Age-Dependent T-Cell Tolerance And AutoImmunity To Myelin Basic Protein
Huseby ES, Sather B, Huseby PG, Goverman J
Immunity 2001 Apr;14(4):471-81
Univ of Washington, Dept of Immunology, 98195, Seattle, WA, USA
Experimental AutoImmune EncephaloMyelitis (EAE), an animal model for Multiple Sclerosis, is induced by activating a subset of Myelin Basic Protein (MBP)-specific T-Cells that have escaped Tolerance induction.
Here, we define the Tolerance mechanisms that eliminate the majority of MBP-specific T-Cells from the periphery.
We show that MBP-specific T-Cells undergo Central Tolerance mediated by Bone Marrow-derived Antigen-Presenting Cells presenting exogenously derived MBP Epitopes.
The efficiency of Tolerance is age dependent, reflecting the developmentally regulated expression of MBP.
Dependence of Tolerance on the amount of MBP expressed in vivo results in an age window of susceptibility to EAE in mice that peaks during puberty.
These results suggest that factors regulating expression of Self-Antigens in vivo can influence susceptibility to AutoImmunity.
ImmunoModulatory Drugs For Multiple Sclerosis: A Systematic Review Of Clinical And Cost Effectiveness
Clegg A, Bryant J
Expert Opin Pharmacother 2001 Apr;2(4):623-39
Southampton Health Technology Assessments Centre (SHTAC), Wessex Institute for Health Research and Development, Univ of Southampton, Biomedical Sciences Building, Bassett Crescent East, Southampton SO16 7PX, UK
Uncertainties about the clinical and cost effectiveness of ImmunoModulatory drugs for Multiple Sclerosis (MS), as well as concerns about funding treatment, continue to influence their use.
The National Institute for Clinical Excellence (NICE) in England and Wales has been appraising the evidence on the clinical and cost effectiveness of IFN-ß and Glatiramer to provide guidance to the NHS. It has proved a difficult task.
This paper is an update of our systematic review which assesses the evidence on the clinical and cost effectiveness of a range of ImmunoModulatory drugs for MS.
Including Azathioprine, IFN-ß, Cladribine, Cyclophosphamide, Glatiramer, IntraVenous ImmunoGlobulin (IVIg), Methotrexate and Mitoxantrone.
Searches of electronic databases (such as Medline, Embase and the Cochrane Library) and bibliographies of related papers, as well as consultation with experts, for systematic reviews of Randomized Controlled Trials (RCTs).
And direct reports of RCTs revealed 26 studies of clinical effectiveness and eight economic evaluations that met the criteria for inclusion.
The quality of the evidence was often poor, affected by methodological limitations.
Evidence on the clinical effectiveness of ImmunoModulatory drugs showed some clinical effect, with reductions in relapse rates and/or progression to disability for people with MS.
However, benefits from these drugs may be lessened by side effects.
Assessment of cost effectiveness was limited to IFN-ß and Glatiramer, showing that any benefit from these drugs was achieved at very high cost.
The inadequacies in the evidence of clinical and cost effectiveness on some ImmunoModulatory drugs for the treatment of people with MS necessitate further rigorous RCTs and comparative economic evaluations of different alternatives.
Expert Opin Pharmacother 2001 Feb;2(2):213-21
St. George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK
PMID# 11336581; UI# 21235126
Human HerpesVirus-6 (HHV-6) was discovered 15 years ago and was then grouped as a member of the family Human HerpesViridae. Its first clinical manifestation was identified 2 years later as the agent responsible for exanthem subitum.
With the advent of newer molecular techniques, its diagnosis is easier and prospective studies have shown that it is the most common pathogen responsible for febrile illness in infants. In some infants, it is associated with febrile convulsions.
Two subtypes, A and B, have been identified, B subtype commonly being responsible for primary infection in infants. Primary infection in healthy adults is rare.
Most of the clinical manifestations are mild, self-limiting and rarely fatal. Reactivation of HHV-6 is frequently found in bone marrow as well as solid organ transplant recipients.
HHV-6 has been shown to be an independent risk factor responsible for recurrence of cytomegalovirus infection, especially in solid organ transplants.
In bone marrow transplant recipients, HHV-6 has been associated with various manifestations like marrow suppression and graft versus host disease, although most infections present as usually mild febrile illness with or without rash.
It has been reported to cause Encephalitis in transplant recipients. Although HHV-6 has been shown to be responsible for upregulation of HIV in vitro studies, its exact role in AIDS is yet to be defined.
In addition to its NeuroTropic manifestation of febrile convulsion in infancy, it has been found in plaques in the Brain of Multiple Sclerosis and Progressive Multifocal Leukoencephalopathy.
Further studies are needed before its role in the PathoGenesis of these Neurological illnesses can be established.
Its Lymphotropic feature was responsible for its discovery and now it has only been detected in some lesions of primary Ocular Mucosa associated Lymphoid tissue Lymphoma.
As HHV-6 is found to be responsible for more and more illnesses, especially causing serious illnesses in the ImmunoCompromized, it is becoming necessary to find effective treatment.
Some agents, like Cidofovir and Phosphonoformic Acid, are effective in in vitro studies and some have shown effectiveness in a clinical setting.
Further studies are needed to identify its role in the PathoGenesis of various Neurological and malignant lesions and AIDS.
Various treatment regimens should be tested in clinical scenario and especially in ImmunoCompromized transplant recipients.
Serum And CSF Levels Of MCP-1 And IP-10 In Multiple Sclerosis With Acute And Stable Disease And Undergoing ImmunoModulatory Therapies
Franciotta D, Martino G, Zardini E, Furlan R, Bergamaschi R, Andreoni L, Cosi V
J NeuroImmunol 2001 Apr 2;115(1-2):192-8
Univ of Pavia, Laboratory of NeuroImmunology, IRCCS, Foundation "Neurological Institute C. Mondino", via Palestro 3, 27100, Pavia, Italy
The two Chemokines, Monocyte Chemoattractant Protein (MCP)-1 and Interferon-gamma Inducible Protein (IP)-10, are thought to be involved in the PathoGenesis of Multiple Sclerosis (MS).
We measured MCP-1 and IP-10 levels in Serum and CSF samples from 38 acute and 25 stable MS patients and from 40 controls.
The latter consisted in patients with Other Inflammatory Neurological Diseases (OIND) or with Non-Inflammatory Neurological Diseases, and healthy controls.
CSF MCP-1 levels exceeded those found in Serum in all the patients studied as well as in healthy controls.
CSF MCP-1 levels were significantly lower in acute MS [468+/-(S.E.M.) 18 pg/ml] than in stable MS (857+/-104 pg/ml).
When detectable, Serum and CSF IP-10 levels were significantly higher in acute MS (serum 331+/-66 pg/ml; CSF 118+/-16 pg/ml) than in stable MS (Serum 69+/-7 pg/ml; CSF 25+/-2 pg/ml).
Among OIND patients, those with HIV-1 associated Dementia showed high Serum and CSF levels of both MCP-1 and IP-10.
Those with Encephalitis showed high Serum and CSF levels of IP-10 and CSF MonoNuclear PleioCytosis.
We also evaluated the effects of 6-MethylPrednisolone or IFN-ß-1a therapy on circulating MCP-1 and IP-10 levels.
Neither MCP-1 nor IP-10 post-therapy levels varied significantly from baseline values.
Our findings suggest that:
- MCP-1 could be constitutively produced within the Brain
- MCP-1 and IP-10 CSF levels in acute MS vary significantly from those in stable MS, and these variations are inverse
- Current MS therapies do not modify circulating levels of MCP-1 and IP-10
Andrade Machado R, Garcia Espinosa A, Barbaro Ramos L
Rev Neurol 2001 Mar 16;32(5):440-444
Hospital Universitario Arnaldo Milian Castro. Hosp. Municipal de Remedios, Santa Clara. Villa Clara, Cuba
The OpsoClonic-MyoClonic-Ataxic Syndrome (OMAS) is that in which there are at least two of the cardinal signs (OpsoClonus, MyoClonus and Ataxia).
To report three cases, their evolution and Etiology, and discuss the main PhysioPathological basis and guidelines for treatment.
We present three cases admitted to the Internal Medicine Dept with the diagnosis of OMAS.
The investigations included standard biochemical and haematological tests, a full study of the CerebroSpinal Fluid, Computerized Axial Tomography of the skull and Thorax, and Magnetic Resonance.
We describe the clinical presentation, evolution, Etiology and treatment given. The results of the complementary tests are shown in the form of tables.
Finally we consider the diagnosis of this condition. Three patients, two men and one woman, aged between 43 and 78 were diagnosed as having OMAS.
The causes were: ParaNeoplasia, Acute Diffuse EncephaloMyelitis and Probable Multiple Sclerosis. The patient with Lung Cancer died whilst the other two showed almost complete recovery on the treatment given.
Our cases show that OMAS may be a feature of a diffuse process affecting the BrainStem and Cerebellum.
The commonest causes found are Multiple Sclerosis, Acute Diffuse EncephaloMyelitis and as a ParaNeoplastic feature of a Tumor.
It may improve with treatment, but depending on the Etiology, death may occur. ImmunoModulation treatment is vital even though symptomatic treatment may be given.
Comi G, Filippi M, Barkhof F, Durelli L, Edan G, Fernandez O, Hartung H, Seeldrayers P, Sorensen PS, Rovaris M, Martinelli V, Hommes OR
Lancet 2001 May 19;357(9268):1576-1582
IRCCS Ospedale S Raffaele, Multiple Sclerosis Centre, Dept of NeuroScience, via Olgettina 60, 20132, Milan, Italy
Interferon-beta reduces activity in Multiple Sclerosis as measured clinically and by Magnetic Resonance Imaging (MRI).
We assessed the effect of Interferon-beta-1a on the occurrence of relapses in patients after first presentation with Neurological events, who are at high risk of conversion to Clinically Definite Multiple Sclerosis.
Eligible patients had had a first episode of Neurological dysfunction suggesting Multiple Sclerosis within the previous 3 months and had strongly suggestive Brain MRI findings.
Patients were randomly assigned Interferon-beta-1a 22 &mgr;g or placebo subcutaneously once weekly for 2 years.
Neurological and clinical assessments were done every 6 months and Brain MRI every 12 months. Analyzes excluded one patient assigned placebo who received no study injections.
241 (78%) of 308 randomized patients received study treatment for 2 years; 278 (90%) remained in the study until termination.
57 (85%) of 67 who stopped therapy did so after conversion to Clinically Definite Multiple Sclerosis.
Fewer patients developed Clinically Definite Multiple Sclerosis in the Interferon group than in the placebo group (52/154 [34%] vs 69/154 [45%]; p=0.047).
The time at which 30% of patients had converted to Clinically Definite Multiple Sclerosis was 569 days in the Interferon group and 252 in the placebo group (p=0.034).
The annual relapse rates were 0.33 and 0.43 (p=0.045).
The number of new T2-weighted MRI lesions and the increase in lesion burden were significantly lower with active treatment.
Interferon-beta-1a treatment at an early stage of Multiple Sclerosis had significant positive effects on clinical and MRI outcomes.