Tolerance Induction By Bone Marrow Transplantation In A Multiple Sclerosis Model
Herrmann MM, Gaertner S, Stadelmann C, van den Brandt J, Boscke R, Budach W, Reichardt HM, Weissert R
Blood 2005 May 17
Hertie Institute for Clinical Brain Research, University of Tubingen, Department of General Neurology, Tubingen, Germany
Experimental Autoimmune Encephalomyelitis (EAE) in rats is a highly valuable model of Multiple Sclerosis (MS) since it mimics major hallmarks of the human disease.
EAE induced with Myelin-Oligodendrocyte-Glycoprotein (MOG) in DA rats is Relapsing/Remitting and lesions in the Central Nervous System show Inflammation, DeMyelination, Axonal and Neuronal Loss.
Recently, Bone Marrow Transplantation (BMT) was introduced as a novel strategy to treat MS but its efficiency and the underlying mechanism are debatable.
In MOG induced EAE we found that BMT at the peak of EAE but not in the chronic phase leads to disease attenuation.
In both settings Bone Marrow (BM) transplanted rats were protected from subsequently induced relapses.
These findings could be confirmed by HistoPathology in which BM transplanted rats did not have lesions compared to non-transplanted controls.
Importantly, the protective effect was achieved by allogeneic, syngeneic and grafts from diseased rats.
BMT resulted in increased numbers of CD4+CD25bright regulatory T-Cells, increased Foxp3 expression, a shift in T-Cell Epitope recognition and a strong reduction of AutoAntiBodies even after re-challenge with MOG.
Thus, our results indicate potential mechanisms of how BMT may contribute to the improvement of MS and provide a rationale for its application in patients suffering from various Autoimmune Diseases.
Motor Neuron Pathology In Experimental Autoimmune Encephalomyelitis: Studies In THY1-YFP Transgenic Mice
Bannerman PG, Hahn A, Ramirez S, Morley M, Bonnemann C, Yu S, Zhang GX, Rostami A, Pleasure D
Brain 2005 May 18
Children's Hospital of Philadelphia, Abramson Pediatric Research Center, Neurology Research, Philadelphia, Pennsylvannia, USA
Using adult male C57BL/6 mice that express a yellow fluorescent protein transgene in their Motor Neurons, we induced Experimental Autoimmune Encephalomyelitis (EAE) by immunization with Myelin Oligodendrocyte Glycoprotein Peptide 35-55 (MOG Peptide) in complete Freund's adjuvant (CFA).
Control mice of the same transgenic strain received CFA without MOG Peptide. Early in the course of their illness, the EAE mice showed LumboSacral Spinal Cord Inflammation, DeMyelination and Axonal fragmentation.
By 14 weeks post-MOG peptide, these abnormalities were much less prominent, but the mice remained weak and, as in patients with Progressive Multiple Sclerosis, Spinal Cord Atrophy had developed.
There was no significant loss of Lumbar Spinal Cord Motor Neurons in the MOG Peptide-EAE mice.
However, early in the course of the illness, Motor Neuron Dendrites were disrupted and Motor Neuron expression of HypoPhosphorylated NeuroFilament-H (hypoP-NF-H) ImmunoReactivity was diminished.
By 14 weeks post-MOG Peptide, hypoP-NF-H expression had returned to normal, but Motor Neuron Dendritic abnormalities persisted and Motor Neuron Perikaryal Atrophy had appeared.
We hypothesize that these Motor Neuron abnormalities contribute to weakness in this form of EAE and speculate that similar Motor Neuron abnormalities are present in patients with Progressive Multiple Sclerosis.
Primary/Progressive Multiple Sclerosis
Curr Opin Neurol 2005 Jun;18(3):261-266
Hospital Universitari Vall d'Hebron, Unitat de NeuroImmunologia Clinica, Barcelona, Spain
Purpose Of Review
The present article reviews the currently ongoing scientific debate on the specific characteristics of Primary/Progressive Multiple Sclerosis.
The most important observations come from the studies using Magnetic Resonance Imaging showing involvement of the Normal-Appearing Brain Tissue and also from the clinical and Magnetic-Resonance-Imaging descriptions in longitudinal studies.
Progress in the diagnosis of Primary/Progressive Multiple Sclerosis has been made. Long- and short-term natural history are now better known, which will allow the designing of clinical trials in the near future.
Magnetic-Resonance-Imaging studies have demonstrated damage of the Normal-Appearing Brain Tissue.
Which may explain in part the apparent clinical and radiological paradox, common to all clinical forms of Multiple Sclerosis but perhaps more evident in the Primary/Progressive form.
Preliminary results from exploratory trials seem to indicate that these patients should no longer be excluded from therapeutic trials.
Current Trials In Multiple Sclerosis: Established Evidence And Future Hopes
Killestein J, Polman CH
Curr Opin Neurol 2005 Jun;18(3):253-60
MS Centre, VU Medical Centre Amsterdam, Department of Neurology, Amsterdam, The Netherlands
Purpose Of Review
The aim of the present report is to briefly review Multiple Sclerosis therapeutic trials published or presented in 2004 to provide an up-to-date overview of the established evidence and new insights.
New data have come available that help us understand how currently approved disease modifying drugs can best be used.
Nonetheless, their limited effectiveness - especially in Progressive forms of Multiple Sclerosis - as well as the inconvenience and toxicity associated with their use, emphasize the need for new treatment strategies.
A substantial number of reports on new emerging treatment modalities were published in 2004, and one of these modalities was newly approved by the US Food and Drug Administration for the treatment of Relapsing forms of Multiple Sclerosis.
Further advances have been made in the treatment of Multiple Sclerosis patients. On the one hand, we know better how and in whom to use existing medications.
On the other hand, it is exciting to witness how increased insight in the pathophysiology of the disease and its symptoms has led to a series of new, innovative treatment modalities.
Clinical Trials In Multiple Sclerosis: Methodological Issues
Comi G, Filippi M
Curr Opin Neurol 2005 Jun;18(3):245-52
Department of Neurology and Clinical NeuroPhysiology, Milan, Italy
Purpose Of Review
The availability of partially effective ImmunoModulatory and ImmunoSuppressive treatments for Relapsing Multiple Sclerosis (MS) opens important ethical, methodological and practical issues in the design and conduct of new clinical trials in these patients.
The recommendation of the National Health Authorities to prioritize phase III clinical trials using placebo arm raises ethical questions. In addition, patients are reluctant to be involved in such trials.
Alternative clinical trial designs will be discussed. Relapses and active lesions are accepted measures of disease activity; new/enlarging T2 lesions and/or enhancing lesions are accepted surrogate markers of disease activity in phase II clinical trials.
On the contrary, there are no accepted Magnetic Resonance Imaging (MRI) surrogate markers of disease progression and also the clinical measures to monitor the degenerative aspects of the disease are not without important limitations.
New scales of impairment, disability and quality of life will be reviewed extensively.
We will also focus on the value of modern and quantitative MRI techniques, which hold substantial promise as tools to estimate the extent of MS-related irreversible tissue loss.
The use of an active comparator in a superior clinical-trial design is becoming an attractive option for testing the efficacy of new drugs in Relapsing MS.
At present there are no fully reliable and sensitive clinical markers of the accumulation of irreversible tissue damage in MS.
Although additional extensive application in longitudinal studies is needed, modern MRI techniques are promising tools to monitor the NeuroDegenerative aspects of MS.
Pathogenesis Of Multiple Sclerosis
Prat A, Antel J
Curr Opin Neurol 2005 Jun;18(3):225-30
CHUM Notre-Dame Hospital, NeuroImmunology Laboratory and Multiple Sclerosis Clinic; Montreal Neurological Institute, NeuroImmunology Unit, Montreal, Quebec, Canada
Purpose Of Review
The aim of this article is to describe recent observations regarding the basis for the initiation and disease evolution of Multiple Sclerosis.
A current debate is where and what initiates the NeuroInflammatory reaction that characterizes the acute Multiple Sclerosis lesion.
Immune sensitization to Neural Antigens could develop within the systemic compartment consequent to exposure to cross-reacting, possibly Viral derived, Peptides (Molecular Mimicry).
Although CD4+ T-Cells are considered central to initiating Central Nervous System inflammation, the actual extent and specificity of tissue injury reflects the array of Adaptive (CD8+ T-Cells and AntiBody) and Innate (Microglia/Macrophages) Immune constituents present in the lesions.
NeuroPathologic studies indicate that lethal changes in Neural Cells (Oligodendrocytes) could also be the initiating event.
Reflecting as yet unidentified acquired insults (e.g. exogenous Virus or reactivated endogenous RetroVirus) or intrinsic abnormalities ('NeuroDegenerative' hypothesis).
Recurrence or persistence of the disease process can reflect events occurring at multiple sites.
Including, expansion of the Immune repertoire in response to Neural Antigens transported to regional Lymph Nodes (Determinant Spreading), especially if Immune regulatory mechanisms are defective.
Alterations in Blood-Brain Barrier properties consequent to initial Cellular TransMigration.
And participation of endogenous (Microglia, Astrocytes) or long lived infiltrating cells (Macrophages, B-Cells in ectopic germinal centers) in regulating and effecting Immune functions within the Central Nervous System.
Accumulating Neurologic deficit reflects the balance between injury and repair; the latter also being negatively or positively (Trophic support and clearance of tissue debris) impacted by inflammatory processes.
Understanding the full spectrum of Multiple Sclerosis presents a continuing challenge for both Immunology and NeuroBiology.
Promoting Repair In Multiple Sclerosis: Problems And Prospects
Lubetzki C, Williams A, Stankoff B
Curr Opin Neurol 2005 Jun;18(3):237-244
Federation de Neurologie, Hopital de la Salpetriere, Universite Pierre et Marie Curie, Paris, France bINSERM U-711, Hopital de la Salpetriere, Universite Pierre et Marie Curie, Paris, France cService de Pharmacologie, Hopital de la Salpetriere, Universite Pierre et Marie Curie, Paris, France
Purpose Of Review
Despite recent progress in treating the inflammatory component of Multiple Sclerosis, current therapies have no clear impact on progression of disability, which closely relates to tissue (Myelin and Axon) injury.
Many scientists now focus their efforts on elucidating the mechanisms that lead to tissue injury, and on developing new strategies for tissue repair. We review recent breakthroughs in this field and discuss their putative applications to therapy.
Several hypotheses have been raised to explain the failure of ReMyelination, including depletion of ReMyelinating Cells, quiescence of Oligodendrocyte Precursor Cells and Axonal inhibitory signals.
Success in ReMyelination therapy may be achieved either by enhancing endogenous repair or by grafting exogenous ReMyelinating Cells.
Several NeuroTrophic Factors have been shown to enhance endogenous ReMyelination, and many immature cells have been shown to induce efficient exogenous ReMyelination in animal models.
Although effective Remyelination probably represents the best way to prevent NeuroDegeneration, several alternative NeuroProtective strategies are emerging.
Statins, Cyclins and Immunophilin Ligands are orally available ImmunoModulatory agents that may protect Neurons. Other promising possibilities include the modulation of ExcitoToxicity, Nitric Oxide synthesis, or Cationic Channels.
Despite the increasing number of putative therapeutic targets, no treatment to achieve ReMyelination or NeuroProtection has yielded positive clinical results in humans.
Forging a link between basic biology and treatment of patients will require us to overcome several challenges, including assessment of efficacy of repair, improving tolerance to and delivery of NeuroTrophic Factors, and better defining the indications for and limitations of transplantation.