in Parkinson's Disease or Unipolar Depression but with an increased lesion load of the projection areas of the Basal Limbic System.
Multiple Sclerosis (2000) 6, 156 - 162
Confabulation And Multiple Sclerosis: A Rare Association
Feinstein A, Levine B, Protzner A
Mult Scler 2000 Jun;6(3):186-91
Sunnybrook and Women's College Health Science Centre and Univ of Toronto, Dept of Psychiatry, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5 Canada
PMID# 10871831; UI# 20332498
Fantastic Confabulation in the context of Multiple Sclerosis (MS) has not previously been reported in the literature.
The association is of interest because clearly demonstrable Brain pathology in MS together with other Cognitive and Behavioral correlates may further our understanding of the Neural basis underlying Confabulation.
A single case report with Magnetic Resonance Imaging of the Brain and detailed NeuroPsychological evaluation.
Confabulation occurred together with disinhibited and stimulus bound behavior.
While the patient's physical and emotional state limited the range of Psychometric Tests administered, the results revealed an inability to maintain focused, regulated information processing.
Although Memory difficulties were present, they were not in the nature of a severe Amnesic Disorder.
The patient appeared to have a broad fund of knowledge, but the associations binding the information together and putting it into context were loose.
All three features of a triad of responses previously described in Confabulating patients were present, namely an inability:
- To withhold answers
- To monitor one's own responses
- To provide verbal self corrections
MRI of the Brain showed bilateral PeriVentricular lesions and discrete Frontal lesions with 53% of the total lesion volume distributed in Frontal areas. Cortical Atrophy, most marked in Frontal regions also was conspicuous.
Confabulation linked to Frontal Lobe involvement may occur as part of the changes in Mentation found in MS.
It is, however, rare and although associated with Impaired Memory, may be found in the absence of a severe Amnesic Disorder.
This conclusion is discussed in the light of observations from the literature suggesting that Frontal involvement is a prerequisite before Fantastic Confabulation occurs.
Multiple Sclerosis (2000) 6, 186 - 191