Human MonoClonal AntiBodies Reactive To Oligodendrocytes Promote ReMyelination
In A Model Of Multiple Sclerosis
Warrington AE, Asakura K, Bieber AJ, Ciric B, Van Keulen V, Kaveri SV, Kyle RA, Pease LR, Rodriguez M
Proc Natl Acad Sci USA 2000 Jun 6;97(12):6820-6825
Mayo Medical and Graduate Schools, Depts of Neurology, Immunology, and Hematology, Rochester, MN 55905; and Institut National de la Sante et de la Recherche Medicale (INSERM) U430, Paris, France; and Nagoya Univ, School of Medicine, Dept of Neurology, Nagoya, 466-8550 Japan
Promoting ReMyelination, a major goal of an effective treatment for DeMyelinating Diseases, has the potential to protect vulnerable Axons, increase Conduction Velocity, and improve Neurologic Deficits.
Strategies to promote ReMyelination have focused on transplanting Oligodendrocytes (OLs) or recruiting endogenous Myelinating cells with Trophic Factors.
Ig-based therapies, routinely used to treat a variety of Neurological and AutoImmune Diseases, underlie our approach to enhance ReMyelination.
We isolated two human mAbs directed against OL surface Antigens that promoted significant ReMyelination in a Virus-mediated model of Multiple Sclerosis. Four additional OL-binding human mAbs did not promote ReMyelination.
Both human mAbs were as effective as human IVIG, a treatment shown to have efficacy in Multiple Sclerosis, and bound to the surface of human OLs suggesting a direct effect of the mAbs on the cells responsible for Myelination.
Alternatively, targeting human mAbs to areas of Central Nervous System (CNS) pathology may facilitate the Opsonization of Myelin debris, allowing repair to proceed.
Human mAbs were isolated from the Sera of individuals with a form of MonoClonal Gammopathy.
These individuals carry a high level of MonoClonal protein in their blood without detriment, lending support to the belief that administration of these mAbs as a therapy would be safe.
Our results are consistent with the hypothesis that CNS-reactive mAbs, are:
- Part of the normal Ig repertoire in humans
- May help repair and protect the CNS from
- Further challenge the premise that Abs that bind OLs are necessarily Pathogenic.
Unique Population Of Circulating AutoAntibodies Promotes
Central Nervous System ReMyelination
Asakura K, Rodriguez M
Mult Scler 1998 Jun;4(3):217-21
Mayo Clinic and Foundation, Dept of Neurology, Rochester, Minnesota, USA
PMID# 9762677; UI# 98435425
In previous studies we demonstrated that the Humoral Immune Response directed against unique Central Nervous System (CNS) Antigens enhanced CNS ReMyelination in the Theiler's Virus experimental model of Multiple Sclerosis (MS).
To expand on this observation, a mouse IgM kappa MonoClonal AntiBody (mAb) which enhances CNS ReMyelination, was raised against normal mouse Spinal Cord homogenate.
Characterization of this mAb revealed that it is PolyReactive towards variety of IntraCellular Antigens but also reacts to an unidentified surface Antigen on Oligodendrocytes.
The mAb is encoded by germline ImmunoGlobulin Genes without Somatic mutations consistent with the observation that it is a natural AutoAntibody.
Recently we generated another mouse IgM kappa mAb raised against normal Spinal Cord homogenate, which also promotes CNS ReMyelination.
Further characterization revealed that both mAbs which promote ReMyelination have similar binding characteristics.
Conventionally Abs which recognize normal CNS components, especially Oligodendrocytes or Myelin, have been considered to be a disease marker or be involved in the PathoGenesis of MS.
However, we have identified a unique population of circulating AutoAntibodies which are beneficial for Myelin repair.
Therefore this observation indicates the need to re-evaluate AutoAntibody production against Myelin components in CSF and blood as markers of disease activity versus repair in MS.