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WO2003000718A2 - Nouveau peptide et son utilisation - Google Patents

Nouveau peptide et son utilisation Download PDF

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Publication number
WO2003000718A2
WO2003000718A2 PCT/JP2001/008221 JP0108221W WO03000718A2 WO 2003000718 A2 WO2003000718 A2 WO 2003000718A2 JP 0108221 W JP0108221 W JP 0108221W WO 03000718 A2 WO03000718 A2 WO 03000718A2
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WO
WIPO (PCT)
Prior art keywords
seq
amino acid
acid sequence
polypeptide
fodrin
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PCT/JP2001/008221
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English (en)
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WO2003000718A3 (fr
Inventor
Yoshio Hayashi
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Fujisawa Pharmaceutical Co., Ltd.
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Priority to AU2001288087A priority Critical patent/AU2001288087A1/en
Publication of WO2003000718A2 publication Critical patent/WO2003000718A2/fr
Publication of WO2003000718A3 publication Critical patent/WO2003000718A3/fr

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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
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4713—Autoimmune diseases, e.g. Insulin-dependent diabetes mellitus, multiple sclerosis, rheumathoid arthritis, systemic lupus erythematosus; Autoantigens

Definitions

  • the present invention relates to a novel peptide and use thereof. More particularly, the present invention relates to a pathogenic T cell epitope in Sj ⁇ gren's syndrome and an analogue thereof.
  • BACKGROUND ART Sj ⁇ gren's syndrome is a mysterious autoimmune disorder characterized by lymphocytic infiltrates and destruction of the salivary and lacrimal glands, and systemic production of autoantibodies to the ribonucleoprotein (RNP) particles SS-A/Ro and SS-B/La (Chan et al., J. Clin. Invest . 87, 68-76 (1991); Kruize et al., Immunol . Today 16, 557-559 (1995)).
  • RNP ribonucleoprotein
  • SS-A/Ro- or SS-B/La-positive patients have complications such as systemic lupus erythematosus and rheumatism (Chan et al., (1991), supra ⁇ Chan et al., Nucleic Acids Research, 17, 2233-2244, (1989)).
  • CTL cytotoxic T lymphocyte
  • the present inventors have identified the pathogenic T cell epitope involved in antigen-specific immune response in urine model of human SS and established autoreactive T cell lines that recognize synthetic N-terminal portion of ⁇ -fodrin (AFN) , which produce Thl cytokines and show significant cytotoxic activities. That is, the present inventors have determined the pathogenic T cell epitope which allows for the regulation of autoimmune response to ⁇ -fodrin in SS, and found that an analogue peptide obtained by introducing a mutation into a specific part of the epitope peptide is useful for the peptide therapy of autoimmune diseases such as Sj ⁇ gren's syndrome. Accordingly, the present invention provides the following.
  • a polypeptide comprising the same amino acid sequence depicted in SEQ ID No:l, SEQ ID No: 2 or SEQ ID No: 4 except that one to several amino acids is (are) substituted, deleted, added or inserted, which can function as a T cell epitope.
  • a reagent for diagnosis of Sj ⁇ gren's syndrome which comprises the polypeptide of any of (1) to (4) above.
  • a pharmaceutical composition comprising the polypeptide of any of (1) to (4) above.
  • polypeptide comprising the same amino acid sequence depicted in SEQ ID No:l, SEQ ID No: 2 or SEQ ID No: 4 except that one to several amino acids is (are) substituted, deleted, added or inserted, which can function as a T cell epitope.
  • a polypeptide comprising the same amino acid sequence depicted in SEQ ID No:l, SEQ ID No:2 or SEQ ID No: 4 except that one to several amino acids is (are) substituted, deleted, added or inserted, which polypeptide binds with an MHC class-II molecule and suppresses a proliferative responses of autoreactive T cell.
  • a pharmaceutical composition comprising a polypeptide of any of (8) to (10) above as an active ingredient.
  • the pharmaceutical composition of (12) above which is for the prophylaxis and treatment of Sj ⁇ gren's syndrome.
  • a method of the prophylaxis and treatment of Sj ⁇ gren's syndrome which comprises administering an effective amount of a polypeptide of any of (8) to (10) above to a patient.
  • a commercial package comprising a pharmaceutical composition of (13) above, and a written matter associated therewith, the written matter stating that the pharmaceutical composition can or should be used for the prophylaxis and treatment of Sj ⁇ gren's syndrome.
  • Fig. 1 shows results of analogue peptide-based therapy.
  • Fig. 2 shows results of analogue peptide-based therapy.
  • Fig. 3 shows results of induction of oral tolerance in mice.
  • Fig. 4 shows results of induction of oral tolerance in mice.
  • polypeptide consisting of a partial amino acid sequence of ⁇ -fodrin used in the present invention is not subject to any particular limitation as regards biological species, molecular weight (number of amino acids) and the like, as long as it is an autoreactive T cell epitope or a polypeptide containing the epitope, or a substance having an equivalent action (hereinafter these are also generally referred to simply as an epitope peptide) .
  • an epitope has a structure recognized by a T cell receptor.
  • This epitope contains an amino acid sequence specifically depicted in SEQ ID No:l, preferably SEQ ID No: 2.
  • the epitope peptide can be prepared in the present invention by chemical synthesis, purification from various organs, or by genetic engineering. As long as the function of a T cell epitope is maintained, this amino acid sequence may have one to several amino acids added to the N- terminal and/or C-terminal of the sequence.
  • the epitope peptide When it is particularly produced by genetic engineering, the epitope peptide may be mutated (substitution, insertion, addition or deletion) as long as the function of an epitope can be maintained. It is also possible to provide the epitope peptide as a protein by adding or inserting a longer polypeptide chai (s) to or in an epitope. Moreover, side chains of the constituent amino acids of the above-mentioned epitope peptides may be protected by suitable protective groups [e.g. C ⁇ _ 6 acyl groups such as formyl, acetyl, benzoyl, etc. (preferably C ⁇ - 6 alkanoyl) ] unless the function of a T cell epitope is lost.
  • suitable protective groups e.g. C ⁇ _ 6 acyl groups such as formyl, acetyl, benzoyl, etc. (preferably C ⁇ - 6 alkanoyl)
  • the epitope peptide of the present invention can be also obtained by decomposing a human ⁇ -fodrin protein by protease etc.
  • the protease that can be used advantageously includes trypsin, chymotrypsin, and calpain (preferably calpain) .
  • an ⁇ -fodrin protein derived from any tissue (e.g., brain) or cells from warm-blooded animals (e.g. guinea pig, rat, mouse, rabbit, swine, sheep, cattle, monkey, etc.) can be used as a starting material.
  • the cleavage of ⁇ -fodrin protein with a protease can be achieved by allowing them to react in a buffer solution of pH from about 6 to about 8 at from about 10 to about 50 °C
  • examples of the mutated amino acid by substitution, insertion, addition or deletion include those that underwent addition of amino acids, deletion of constituent amino acids, or substitution of different amino acids for constituent amino acids, to the extent that the epitope peptide can maintain the function of a T cell epitope.
  • examples of the mutated epitope peptide obtained by addition of amino acid(s) include that obtained by adding at least one amino acid added to the amino acid sequence depicted in SEQ ID No:l, SEQ ID No:2 or SEQ ID No: 4.
  • Examples of the mutated epitope obtained by deletion of constituent amino acid(s) include that obtained by deleting at least one ⁇ -fodrin constituent amino acid from the amino acid sequence depicted in SEQ ID No:l, SEQ ID No: 2 or SEQ ID No: 4.
  • Examples of the mutated epitope obtained by substitution of amino acid(s) include that obtained by substituting at least one ⁇ -fodrin constituent amino acid by a different amino acid.
  • the number of amino acid to be added is at least one, but it could be any number as long as the amino acid sequence does not lose the function of a T cell epitope.
  • the number of amino acid to be deleted is at least one, but it could be any number as long as the amino acid sequence does not lose the function as a T cell epitope.
  • the number of the substituted amino acid is at least one, but it could be any number as long as the amino acid sequence does not lose the function of a T cell epitope.
  • an epitope peptide is mutated, a method generally known in this field is used or two or more such methods are used in an appropriate combination.
  • the epitope peptide of the present invention can be easily produced by the peptide synthesis method.
  • the method for chemical synthesis of the epitope peptide of the present invention may be whichever of solid-phase synthesis and liquid-phase synthesis. That is, a partial peptide or amino acid capable of constituting the epitope peptide of the present invention is condensed with the residual part, and, when the resulting product has a protecting group, the protecting group is removed to produce the objective peptide.
  • the epitope peptide can be easily prepared by one cycle of peptide synthesis.
  • a polypeptide having a relatively long amino acid sequence is synthesized and cleaved at the N-terminal and/or C-terminal to give a desired peptide.
  • the base polypeptide having a long amino acid sequence can be chemically synthesized by peptide synthesis, or by genetic engineering based on a DNA sequence encoding the base polypeptide, according to a known method or a combination of known methods (USP No. 6,121,057).
  • the condensation and deprotection of amino acid or peptide can be carried out by, for example, the methods described in the following literatures (1)- (5) .
  • the epitope peptide of the present invention can be purified and isolated by using such techniques as solvent extraction, distillation, column chromatography, liquid chromatography, recrystallization, etc. in a suitable combination.
  • Introduction of a mutation into an epitope peptide may result in the loss of the function of an epitope, depending on the site and the kind of mutation, and may sometimes suppress the reactivity of T cell to the epitope peptide.
  • the present invention provides a polypeptide having the same amino acid sequence depicted in SEQ ID No:l except that one to several amino acids underwent substitution, deletion, addition or insertion, and have a low autoreactive T cell growth stimulant action and an MHC class-II binding capability (hereinafter this polypeptide is to be also referred to as an epitope analogue) .
  • the epitope analogue of the present invention can be chemically synthesized in the same manner as in the above- mentioned epitope peptide.
  • An autoreactive T cell reacts with self-components, which are specifically autoreactive CTL (cytotoxic T lymphocyte) and the like.
  • An autoreactive T cell can be generally induced and prepared by a method known in this field.
  • An autoimmune disease is caused by an attack on the self-components by the T cell. If the growth of the autoreactive T cell can be suppressed, it leads to the prophylaxis and treatment of autoimmune diseases.
  • the epitope analogue of the present invention maintains an MHC class-II binding capability but suppresses proliferative responses of the autoreactive T cell.
  • the “suppresses proliferative responses of the autoreactive T cell” is meant that it shows a significantly lower proliferation of autoreactive T cell as compared to that by the use of an epitope peptide, and is not subject to any particular limitation.
  • the proliferation stimulating action is completely absent or very little if there is found any.
  • the level of the proliferation of autoreactive T cell can be measured by a method known in this field. For example, the CTL-induced T lymphocyte growth stimulant action can be determined by 3 H thymidine uptake test etc.
  • the MHC class- II binding assay was modified from the protocol previously described (Wauben et al., J. Immunol . 152, 4211-4220 (1994)).
  • the binding with an MHC class-II molecule can be determined by assessing the relative affinity of peptide using class II (I-A q ) spleen cells from NFS/sld mice.
  • the preferable relative affinity is more than 30%. More preferably, the relative affinity is more than 55%. And the most relative affinity is more than 80%.
  • the epitope peptide and epitope analogue of the present invention can be used as a pharmaceutical composition containing either of them as an agent for the prophylaxis and treatment of autoimmune disease, such as systemic lupus erythematosus, rheumatoid arthritis, Sj ⁇ gren's syndrome and the like, and particularly as an agent for the prophylaxis and treatment of autoimmune disease, such as systemic lupus erythematosus, rheumatoid arthritis, Sj ⁇ gren's syndrome and the like, and particularly as an agent for the prophylaxis and treatment of autoimmune disease, such as systemic lupus erythematosus, rheumatoid arthritis, Sj ⁇ gren's syndrome and the like, and particularly as an agent for the prophylaxis and treatment of autoimmune disease, such as systemic lupus erythematosus, rheumatoid arthritis, Sj ⁇ gren's syndrome and the like, and
  • the epitope peptide or epitope analogue of the present invention by the administration of the epitope peptide or epitope analogue of the present invention, inflammation observed in the salivary and lacrimal glands in autoimmune diseases, particularly Sj ⁇ gren's syndrome, can be treated or prevented.
  • the epitope peptide of the present invention can establish the tolerance to autoantigen before and after the onset of the disease.
  • an epitope analogue is administered, the growth of an autoreactive T cell observed with an autoimmune disease can be suppressed.
  • the administration of the epitope analogue results in the suppression of autoantibody.
  • the epitope peptide and epitope analogue of the present invention can be administered as a pharmaceutical composition containing either of them along with a known immunosuppressant or an anti-inflammatory agent, for the prophylaxis and treatment of autoimmune diseases, particularly as an agent for the prophylaxis and treatment of Sj ⁇ gren's syndrome.
  • the epitope peptide or epitope analogue of the present invention can be administered either as it is in a bulk form or in a dosage form containing it in combination with a pharmaceutically acceptable carrier, excipient or diluent (e.g. as an injection, tablets, capsules, a liquid, an ointment, or a suppository etc.) to warm-blooded animals (e.g. human etc.) safely by the oral or other route.
  • a pharmaceutically acceptable carrier e.g. as an injection, tablets, capsules, a liquid, an ointment, or a suppository etc.
  • warm-blooded animals e.g. human etc.
  • Injections can be prepared by using physiological saline or an aqueous solution of glucose or the like in the routine manner. Tablets, capsules, and other dosage forms can also be manufactured by the established corresponding pharmaceutical procedures.
  • an epitope peptide or epitope analogue of the present invention is administered to warm-blooded animals in the doses selected from the daily dose range of from about 0.01 ng to about 1000 mg/kg, preferably from about 0.1 ng to about 10 mg/kg, more preferable from about 1 ng to about 100 ⁇ g/kg, more preferably from about 10 ng to about 10 ⁇ g/kg, taking the route of administration, clinical symptoms, and other factors into consideration.
  • the epitope peptide of the present invention can be used for the diagnosis of autoimmune diseases inclusive of Sj ⁇ gren's syndrome. Specifically, by detecting and assaying autoantibodies to the ⁇ -fodrin or ⁇ -fodrin fragment protein in the blood of a warm-blooded animal, the diagnosis, disease staging, or prediction of onset of autoimmune disease, particularly Sj ⁇ gren's syndrome can be successfully accomplished.
  • the detection and assay of autoantibodies to ⁇ -fodrin and ⁇ -fodrin fragment protein can be made typically by the following method.
  • the epitope peptide of the present invention (hereinafter referred to collectively as antigen peptide) is coupled to a matrix such as cellulose beads in the routine manner. Then, the sample to be assayed is added and allowed to react at a given temperature
  • the assay method is, for example, as follows.
  • a sample to be assayed is added to an antigen peptide immobilized on a matrix to conduct an antigen-antibody reaction. Then, a conjugate of a label enzyme such as peroxidase with an antibody binding to the antibodies of the same species as that of the sample (enzyme-labeled antibody) is added and reacted.
  • a label enzyme such as peroxidase with an antibody binding to the antibodies of the same species as that of the sample (enzyme-labeled antibody) is added and reacted.
  • amino acids are designated with abbreviations, the abbreviations recommended by IUPAC-IUB Commission on Biochemical Nomenclature or those used commonly in the art are employed. Some examples are listed below. Any amino acid that may exist in an optically active form means an L- compound, unless otherwise indicated. alanine arginine aspartic acid cysteine glutamine glutamic acid glycine isoleucine : leucine lysine methionine proline serine : threonine valine
  • Amino acid sequence of human ⁇ -fodrin comprising amino acids 303 - 318, wherein the 308th gultamic acid is substituted by alanine .
  • Amino acid sequence of human ⁇ -fodrin comprising amino acids 301 - 320.
  • SEQ ID No: 5 Amino acid sequence of human ⁇ -fodrin comprising amino acids 301 - 320.
  • Amino acid sequence of human ⁇ -fodrin comprising amino acids 306 - 315. [SEQ ID No : 6]
  • Amino acid sequence of human ⁇ -fodrin comprising amino acids 303 - 318, wherein the 303rd aspartic acid is substituted by alanine.
  • Amino acid sequence of human ⁇ -fodrin comprising amino acids 303 - 318, wherein the 303rd aspartic acid is substituted by alanine.
  • Amino acid sequence of human ⁇ -fodrin comprising amino acids 303 - 318, wherein the 309th aspartic acid is substituted by alanine .
  • Amino acid sequence of human ⁇ -fodrin comprising amino acids 303 - 318, wherein the 312th lysine is substituted by alanine.
  • Amino acid sequence of human ⁇ -fodrin comprising amino acids 303 - 318, wherein the 314th leucine is substituted by alanine.
  • Example 1 Identification of the pathogenic T cell epitope (1) To determine the autoreactive T cell peptide epitope which allows for the regulation of autoimmune response to ⁇ -fodrin in SS, a fused protein containing a partial fragment of human ⁇ - fodrin was prepared and examined for a proliferative responses of T-cell. Materials and Methods (1) Mice
  • NFS/ si d mice develop Sj ⁇ gren's syndrome in 4-20 weeks after operation. Moreover, the symptoms observed then are known to well reflect the manifestations of primary Sj ⁇ gren's syndrome.
  • NFS/N strains carrying the mutant gene sld (Hayashi et al., Am. J. Pathol . , 132, 187-191 (1988)) were reared in specific pathogen-free mouse colony. Thy ectomy was performed on day 3 after birth (3d-Tx) in NFS/ sld mice.
  • the DNAs coding for human ⁇ -fodrin protein and fragment thereof are known [Journal of Biological Chemistry, 265, 4427- 4433 (1990)).
  • a human ⁇ -fodrin fragment was produced using JS-1 cDNA (1-1784 bp) , 2.7A cDNA (2258-4884 bp) and 3'DA cDNA (3963- 7083 bp) .
  • the JS-1 cDNA, the 2.7A cDNA and the 3'DA cDNA were completely digested with the restriction enzyme EcoRI and each ligated to the EcoRI site of E. coli pGEX-4Ts vector (Pharmacia) . According to the manufacturer' s instructions for this vector, the vector was introduced into E.
  • GST glutathione S-transferase
  • ⁇ -fodrin fragment protein was harvested. According to the instructions, this fusion protein was digested with thrombin and the ⁇ -fodrin fragment protein was isolated and purified independently of glutathione S-transferase.
  • SSCP single-strand conformation polymorphisms
  • LNCs (5xl0 5 /ml) were cultured with JS-1, 2.7A, 3'DA, or GST recombinant proteins at a concentration of 5 ⁇ g/ml for 4 days in RPMI 1640 with 1 U/ml of recombinant IL-2 and 10% FCS.
  • Total RNA was prepared with Isogen (Nippon Gene, Co., Tokyo) .
  • cDNA synthesis and PCR were carried out using method as described (Furukawa et al., Br. J. Rheumatol . , 35, 1223-1230 (1996)).
  • Amplification was performed with Taq polymerase with 5' primer specific for TCRV ⁇ 6 and V ⁇ 8 genes and 3' primer specific for TCR C ⁇ gene (Furukawa et al., (1996), supra) .
  • Amplified DNA was diluted at 1:20 in a denaturing solution and held at 90 °C for 2 min.
  • the diluted sample (2 ⁇ l) was electrophoresed in non- denaturing 5% polyacrylamide gels containing 10% glycerol. The gel was run at 35W constant power for 2 hrs.
  • LNCs regional lymph node cells
  • JS-1, 2.7A, and 3'DA recombinant ⁇ - fodrin fusion protein
  • 430A peptide synthesizer (Applied Biosystems, Foster City, CA) .
  • the peptides were purified by reverse-phase HPLC, and all peptides were analyzed for purity by mass spectrometry.
  • LNCs The ability of LNCs to respond peptide was assessed by interleukin-2 (IL-2), interferon- ⁇ (IFN- ⁇ ) , and IL-4 production, as detected by sandwich ELISA (Haneji et al., (1997), supra; Yanagi et al., (1998), supra) .
  • IL-2 interleukin-2
  • IFN- ⁇ interferon- ⁇
  • IL-4 sandwich ELISA
  • N-terminal portion of ⁇ -fodrin p21 is an important T cell epitope, accounting for the increased concentration of Thl cytokines in these cultures.
  • Peptides were further tested for their ability to initiate a proliferative response and cytokine production, indicating that an appropriate T cell epitope peptide capable of inducing SS lesions is a peptide p21-16 [AFN 303 - 318 , SEQ ID No:l] or p21-14 [AFN 304 - 317 , SEQ ID No: 2] (see Table 1) .
  • ⁇ p21-16 a modified p21 containing 16 amino acids, which is prepared by truncating 2 amino acids each from the N terminal and C terminal of p21 peptide
  • p21-14 a modified p21 containing 14 amino acids, which is prepared by truncating 3 amino acids each from the N terminal and C terminal of p21 peptide.
  • LNCs from 3d-Tx NFS/sld mice (5-week-old) were cultured with ⁇ -fodrin peptides (10 ⁇ g/ml) in RPMI 1640 supplemented with 10% fetal calf serum (FCS) , 10 mM HEPES and lOOU/100 ⁇ g per ml penicillin/streptomycin in 96-well plates at lxlO 6 cells/well.
  • FCS fetal calf serum
  • IL-2 Gibzyme Diagnostics, Cambridge, MA
  • an aliquot was analyzed for reactivity to ⁇ - fodrin peptides.
  • LDA limiting dilution analysis
  • T cell lines from p21-stimulated LNCs, but not from p31- and p32-stimulated cells.
  • the majority of these autoreactive T cells were CD4+ T cells bearing V ⁇ 6 containing Thl cytokines such as IL-2 and IFN- ⁇ , but not IL-4.
  • the TCRV ⁇ usage and third complementary determining regions (CDR3) sequence of three T cell lines were determined by RT-PCR amplification and sequencing of the PCR products (Sanger et al., Proc. Natl . Acad. Sci . , 74, 5463-5467 (1977)).
  • each line was transferred intraperitoneally (i.p.) into irradiated (20 Gy) non-Tx NFS/sld mice at 4 weeks.
  • Organ-specific autoimmune lesions in the salivary and lacrimal glands developed at 8 and 12 weeks after the i.p. injection in all mice, and tissue-infiltrating lymphocytes were positive for CD4 and V ⁇ 6.
  • the inflammatory lesions in the salivary and lacrimal glands were associated with "sicca syndrome" showing decreased secretion of saliva and tear (Saito et al., (1999), supra) .
  • Example 4 Alanine scanning mutagenesis and Class II binding studies
  • the peptide-MHC-binding assay was modified from the protocol previously described (Wauben et al., J. Immunol . , 152, 4211-4220 (1994)).
  • the relative affinity of peptide was determined using class II (I-A q ) + spleen cells from NFS/sld mouse.
  • I-A q+ cells (lxloVwell) were incubated at 37°C for 24 hrs in 96- well microtiter plates in a total volume of 100 ⁇ l culture medium containing 700 pg/ml of IFN- ⁇ .
  • Example 5 Analogue peptide-based therapy
  • IFN- ⁇ -stimulated MSG cells (Wahren-Herienius et al., (1999), supra) were fixed with 1% paraformaldehyde, and were incubated with mAb to I-A q molecule (PharMingen) , and FITC-labeled AF30 3 - 31 8 peptide.
  • the labeled second antibody was Texas Red-conjugated goat anti-mouse IgG (molecular probes, Eugene OR) .
  • a LEICA TCSNT laser scanning microscope Nussloch, Germany

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Abstract

La présente invention concerne un polypeptide constitué d'une séquence partielle d'acides aminés de α-fodrine renfermant une séquence d'acides aminés décrite dans SEQ ID No:1, SEQ ID No:2 ou SEQ ID No:4, son mutant, et en particulier un analogue épitope analogue contenant une séquence décrite dans SEQ ID No:3, ainsi que leur utilisation.
PCT/JP2001/008221 2001-06-22 2001-09-21 Nouveau peptide et son utilisation WO2003000718A2 (fr)

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AU2001288087A AU2001288087A1 (en) 2001-06-22 2001-09-21 Polypeptides comprising t cell epitopes from alpha-fodrin and the uses thereof in treatment of sjogren's syndrome

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AUPR5897A AUPR589701A0 (en) 2001-06-22 2001-06-22 Novel peptide and use thereof

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100572391C (zh) * 2006-08-30 2009-12-23 中国科学院广州生物医药与健康研究院 β-胞衬蛋白抗原表位多肽及其筛选方法与应用

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JPH10251157A (ja) * 1996-04-23 1998-09-22 Yoshio Hayashi α−フォドリンまたはα−フォドリン断片蛋白質を含む剤
CA2188816C (fr) * 1996-04-23 2009-09-22 Takeda Chemical Industries, Ltd. Composition renfermant de l'o-fodrine ou un fragment proteinique d'o-fodrine

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Title
DATABASE WPI Section Ch, Week 199820 Derwent Publications Ltd., London, GB; Class B04, AN 1998-217935 XP002223821 -& CA 2 188 816 A (HAYASHI Y), 23 October 1997 (1997-10-23) *
HANEJI N ET AL: "Identification of alpha-fodrin as a candidate autoantigen in primary Sjögren's syndrome." SCIENCE. UNITED STATES 25 APR 1997, vol. 276, no. 5312, 25 April 1997 (1997-04-25), pages 604-607, XP002223818 ISSN: 0036-8075 *
ISHIMARU N ET AL: "Severe destructive autoimmune lesions with aging in murine Sjögren's syndrome through Fas-mediated apoptosis." AMERICAN JOURNAL OF PATHOLOGY. UNITED STATES MAY 2000, vol. 156, no. 5, May 2000 (2000-05), pages 1557-1564, XP002223819 ISSN: 0002-9440 *
PATENT ABSTRACTS OF JAPAN vol. 1998, no. 14, 31 December 1998 (1998-12-31) -& JP 10 251157 A (HAYASHI YOSHIO;TAKEDA CHEM IND LTD), 22 September 1998 (1998-09-22) *
SAEGUSA K ET AL: "Mechanisms of neonatal tolerance induced in an animal model for primary Sjögren's syndrome by intravenous administration of autoantigen." SCANDINAVIAN JOURNAL OF IMMUNOLOGY. ENGLAND SEP 2000, vol. 52, no. 3, September 2000 (2000-09), pages 264-270, XP002223820 ISSN: 0300-9475 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100572391C (zh) * 2006-08-30 2009-12-23 中国科学院广州生物医药与健康研究院 β-胞衬蛋白抗原表位多肽及其筛选方法与应用

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