WO1999063084A1 - Sequences de recepteurs d'antigenes de lymphocytes t specifiques d'arthrosis deformans - Google Patents

Sequences de recepteurs d'antigenes de lymphocytes t specifiques d'arthrosis deformans Download PDF

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Publication number
WO1999063084A1
WO1999063084A1 PCT/JP1999/002814 JP9902814W WO9963084A1 WO 1999063084 A1 WO1999063084 A1 WO 1999063084A1 JP 9902814 W JP9902814 W JP 9902814W WO 9963084 A1 WO9963084 A1 WO 9963084A1
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WIPO (PCT)
Prior art keywords
gly
patient
osteoarthritis
amino acid
antigen
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Application number
PCT/JP1999/002814
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English (en)
Japanese (ja)
Inventor
Kusuki Nishioka
Shinichi Yoshino
Original Assignee
St. Marianna University School Of Medicine
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Application filed by St. Marianna University School Of Medicine filed Critical St. Marianna University School Of Medicine
Priority to AU40577/99A priority Critical patent/AU4057799A/en
Publication of WO1999063084A1 publication Critical patent/WO1999063084A1/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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/7051—T-cell receptor (TcR)-CD3 complex
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies

Definitions

  • the present invention relates to a substance useful for diagnosing, preventing and treating osteoarthritis. More specifically, the present invention relates to an amino acid sequence containing a CDR3 region of a T cell antigen receptor (TCR) chain of ⁇ cells present in synovial cells and / or synovial fluid of osteoarthritis patients.
  • TCR T cell antigen receptor
  • Osteoarthritis is a disease caused by aging or dysplasia of joints, preceding joint disease or trauma, and is particularly common in weight-bearing joints.
  • the cartilage matrix production decreases and the degeneration of the synovial fluid, which supplements the cartilage, becomes insufficient due to insufficient penetration of the synovial fluid into the cartilage matrix.
  • Articular cartilage is damaged by the mechanical load. Articular cartilage has poor self-healing capacity due to the absence of blood vessels, and once damage occurs, degenerative changes can easily develop.
  • various chemical mediators and cytokines are released from the destroyed chondrocytes and the like, and it has been thought that they cause chronic inflammation of the synovium (CI.
  • rheumatoid arthritis is classified as an autoimmune disease.
  • the immune system's response is a response that is originally triggered to destroy and eliminate foreign invaders, and is usually specific for non-self molecules (antigens). However, if for some reason the identification of self and non-self molecules is impaired, an autoimmune disease results.
  • rheumatoid arthritis rheumatic arthritis
  • abnormal proliferation of synovial tissue is observed.
  • accumulation of T cells is observed in the proliferated tissue.
  • T cells responsible for cellular immunity to recognize antigens, not only antigens but also antigen-presenting cells such as macrophages are required.
  • T cell antigen receptor recognizes the complex with the foreign antigen that has undergone immunization. ⁇ cells that have received an antigen signal from antigen presenting cells proliferate locally, release various cytokines, and develop inflammation.
  • the TCR is a heterodimer due to the disulfide bond of two polypeptide chains, ⁇ and ⁇ , or ⁇ and ⁇ , respectively.
  • ⁇ cell clones expressing a specific V region of TCR accumulate in the joints of patients with rheumatoid arthritis.
  • the mainstays of treatment for rheumatoid arthritis are non-steroidal anti-inflammatory drugs, immunomodulators, and steroid drugs.
  • Rheumatoid arthritis In patients with osteoarthritis, inflammation in synovial tissue is observed as in patients with rheumatoid arthritis, which is an autoimmune disease, but is weaker than in rheumatoid arthritis.
  • Rheumatoid arthritis is an autoimmune disease in which strong ⁇ ⁇ cells accumulate in the synovium and synovial fluid, but no ⁇ cells infiltrate into the synovium and synovial fluid in osteoarthritis.
  • immunocompetent cells such as CD4 and CD8 positive T cells, B cells, and monocytes Z macula phage infiltrate the synovial tissue
  • An object of the present invention is to provide a method for treating oligoarthritis present in the synovial membrane and synovial fluid, based on the idea that osteoarthritis, like rheumatoid arthritis, is based on chronic arthritis involving autoreactive T cells.
  • the purpose of the present invention is to clarify the accumulation and proliferation of null T cells, determine the amino acid sequence of the CDR3 region of the TCR, and provide a diagnostic, preventive and therapeutic agent for osteoarthritis.
  • the present inventors aimed to elucidate the ⁇ cells associated with the development of osteoarthritis, and investigated the TCR of pathogenic T cells oligoclonally proliferating in the synovial tissue of osteoarthritis patients.
  • the amino acid sequence containing the V] 3 chain CDR3 region was determined.
  • TCRV in the synovial tissue of patients with osteoarthritis, almost all TCRV from VjS1 to V
  • the CDR3 region of the TCR is said to be a site where the amino acid sequence is most different depending on individual T cells.
  • T cells having the amino acid sequence of the present invention in the CDR3 region of the TCRV chain are pathogenic ⁇ cells of osteoarthritis
  • the amino acid sequence of the present invention can be used as a tool for confirmatory diagnosis of osteoarthritis.
  • the treatment of osteoarthritis can be performed. It can greatly contribute to the development of diagnostic and prophylactic drugs.
  • the amino acid sequence of the present invention may be used for TCR protein, TCR DNA protein, activation of immunoregulatory cells or anti-TCR By using it to elicit antibodies, it can also be used for immunotherapy of osteoarthritis.
  • a peptide having homology to the peptide having the amino acid sequence of the present invention can produce T cells that cannot attack a patient's antigen and can block antigen-specific TCR by direct administration to a patient.
  • the antigen peptide or antigen protein which specifically reacts with the TCR having the amino acid sequence in the CDR3 region of the present invention is a therapeutic agent for osteoarthritis which induces antigen-specific immune tolerance and / or Useful as a prophylactic.
  • FIG. 1 is a photograph of an electrophoresis chromatogram showing the results of detecting samples obtained from peripheral venous blood and synovial membrane of a patient with human osteoarthritis by the SSCP method.
  • the partial sequence of the TCR involved in osteoarthritis has been elucidated, and the partial peptide involved in the recognition of osteoarthritis-related antigen using the sequence, DNA encoding the same, and By obtaining the DNA fragment and expressing it in a suitable host cell, it can be used for diagnosis of osteoarthritis. Diagnosis of osteoarthritis is based on clinical characteristics, but the amino acid sequence of the present invention is compared with the sequence of the TCRV
  • mRNA is removed from the body fluid of a patient suspected of having osteoarthritis, a cDNA library is created by RT-PCR, and each V] 3 chain subclass is expressed using a V] 3 chain probe.
  • the expressed T cell clone can also be observed by SSCP. Thereafter, the nucleotide sequence of the clonally expressed CDR3 portion of the TCRVj3 chain and the amino acid sequence derived therefrom are compared.
  • the body fluid here includes synovial fluid.
  • the antigen peptide can be used alone or in combination of two or more of these as a therapeutic or prophylactic agent for osteoarthritis.
  • These peptides can be used systemically, orally or topically in various commonly used dosage forms. Dosage form For example, oral preparations, injection preparations, nasal preparations and the like can be mentioned.
  • Preparations in these dosage forms can be prepared according to a conventional method, using commonly used carriers such as a vehicle, a binder, a solubilizer, an emulsifier, and a suspending agent.
  • the oral preparations include solid preparations such as tablets, granules and powders, and liquid preparations such as solutions, suspensions and emulsions.
  • the peptide of the present invention is not limited by genetic recombination, and generally employs a method as described in RB Merrifield, J. Am. Chem. Soc. 85, 2149 (1963). However, other equivalent known chemical synthetic methods can be used.
  • Peripheral blood of an osteoarthritis patient 1 Om1 was collected by adding heparin to blood, and lymphocytes were isolated by specific gravity centrifugation using Fico 11 P aque (Pharmacia Biotech). MRNA was extracted from the lymphocytes according to the kit of ISOGEN (Nitsubon Gene Co., Ltd.). That is, 1. Oml of IS1GEN was added to the lymphocyte pellet, mixed for 1 minute, and allowed to stand at room temperature for 5 minutes. Further, 0.2 ml of black-mouthed form was added, mixed for 15 seconds, and allowed to stand at room temperature for 2 minutes. Next, the mixture was centrifuged at 15,000 rpm at 4 ° C. for 15 minutes to obtain a supernatant.
  • Isopropanol 500 1 was added to the supernatant, and mixed several times by inversion. Incubate at room temperature for 5 minutes, 15,000 rpm, 4. The mixture was centrifuged at C for 10 minutes, and the obtained RNA pellet was washed with 75% ethanol.
  • the degree of purification and the concentration of the obtained RNA was confirmed by agarose gel.
  • cDNA was synthesized using mo lecule (Amersham). That is, TE buffer RNA pellet obtained in 1) (1 0 mM Tris-HCl buffer, 1 mM E DT A) 1 00 ⁇ 1 was added and dissolved, the RNA solution 1 0 y ul, 5 X Li carbonochloridate 1 ⁇ l of RNase inhibitor, 1 ⁇ l of RNase inhibitor, 2 ⁇ m of lNTPl, 2 ⁇ l of transcriptase reaction mixture, and 2 ⁇ l of oligo dT (An chored dT25 ) And reverse transcriptase 11 at 42 °. For 1 hour to obtain cDNA.
  • a DNA fragment encoding the TCRj 3 chain V region and a DNA fragment encoding the 3 chain C region were used as PCR primers. (Base sequences shown in Table 2) were synthesized using a DNA synthesizer manufactured by Applied Biosystems. (Choi.Y.eta1 and Proc.Natl.
  • VVO 331 ⁇ ⁇ V VOX 303 ⁇ ⁇ V VOV
  • V V3I VOV 131 310 1DV JLV ⁇ ⁇ V VOV 131 ⁇ - ⁇ ⁇ £ / ⁇ V ⁇ VV 9V3 3X3 I9V OVV 313 IIV VOV 131 zm i ⁇ ⁇ OL VV3 330 VII ⁇ ⁇ ⁇ VOO ⁇ ⁇ V VOV 131 2- ⁇ ⁇ m
  • the target CDR3 region was amplified with a primer of each family of the TCRV] 3 chain in Table 1 and a C ⁇ primer (1 st PCR).
  • the target CDR3 region was further amplified with primers of each family of the CRVJ3 chain in Table 2 and Cj3 primer (2nd PCR).
  • this cDNA was used in the presence of each V region primer in Table 1 and 50 pmo 1 of each of the C-region 5, terminal-end biotinylated primers, and 10 nmo 1 of each of the four types of deoxynucleotide triphosphates.
  • lO XT aq (thermostable DNA) polymerase buffer 50 OmM KC 1, l O OmM Tris-HCl,
  • the PCR product obtained above was subjected to the SSCP method (single-strand 'conformation. Polymorphism) (Ori t a Me t a 1.
  • the obtained PCR product is diluted 1:20 in a denaturing solution (95% formamide, 10 mM EDTA, 0.1% bromophenol blue, 0.1% xylene cyanol), and is then diluted to 90 ° C for 2 minutes. It was left still.
  • a denaturing solution 95% formamide, 10 mM EDTA, 0.1% bromophenol blue, 0.1% xylene cyanol
  • Synovial tissue which is a joint lesion of a patient with osteoarthritis, was taken, placed in 1 ml of ISOGEN, and homogenized, and then RNA was isolated in the same manner as 1) in Example].
  • RNA obtained in 1) above was detected according to 2) to 5) of Example 1.
  • the results are shown in FIG. As is clear from the figure, in the synovium of the local knee, several bands were detected in all V / 3 chain repertoires from V ⁇ 1 force to V ⁇ 20, and oligo-specific ⁇ It became clear that the cells had accumulated.
  • the sequence can be determined by analyzing the mRNA extracted from the synovial tissue of Example 2 as type II using the RT-PCR method using the entire cellular RNA.
  • Total cellular RNA is isolated from peripheral blood or synovial tissue as described in the manual (ISOGEN, Nippon Gene).
  • the single-stranded cDNA is reverse-transcribed using a cDNA synthesis kit (cDNA Synthes ismodel, Amersham).
  • the TCRV 3 gene segment is amplified by PCR using the primers shown in Table 1 above.
  • sequence is determined by using SequencIngReadyReaction-2 1M1 3, PEApPli (EdBiosystems). (Array No .:! ⁇ 376)
  • the amino acid sequence of the present invention is used as a tool for confirmatory diagnosis of osteoarthritis. be able to. Furthermore, since it is possible to isolate and identify an antigen that the TCR specifically recognizes using a cell having the amino acid sequence of the present invention in the CDR3 region of the TCR V 3 chain, osteoarthritis Can greatly contribute to the development of therapeutic, diagnostic and prophylactic drugs.
  • the amino acid sequence of the present invention can also be used for immunotherapy of osteoarthritis by using it for TCR cutination, activation of immune control cells or induction of anti-TCR antibodies.
  • the peptide having homology to the peptide having the amino acid sequence of the present invention can create cells that cannot attack the antigen of the patient and can block the antigen-specific TCR by direct administration to the patient. It is. Further, an antigen peptide or antigen protein to which TCR having the amino acid sequence of the present invention in the CDR3 region specifically reacts is a therapeutic and / or prophylactic agent for osteoarthritis that induces antigen-specific immune tolerance. Useful as

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
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Abstract

L'invention concerne des séquences d'acides aminés de la région CDR3 chaîne Vβ d'un récepteur d'antigènes de lymphocytes T pathogènes oligoclonaux, accumulées et proliférant dans les membranes synoviales articulaires des patients souffrant d'Arthrosis deformans. L'utilisation de ces séquences d'acides aminés permet de diagnostiquer Arthrosis deformans. En outre, les peptides d'antigènes de soi ou leurs dérivés auxquels se lient spécifiquement les lymphocytes T contenant ces séquences d'acides aminés et les protéines d'antigènes de soi dont proviennent ces peptides d'antigènes de soi peuvent servir de médicament pour le traitement ou la prévention, capables d'induire une tolérance immunologique spécifique d'antigènes vis-à-vis d'Arthrosis deformans.
PCT/JP1999/002814 1998-05-29 1999-05-28 Sequences de recepteurs d'antigenes de lymphocytes t specifiques d'arthrosis deformans WO1999063084A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU40577/99A AU4057799A (en) 1998-05-29 1999-05-28 T cell antigen receptor sequences specific to arthrosis deformans

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP10/149855 1998-05-29
JP14985598 1998-05-29
JP10/328761 1998-10-14
JP32876198 1998-10-14

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003020751A2 (fr) * 2001-09-05 2003-03-13 King's College London Peptides d'accueil
JP2013510863A (ja) * 2009-11-10 2013-03-28 アレグロ ファーマシューティカルズ インコーポレイテッド 細胞接着を阻害するため、またはｒｇｄ結合部位に診断用薬もしくは治療薬を送達するための組成物および方法
US9896480B2 (en) 2009-11-10 2018-02-20 Allegro Pharmaceuticals, Inc. Integrin receptor antagonists and their methods of use
US11673914B2 (en) 2009-11-10 2023-06-13 Allegro Pharmaceuticals, LLC Peptide therapies for reduction of macular thickening

Non-Patent Citations (9)

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EPPLEN C, ET AL.: "IMMUNOPRINTING REVEALS DIFFERENT GENETIC BASES FOR (AUTO)IMMUNE DISEASES", ELECTROPHORESIS, WILEY INTERSCIENCE, DE, vol. 16, no. 09, 1 January 1995 (1995-01-01), DE, pages 1693 - 1697, XP002926586, ISSN: 0173-0835, DOI: 10.1002/elps.11501601281 *
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KIEBER-EMMONS T, ET AL.: "STRUCTURAL MOTIFS IN RHEUMATOID T-CELL RECEPTORS", DNA AND CELL BIOLOGY, MARY ANN LIEBERT, NEW YORK, NY, US, vol. 17, no. 02, 1 January 1998 (1998-01-01), US, pages 133 - 149, XP002926583, ISSN: 1044-5498 *
KIYOSHI TAKATSU, "Men'ekibyou no Bunshi Kikou to Sono Shuufuku", MOMBUSHOU KAGAKU KENKYUUJI HOJOKIN JUUTEN RYOUIKI KENKYUU HEISEI 9 NENDO KENKYUU SEIKA HOUKOKUSHO, (03-98), pages 120-121, XP002926581 *
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ZWILLICH S H, ET AL.: "V ALPHA GENE USAGE IN RHEUMATOID COMPARED WITH OSTEOARTHRITIC SYNOVIAL TISSUE T CELLS", DNA AND CELL BIOLOGY, MARY ANN LIEBERT, NEW YORK, NY, US, vol. 13, no. 09, 1 January 1994 (1994-01-01), US, pages 923 - 931, XP002926584, ISSN: 1044-5498 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003020751A2 (fr) * 2001-09-05 2003-03-13 King's College London Peptides d'accueil
WO2003020751A3 (fr) * 2001-09-05 2003-08-21 King S College London Peptides d'accueil
JP2013510863A (ja) * 2009-11-10 2013-03-28 アレグロ ファーマシューティカルズ インコーポレイテッド 細胞接着を阻害するため、またはｒｇｄ結合部位に診断用薬もしくは治療薬を送達するための組成物および方法
US9872886B2 (en) 2009-11-10 2018-01-23 Allegro Pharmaceuticals, Inc. Compositions and methods for inhibiting cellular adhesion or directing diagnostic or therapeutic agents to RGD binding sites
US9896480B2 (en) 2009-11-10 2018-02-20 Allegro Pharmaceuticals, Inc. Integrin receptor antagonists and their methods of use
US10307460B2 (en) 2009-11-10 2019-06-04 Allegro Pharmaceuticals, LLC Compositions and methods for inhibiting cellular adhesion or directing diagnostic or therapeutic agents to RGD binding sites
US10590166B2 (en) 2009-11-10 2020-03-17 Allegro Pharmaceuticals, LLC Peptides useable for treating cancer
US10639347B2 (en) 2009-11-10 2020-05-05 Allegro Pharmaceuticals, LLC Peptides useable for treatment of disorders of the eye
US11666625B2 (en) 2009-11-10 2023-06-06 Allegro Pharmaceuticals, LLC Pharmaceutical compositions and preparations for administration to the eye
US11673914B2 (en) 2009-11-10 2023-06-13 Allegro Pharmaceuticals, LLC Peptide therapies for reduction of macular thickening

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