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WO1992015884A1 - Nouvelle proteine, procede et produits de detection d'oligodendrocytes - Google Patents

Nouvelle proteine, procede et produits de detection d'oligodendrocytes Download PDF

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Publication number
WO1992015884A1
WO1992015884A1 PCT/US1992/001907 US9201907W WO9215884A1 WO 1992015884 A1 WO1992015884 A1 WO 1992015884A1 US 9201907 W US9201907 W US 9201907W WO 9215884 A1 WO9215884 A1 WO 9215884A1
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Prior art keywords
myelin
protein
ligand
detecting
oligodendrocyte
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English (en)
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Eldon E. Geisert, Jr.
Charissa A. Dyer
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UAB Research Foundation
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UAB Research Foundation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants

Definitions

  • the myelin sheath is a lipoproteinaceous envelope in vertebrates surrounding most axons of greater than 0.5 ⁇ H diameter and consists of plasma membrane of oligodendrocytes or Schwann cells wound tightly around the axon in a variable number of turns.
  • This myelin membrane is a bylayer consisting of about 80% lipid and 20% protein.
  • oligodendrocytes produce multiple wraps of myelin membrane that ensheath axons and alter the passive electrical properties of the axons, increasing the conduction velocity and efficiency of action potentials.
  • Oligodendrocytes are one of five types of glial cells (astrocytes, microglia, ependymal cells and Schwann cells) which together make up about 90% of all neural tissue; neurons make up the other 10% of neural tissue. Glial cells surround neurons, both their cell bodies and their processes, providing structural and functional support to the neurons.
  • the myelin of the peripheral nervous system (PNS) is produced by a different cell type, the Schwann cell.
  • CNS and PNS myelin share a variety of unique lipids and proteins; until now only myelin/oligodendrocyte glycoprotein (MOG) has been shown to be selectively expressed in CNS myelin.
  • a number of proteins, such as proteolipid protein (PLP) , MOG, cerebellar soluble lectin (CSL) , and myelin basic protein (MBP) are found in myelin-producing cells. Although these proteins are highly enriched in myelin, PLP and MBP and CSL are not specific to CNS myelin, and MOG is present in only small or undetectable levels in mature oligodendrocytes, thus making them unsuitable for identification of oligodendrocyte cell bodies in adult tissue.
  • markers such as 2 ' , 3' cyclic nucleophosphohydrolase (CNPase) , carbonic anhydrase, galactocerebroside and sulfatide are present in oligodendrocytes but are not unique to the CNS.
  • CNPase 2 ' , 3' cyclic nucleophosphohydrolase
  • carbonic anhydrase galactocerebroside
  • sulfatide are present in oligodendrocytes but are not unique to the CNS.
  • Antibodies to the above markers have been used to detect the presence of the markers in CNS and PNS.
  • CNS specific such as multiple sclerosis.
  • a clear understanding of the pathogenesis of multiple sclerosis has been hindered by the lack of a specific marker for mature oligodendrocytes. Defining the differences between CNS and PNS myelin may provide dramatic insights into the process of demyelination and the pathogenesis of certain idiopathic diseases involving myelin such as multiple sclerosis, certain leukodystrophies and other myelinopathies.
  • MOSP myelin/oligodendrocyte specific protein
  • MOG central nervous system
  • CNS myelin central nervous system
  • This invention provides a novel surface membrane protein expressed only in CNS myelin and oligodendrocytes of higher vertebrates which has been identified by a monoclonal antibody (CE1) .
  • This CNS myelin/oligodendrocyte specific protein, MOSP has a molecular weight of about 48 kDa and a pi of approximately 6.7.
  • MOSP In the presence of the monoclonal antibody, MOSP remains on the surface of cultured oligodendrocytes but becomes associated with cytoplasmic microtubules, indicating that MOSP is capable of forming a stable link with the oligodendrocyte cytoskeleton, unlike any other known myelin protein.
  • the present invention provides the discovery of a novel protein found in central nervous system myelin and oligodendrocytes.
  • the protein has a molecular weight of about 48,000 and an isoelectric focusing point of about 6.7.
  • the protein is specific for central nervous system myelin and oligodendrocytes.
  • Standard methods can be applied to determine the amino acid sequence and the nucleic acids which encode the protein. Once the sequence is determined, nucleotide probes can be made and standard methods, such as polymerase chain reaction, can be used to detect the nucleic acids.
  • the invention also provides ligands which are specifically reactive with the protein. While only antibodies are exemplified below, the skilled artisan will recognize that modifications of the antibodies or other ligands would be effective in the methods described in the example. Such modifications include isotype switching.
  • the monoclonal antibody CE1 is a ligand which reacts with the antigenic epitope of MOSP. It was produced from mice first immunized with rat glial membrane proteins and then with a final boost of rat CNS white matter. Five days following the final boost, the animals were anesthetized with KETALAR (Parke-Davis) (10 mgs) and the inguinal lymph nodes were dissected from the mice. Lymphocytes, obtained from the lymph nodes, were disassociated and added to an equal number of AG8 myeloma cells (American Type Culture) or other myeloma cell lines such as SP20; fusion was performed in PEG 1000 (Boehringer Manneheim) . CE1 was detected in an ELISA (enzyme linked immunosorbent assay) using live cultures of mixed glial cells.
  • KETALAR Parke-Davis
  • CE1 was purified and concentrated from tissue culture supernatents with ammonium sulfate precipitation followed by dialysis in distilled water. The water insoluble IgM was resuspended in Delbeco's Modified Eagles Medium (DMEM) (Gibco) . Other antibodies were used in the characterization of CE1 and its antigen MOSP.
  • DMEM Delbeco's Modified Eagles Medium
  • a rabbit polyclonal antibody directed against sulfatide (007) was a gift from Dr. Robert Lisak.
  • the murine monoclonal antibody Tu27 was a gift from Dr. Lester Binder.
  • the rabbit polyclonal antibody directed against galactocerebroside was produced in the laboratoy of Dr. Joyce Benjamins.
  • a variety of second antibodies were used to detect antibody:antigen complexes.
  • Second antibodies goat anti-mouse IgM conjugated to rhodamine (GAM-TRITC) and goat anti-rabbit IgG conjugated to fluorescein (GAR- FITC) , were purchased from Organontechnika (Malvern, PA) .
  • GAM-TRITC crossreacts well with rat IgM and to a lesser degree with rabbit IgG. Therefore, to remove the population of antibodies in GAM-TRITC that reacted with rabbit IgG, GAM-TRITC was passed through a rabbit affinity column.
  • detectable agents such as horseradish peroxidase, alkaline phosphatase and ⁇ - galactosidase may be conjugated to other second antibodies directed against mouse IgM and mouse IgG and anti-rabbit IgG.
  • biotin coupled to a primary antibody or a biotin-streptavidin sandwich assay may be used to detect the presence of complexes.
  • complex refers to a "ligand complex," an "immune complex” and an “antigen:antibody complex,” which are treated herein as synonymous and are defined as the reaction of an antigenic epitope with a ligand specific for that epitope.
  • immunohistochemistry as used herein, denotes immune complex formation.
  • a ligand is a substance capable of reacting with, binding to, or •forming a stable interaction with another substance.
  • Indirect immunohistochemistry as used herein, is a means for detecting the formation of complexes between a first ligand and its antigen using a second more readily detectable ligand which reacts with the complex formed between the first ligand and its antigen.
  • Indirect immunohistochemical means include immunostaining, enzyme- linked immunosorbent assay (ELISA) , immunoaffinity chr ⁇ matography, immunoprecipitation, immunoblotting (Western blot and dot blot) and radioimmunoassay.
  • ELISA enzyme- linked immunosorbent assay
  • rat tissues were screened using indirect immunohistochemical methods.
  • the biological samples were sectioned on a freezing microtome at 40 ⁇ m or on a cryostat at 20 ⁇ m.
  • the sections were placed in a blocking solution of borate-buffered saline (BBS) with 4% bovine serum albumin and 2% normal goat serum.
  • BBS borate-buffered saline
  • the primary antibody was then added to the sections ovenight at 4'C to allow formation of antigen:antibody complexes.
  • MOSP The cellular distribution of MOSP was further characterized by immunostaining a variety of culture systems: enriched mouse oligodendrocytes, mixed rat glial cells, meningeal fibroblasts, rat neurons, and Schwann cells. In these cultures, only oligodendrocytes were labeled and all other cell types including type 1 astrocytes, type 2 astrocytes, fibroblasts, neurons, macrophages, microglia and Schwann cells were negative. Indirect immunofluorescent staining for the CE1 antigen was performed on live cultures by treating them at 37°C with CE1 for 15 minutes and then with second antibody rhodamine-conjugated goat anti-mouse IgM for 15 minutes.
  • Live oligodendrocytes were intensely immunostained following brief (ten minute) exposures to CE1 and second antibody directed against mouse IgM. Immunofluorescent staining of live cultured rat oligodendrocytes was detected after a 5 minute application of CE1 followed by fixation and addition of goat anti- mouse IgM or other anti-mouse IgM conjugated to fluorescein. These results indicate that the antigen detected by CE1 is constitutively expressed on the external surface of oligodendrocyte cell membranes. The results also show that immunohistochemical staining can detect the presence or absence of oligodendrocytes in both live and fixed biological samples. Oligodendrocytomas, tumors of oligodendrocyte origin, may also be detected by immunostaining as described above.
  • MOSP myelin basic protein
  • CE1 stains normal CNS myelin and that when demyelination occurs, immunoreactivity for MOSP, like MBP, is no longer detected.
  • CE1 may be used to detect abnormal distributions of MOSP, and thereby provides a means for diagnosing multiple sclerosis in humans.
  • CE1 To define the antigen recognized by CE1, the reactivity of the antibody with myelin lipids and proteins was examined. A variety of glycolipids, including the two highly antigenic myelin-enriched glycolipids, galactocerebroside and sulfatide, were screened in a liposome enzyme linked immunosorbent assay (ELISA) . The reactivity of CE1 with mixed gangliosides, ceramide, sulfatide, galactocerebroside, glucocerebroside, ganglioside, asialo ganglioside, and phosphatidyl choline:cholesterol vesicles (negative control) was determined in the ELISA.
  • ELISA liposome enzyme linked immunosorbent assay
  • Electrophoresis and immunoblotting with a peroxidase- conjugated second antibody were performed. This sequence of protein detection steps is designated "Western blotting.” Samples of CNS proteins were separated by 4 to 16% SDS polyacrylamide gel electrophoresis (SDS-PAGE) . The samples were transferred to nitrocellulose, blocked with 5% non-fat dry milk in borate buffer (pH 8.4) and stained with the monoclonal antibody CE1. After rinsing in borate buffer 3 times, the blots were placed in second antibody (peroxidase- conjugated goat anti-mouse IgG and IgM, Pierce) for two hours at room temperature.
  • SDS-PAGE SDS polyacrylamide gel electrophoresis
  • second antibodies directed against mouse IgM and IgG conjugated to a variety of other detectable agents such as fluorescein, rhodamine, alkaline phosphatase or ⁇ -galactosidase, or a biotin-streptavidin sandwich assay, may be used.
  • detectable agents such as fluorescein, rhodamine, alkaline phosphatase or ⁇ -galactosidase, or a biotin-streptavidin sandwich assay.
  • dot blot hybridization alone may be used to detect the presence of immune complexes between MOSP and CEl.
  • Adherent proteins were eluted with 0.2M glycine, pH 2.3 plus 0.02% TRITON X-100 (Sigma); column fractions were immediately neutralized with 0.5 Tris. pH 8.5. The column fractions containing radioactivity were separated on a 5-20% SDS polyacrylamide gel to identify the molecular weight of the isolated protein (standard molecular weight markers were also electrophoresed) . Gels were sliced, treated with PROTOSOL (New England Nuclear) overnight, scintillation cocktail was added and samples were counted in a Beckman counter for 10 min per sample. A 48 kDa protein corresponding to MOSP was detected.
  • A-SEPHAROSE (Pharmacia) bound to goat anti-mouse IgM 2) another 50 ⁇ g of anti-sulfatide IgM and protein A- SEPHAROSE (Pharmacia) bound to goat anti-mouse IgM, and 3) 50 ⁇ l of protein A-SEPHAROSE (Pharmacia) bound to goat anti-mouse IgM or other anti-mouse IgM. After overnight incubation with constant mixing at 4"C the beads were sedimented by low speed centrifugation and the lysate removed and used for the next immunoprecipitation step.
  • Steps 1-3 were used to clear proteins from the lysate that non-specifically adhere to either antibodies or to protein A-SEPHAROSE (Pharmacia) .
  • the cleared lysate was then treated with CEl followed by protein A-SEPHAROSE (Pharmacia) to precipitate the antigen recognized specifically by CEl.
  • protein A-SEPHAROSE beads (Pharmacia) were washed six times in TBS and Laemmli sample buffer was added to dissociate the immune complexes.
  • the samples were boiled 3 min and loaded on a 5-20% SDS polyacrylamide gel for analysis. Gels were sliced and radioactivity detected as described for antibody affinity columns above. This procedure resulted in the detection of a major radioactive peak at 48 kDa (MOSP) precipitated by CEl that was not precipitated by the anti-sulfatide control.
  • MOSP major radioactive peak at 48 kDa
  • Equilibrium isoelectric focusing (EIF) of precipitates from ( 35 S) methionine labeled oligodendroglial culture TRITON X-100 (Sigma) lysates was performed.
  • the lysate was first treated with anti-sulfatide IgM as described for immunoprecipitation above and then treated with CEl and protein A-SEPHAROSE (Pharmacia) bound to goat anti-mouse IgM or other anti-mouse IgM.
  • the immunoprecipitates were washed extensively and loaded onto separate IEF tube gels.
  • the pH gradient in the focused gels was determined by slicing duplicate gels into 0.5 cm sections, placing each section into 0.5 ml dH 2 0 and measuring the pH after 30 min.
  • the pi of the CEl protein spots detected on the two- dimensional gel autoradiograph was determined by measuring the distance the proteins migrated through IEF gel and comparing that to the pH gradient obtained from the sliced gels. After focusing, each gel was placed on top of a SDS 5-20% acrylamide gradient slab gel and run on the second dimension. The gels were stained, destained and impregnated with the scintillant PPO (New England
  • MOSP contains carbohydrate side chains containing mannose or sialic acid
  • the radiolabeled lysates were passed through two lectin affinity columns. 0.5% TRITON X-100 (Sigma) lysates from ( 35 S)methionine labeled oligodendrocyte shakeoff cultures were passed through concanavalin A-AGAROSE (Sigma) and wheat germ agglutinin-AGAROSE (Sigma) columns. The columns were washed extensively with 0.2% TRITON X-100 (Sigma) Tris buffered saline (TBS), pH 7.4, until background counts were obtained.
  • TBS Tris buffered saline
  • Glycoproteins were eluted from the concanavalin A column with 0.2M D-mannose in 0.2% TRITON X-100 TBS and from the wheat germ column with 0.2% N- acetyl D-glucosamine in 0.2% Triton X-100 TBS. The adherent glycoprotein fractions were then immunoprecipitated and analyzed by gel electrophoresis. No proteins were immunoprecipitated. MOSP was not retained on either column, indicating that carbohydrates containing high mannose (concanavalin A) or polysialic acid (wheat germ agglutinin) are not covalently attached to MOSP.
  • oligodendrocytes In tissue culture, murine oligodendrocytes elaborate extensive membrane sheets that have uniform surface distributions of MOSP, and other selected myelin markers such as galactocerebroside and myelin/oligodendrocyte glycoprotein (MOG) . These membrane sheets contain an internal network of microtubular veins that surround cytoplasmic domains of myelin basic protein (MBP) . The normal distribution of surface antigens on cultured oligodendrocytes can be visualized by fixation and then immunocytochemical staining.
  • MOSP galactocerebroside and myelin/oligodendrocyte glycoprotein
  • MOSP redistributes in a lacy surface pattern that directly overlies internal microtubular veins. Furthermore, this redistribution pattern is dependent upon the integrity of the microtubular network. Following pretreatment of oligodendrocytes with colchicine, a drug which depolymerizes microtubules, the redistribution of MOSP to produce the lacy surface pattern does not occur; the membrane sheets remain solidly stained for MOSP.
  • MOSP has physical and biological properties that are distinct from MOG and PLP, the only other known integral membrane proteins described to date that are specific to CNS myelin and oligodendrocytes. PLP is also present in the cytoplasm of Schwann cells, but is not inserted into the plasma membrane. The molecular weight of MOSP (48 kDa) is considerably higher than MOG (26 and 28 kDa) or PLP (27 kDa) . These data show that MOSP is a novel myelin/oligodendrocyte specific protein.
  • Cerebrospinal fluid (CSF) or other biological fluids such as urine or serum, from patients with neurological disorders such as multiple sclerosis can be screened for the presence of MOSP by, for example, an immunoblotting test using CEl and second antibody to detect MOSP. Similar screening has been performed using antisera raised against MBP in a radioimmunoassay to detect the presence of MBP in CSF of patients with acute demyelinating events (Cohen et al.. Annals of Neurology 25:107 (1989)). Similar methods can be applied to MOSP.
  • circulating CEl can be detected by contacting a sample of biological fluid with MOSP and detecting the presence of complexes between MOSP and CEl.
  • This test can indicate an autoimmune response to MOSP before MOSP can be detected in the biological fluid.
  • CSF and plasma from patients with serious neurological disorders has also been screened for the presence of autoantibodies to an endogenous mannose-binding protein, the cerebellar soluble lectin (CSL) , by means of an immunoblotting test with rat CSL as the antigen (Zanetta et al. Lancet 335:1482-4 (1990)). 47 of 51 patients with multiple sclerosis were positive for anti-CSL compared with 30 of 188 patients with other neurological disorders.
  • the specificity of the CSL test for multiple sclerosis is 85% and the sensitivity 93.5% (Zanetta et al. (1990)).
  • the effects caused by binding of the monoclonal antibody CEl to MOSP on cultured oligodendrocytes can also mimic the effects elicited by interaction of MOSP with an in vivo endogenous ligand present on other cell types or in myelin itself.
  • the association of MOSP with cytoplasmic microtubules of cultured oligodendrocytes after antibody binding suggests an important role for MOSP in membrane/cytoskeletal interactions during assembly and maintenance of the multiple myelin sheaths elaborated by individual oligodendrocytes and in the interactions of oligodendrocytes with other cells of the CNS during development.
  • MOSP Abnormalities in the metabolism of MOSP may be central to the pathogenesis of specific myelinopathies or leukodystrophies. Moreover, since MOSP is expressed on the extracellular surface of normal cultured oligodendrocytes and myelin, it is likely that MOSP serves as an antigenic target in certain idiopathic diseases such as multiple sclerosis that selectively affect CNS myelin.

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Abstract

Nouvelle protéine spécifique de myéline/oligodendrocyte rencontrée dans la substance blanche du système nerveux central (CNS), et exprimée exclusivement dans la myéline du CNS ainsi que la surface d'oligodendrocytes. L'invention concerne également un ligand réagissant avec un épitope antigénique de la protéine spécifique de myéline/oligodendrocytes (MOSP). L'invention concerne aussi des hybridomes produisant des anticorps réagissant avec la nouvelle protéine, ainsi que des acides nucléiques codant la protéine. En outre, l'invention concerne des procédés de détection de la démyélinisation et de la sclérose en plaques.
PCT/US1992/001907 1991-03-08 1992-03-09 Nouvelle proteine, procede et produits de detection d'oligodendrocytes Ceased WO1992015884A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997017984A1 (fr) * 1995-11-14 1997-05-22 Research Genetics, Inc. Proteine specifique des oligodendrocytes et procede correspondant pour le traitement de maladies
EP0674661A4 (fr) * 1992-12-18 1997-12-10 Molecular Rx Inc Titrage et traitement destines aux maladies demyelinisantes telles que la sclerose en plaques.
US6150136A (en) * 1995-11-14 2000-11-21 The Regents Of The University Of California Nucleotide sequence encoding oligodendrocyte-specific protein
CN112611874A (zh) * 2020-12-22 2021-04-06 安徽恩禾生物技术有限公司 一种髓鞘少突胶质细胞糖蛋白抗体试剂盒及其检测方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CLINICAL BIOCHEMISTRY, Volume 18, issued October 1985, A. MUKHERJEE et al., "Measurement of Myelin Basic Protein by Radioimmunoassay in Closed Head Trauma, Multiple Sclerosis and Other Neurological Diseases", pages 304-307. *
JOURNAL OF NEUROIMMUNOLOGY, Volume 6, issued 1984, C. LINNINGTON et al., "A Novel Myelin-Associated Glycoprotein Defined by a Mouse Monoclonal Antibody", pages 387-396. *
THE JOURNAL OF IMMUNOLOGY, Volume 124, No. 3, issued March 1980, J.N. WHITAKER et al., "Antigenic Features of Myelin Basic Protein-like Material in Cerebrospinal Fluid", pages 1148-1153. *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0674661A4 (fr) * 1992-12-18 1997-12-10 Molecular Rx Inc Titrage et traitement destines aux maladies demyelinisantes telles que la sclerose en plaques.
WO1997017984A1 (fr) * 1995-11-14 1997-05-22 Research Genetics, Inc. Proteine specifique des oligodendrocytes et procede correspondant pour le traitement de maladies
US5756300A (en) * 1995-11-14 1998-05-26 Research Genetics, Inc. Oligodendrocyte-specific protein and method for diagnosing and treating disease
US6147191A (en) * 1995-11-14 2000-11-14 The Regents Of The University Of California Oligodendrocyte-specific protein
US6150136A (en) * 1995-11-14 2000-11-21 The Regents Of The University Of California Nucleotide sequence encoding oligodendrocyte-specific protein
CN112611874A (zh) * 2020-12-22 2021-04-06 安徽恩禾生物技术有限公司 一种髓鞘少突胶质细胞糖蛋白抗体试剂盒及其检测方法

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