NeuroProtective Effect Of Inflammation: Implications For The Therapy Of Multiple Sclerosis
Hohlfeld R, Kerschensteiner M, Stadelmann C, Lassmann H, Wekerle H
J NeuroImmunol 2000 Jul 24;107(2):161-166
Institute for Clinical NeuroImmunology and Dept of Neurology, Klinikum Grosshadern, Ludwig-Maximilians University, Marchioninistrasse 15, D-81366, Munich, Germany
AutoReactive T-Cells are a component of the normal Immune System. It has been proposed that some of these AutoReactive T-Cells even have a protective function.
Recent studies support this notion by demonstrating that:
- Myelin Basic-Protein (MBP-) specific T-Cells show NeuroProtective effects in vivo
- Activated Antigen-specific human T-Cells and other Immune Cells produce bioactive Brain-Derived NeuroTrophic Factor (BDNF) in vitro
- BDNF is expressed in different types of Inflammatory Cells in Brain lesions of patients with Acute Disseminated LeukoEncephalopathy or Multiple Sclerosis.
We postulate that the NeuroProtective effect of T-Cells and other Immune Cells observed in vivo is at least partially mediated by BDNF and other NeuroTrophic Factors.
The concept of NeuroProtective AutoImmunity has obvious implications for the therapy of Multiple Sclerosis and other NeuroImmunological Diseases.
T-Cell Vaccination In Secondary/Progressive Multiple Sclerosis
Correale J, Lund B, McMillan M, Ko DY, McCarthy K, Weiner LP
J NeuroImmunol 2000 Jul 24;107(2):130-139
USC School of Medicine, Dept of Neurology, 1333 San Pablo Street, MCK 142, 90033, Los Angeles, CA, USA
Four Secondary/Progressive MS patients were vaccinated with bovine Myelin-reactive irradiated T-Cell lines from their peripheral blood.
Patients were followed for 30-39 months, and monitored for Immunological responses toward the vaccine, and for their clinical characteristics.
Two patients showed stable EDSS score over time, one patient showed improvement by one EDSS step, and in the remaining patient her EDSS advanced over time.
After the second inoculation there was a progressive decline of circulating whole Myelin-reactive T-Cells, MBP143-168, PLP104-117, and MOG43-55-peptide-reactive T-Cells.
In contrast the frequency of Tetanus toxoid-reactive T-Cells remained unchanged. T-Cell Vaccination (TCV) was also associated with a decline of Myelin-specific IL-2- and IFN--secreting T-Cells.
Twelve T-Cell Lines (TCL) that recognize the inoculates were isolated from the peripheral blood of two patients. Ten of these TCL were CD8+ and Lysed the inoculates in a MHC Class I restricted manner.
The remaining two TCL were CD4+, and Lysed the inoculates by MHC Class II restricted Cytolytic activity.
All T-Cell Lines lysed not only Myelin-reactive T-Cells, but also TCL specific for MBP143-168, PLP104-117 and MOG43-55 Peptides. Control TCL specific for Tetanus toxoid were not lysed.
Neutralizing anti-Fas mAb did not influence the killing. Moreover, culture supernatants from two TCL which produce IL-10, were able to block the proliferation of Myelin protein-specific TCL. This effect was abrogated using mAbs specific for IL-10.
The data obtained indicated that TCV using autologous irradiated bovine Myelin-reactive T-Cells promotes an effective depletion of T-Cells reactive against different Myelin Antigens.
Evidence For A Role Of delta T-Cells In DeMyelinating Diseases As Determined By Activation States And Responses To Lipid Antigens
Borsellino G, Koul O, Placido R, Tramonti D, Luchetti S, Galgani S, Salvetti M, Gasperini C, Ristori G, Bonetti B, Bach S, Cipriani B, Battistini L
J NeuroImmunol 2000 Jul 24;107(2):124-129
Laboratory of NeuroImmunology, IRCCS Santa Lucia, Via Ardeatina, 306, 00179, Rome, Italy
In this report we review current information on the phenotypic and functional properties of delta T-Cells in DeMyelinating Disorders.
The results support the conclusion that although delta T-Cells show evidence of activation in patients with either Multiple Sclerosis (MS) or Guillain Barre Syndrome (GBS), differences exist in the phenotypic and functional properties of these cells between the two diseases.
In particular, our data indicate that in patients with MS the Vdelta2 subset is activated and that these cells can be induced to secrete high levels of ProInflammatory Cytokines.
In contrast, in patients with GBS, the Vdelta1 subset is expanded and can be induced to secrete Cytokines more associated with a Humoral Response.
Theiler's Murine EncephaloMyelitis Virus Induces Rapid Necrosis And Delayed Apoptosis In Myelinated Mouse Cerebellar Explant Cultures
Anderson12 R, Harting2 E, Frey MS, Leibowitz3 JL, Miranda3 RC
Brain Res 2000 Jun 23;868(2):259-267
Texas A&M UnivHealth Science Center, Dept of Human Anatomy, 228 Reynolds Medical Bldg., 77843-1114, College Station, TX, USA
Infection with the Daniel strain of Theiler's Murine EncephaloMyelitis (TMEV-DA) Virus induces persistent DeMyelinating lesions in mice and serves as a model for Multiple Sclerosis.
During the acute phase of the disease, however, Viral infection leads to cell death in vivo. Viral-induced death may result directly from Viral infection of Neural Cells, or indirectly, by activation of the Immune System.
To examine the direct effects of TMEV infection on Neural Cells, Myelinated explant cultures of the murine Cerebellum were infected with 10(5) pfu of TMEV-DA for periods ranging from 1 to 72 h.
Our results indicate that TMEV-DA replicates in cultured Neural tissue. Initially, Viral Antigen is localized to a few isolated Neural Cells.
However, within 72 h Antigen was observed in multiple Foci that included damaged cells and ExtraCellular debris.
Viral infection led to a rapid and cyclical induction of Necrosis with a time period that was consistent with the Lytic phase of the Viral life-cycle. Simultaneously, we observed an increase in Apoptosis 48 h post-infection.
Electron micrographic analysis indicated that Viral-infected cultures contained cells with fragmented Nuclei and condensed CytoPlasm, characteristic of Apoptosis.
The localization of Apoptosis to the Cerebellar Granule Cell Layer, identified these cells as presumptive Granule Neurons. Viral infection, however, did not lead to Myelin damage, though damaged Axons were visible in TMEV-infected cultures.
These results suggest that during the acute phase of infection, TMEV targets Neural Cells for Apoptosis without directly disrupting Myelin. Myelin damage may therefore result from the activation of the Immune System.
The Role Of B-Cells And AutoAntiBodies In Multiple Sclerosis
Archelos JJ, Storch MK, Hartung HP
Ann Neurol 2000 Jun;47(6):694-706
Karl-Franzens-Universitat, Dept of Neurology, Graz, Austria
PMID#10852535; UI# 20309375
A variety of Cellular and Humoral Immunological abnormalities have been observed in Multiple Sclerosis (MS).
In the past few years, several lines of evidence converged to imply an important role of AutoReactive AntiBodies and B-Cells in the PathoGenesis of MS.
Recent data suggest that AutoAntiBodies may be harmful in Lesion formation but also potentially beneficial in repair.
This review surveys recent advances in the concepts of generation and nature of PathoGenetic AutoAntiBodies, their potential modes of action, mechanisms of their long-term persistence, and the role of the inflamed Brain tissue as a B-Cell-supporting MicroEnvironment in MS.
Based on the presence of specific AutoAntiBodies, it seems possible to define distinct MS subgroups in the near future. The therapeutic relevance of these new findings is presented.
CC-Chemokine Receptor 5 PolyMorphism And Age Of Onset In Familial Multiple Sclerosis. Multiple Sclerosis Genetics Group
Barcellos LF, Schito AM, Rimmler JB, Vittinghoff E, Shih A, Lincoln R, Callier S, Elkins MK, Goodkin DE, Haines JL, Pericak-Vance MA, Hauser SL, Oksenberg JR
Immunogenetics 2000 Apr;51(4-5):281-8
Univ of California at San Francisco, Dept of Neurology, 94143-0435, USA
PMID# 10803840; UI# 20260985
Multiple Sclerosis (MS) is a common disease of the Central Nervous System characterized by Myelin loss and Progressive Neurological Dysfunction.
An underlying Genetic susceptibility plays a clear role in the etiology of MS, likely acting in concert with an undefined environmental exposure.
Full-Genome screenings in multiplex MS families have identified several susceptibility regions, supporting a polygenic model for MS.
Among these regions, evidence for weak linkage was observed at 3p/3cen suggesting the presence of an MS Gene(s) of modest effect. Encoded here are two Chemokine receptors, CCR5 and CCR2B.
We examined the Chromosome 3p21-24 region in 125 MS families (322 total affecteds and 200 affected sib-pairs), and performed Genetic analyzes of CCR5 and CCR2B loci and two nearby markers (D3S1289 and D3S1300) using both linkage - and association-based tests.
No evidence of linkage to MS was observed for any of the tested markers. Affected relative-pair (SimIBD) and sib-pair analyzes (ASPEX), and association testing (sib-TDT) for each locus were also not significant.
However, age of onset was approximately 3 years later in patients carrying the CCR5delta32 deletion (P=0.018 after controlling for gender effects).
Thus, Chemokine receptor expression may be associated with differential disease onset in a subset of patients, and may provide a therapeutic target to modulate Inflammatory DeMyelination.