WO2004007682A2 - Methods and compositions for modulating t helper (th) cell development and function - Google Patents

Methods and compositions for modulating t helper (th) cell development and function Download PDF

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Publication number
WO2004007682A2
WO2004007682A2 PCT/US2003/021975 US0321975W WO2004007682A2 WO 2004007682 A2 WO2004007682 A2 WO 2004007682A2 US 0321975 W US0321975 W US 0321975W WO 2004007682 A2 WO2004007682 A2 WO 2004007682A2
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WIPO (PCT)
Prior art keywords
cell
cell population
cells
thp
thl
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PCT/US2003/021975
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English (en)
French (fr)
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WO2004007682A3 (en
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Michael Grusby
Andrea Wurster
Deborah A. Young
Mary Collins
Matthew J. Whitters
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Wyeth LLC
Harvard University
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Wyeth LLC
Harvard University
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Priority to MXPA05000655A priority Critical patent/MXPA05000655A/es
Priority to CA002491320A priority patent/CA2491320A1/en
Priority to JP2004521793A priority patent/JP4776228B2/ja
Priority to EP03764624A priority patent/EP1553982A4/en
Priority to BRPI0312738-9A priority patent/BR0312738A/pt
Priority to AU2003251900A priority patent/AU2003251900B2/en
Priority to EA200500206A priority patent/EA011686B1/ru
Application filed by Wyeth LLC, Harvard University filed Critical Wyeth LLC
Publication of WO2004007682A2 publication Critical patent/WO2004007682A2/en
Priority to IL16599004A priority patent/IL165990A0/xx
Publication of WO2004007682A3 publication Critical patent/WO2004007682A3/en
Anticipated expiration legal-status Critical
Priority to NO20050717A priority patent/NO20050717L/no
Priority to IL195769A priority patent/IL195769A0/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • 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
    • C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • C07K14/7155—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for interleukins [IL]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0636—T lymphocytes
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • 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
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/20—Cytokines; Chemokines
    • C12N2501/23—Interleukins [IL]

Definitions

  • the contacting step is carried out ex vivo, in vitro or in vivo.
  • the contacting step can be carried out in a mammalian subject, for example, the mammalian subject is a human.
  • FIG. 1 A is a representation of a Northern blot hybridization analysis examining expression of IL-21, IL-4, IFN ⁇ , and ⁇ actin under the various Thl and Th2 skewing conditions described in the appended Examples.
  • FIG. IB is a histogram showing the level of IL-21 mRNA relative to GAPDH mRNA in Thl and Th2 cells following primary and secondary stimulation.
  • FIG. IC is a histogram showing the level of IL-21 mRNA relative to GAPDH mRNA in primary and secondary Thl and Th2 cells cultured in the presence or absence of LL-4 and IFN ⁇ .
  • FIG. ID is a histogram showing the level of IL-21 mRNA, EL-4 mRNA, and IFN ⁇ mRNA relative to GAPDH mRNA in C57BL/g and BALB/c mice following infection with L. major.
  • FIG. 2 A is a graphic representation of IL-4 and IL-21 cytokine production in Thp cells cultured under neutral conditions, or Thl skewing conditions.
  • FIG. 2B is a histogram showing IFN ⁇ production in IL-21 treated or mock treated Thp cells.
  • FIG. 3 A is a graphic representation of IL-4 and IFN ⁇ production in Thp cells cultured under Thl skewing conditions in the presence or absence of EL-22.
  • FIG. 3B is a graphic representation of IL-4 and IFN ⁇ production in LL-21 treated or mock treated Thp cells treated in Thl skewing conditions from wild-type and Stat ⁇ -/- mice.
  • FIG. 3C is a graphic representation of IFN ⁇ , IL-2, and TNF ⁇ expression in IL-21 treated or mock treated Thl cells from wild-type and Stat ⁇ -/- mice.
  • FIG. 4A is a representation of a western blot analysis of T-bet and actin protein levels in Thp cells cultured under Thl or Th2 skewing conditions.
  • FIG. 4B is a histogram showing relative levels of IL-12R ⁇ 2 mRNA relative to levels in Thl cells.
  • FIG. 4C is a representation of a western blot analysis of phosphorylated Stat4, Stat4, Statl, and IL-12 polypeptide levels in Thp cells stimulated with anti-CD3 in the presence of LL- 21 or mock supernatants.
  • FIG. 4D is a histogram showing levels of Stat4 mRNA relative to GAPDH mRNA in mock treated and IL-21 Thp cells stimulated with anti-CD3 for 48 hours in the presence of IL-21 or mock supernatants.
  • IL-4 mRNA and IFN ⁇ are examples
  • FIG. 5 A is a graph showing specific swelling in TNP-KLH-immunized wild type and IL21-21R-/- mice subsequently injected with TNP-KLH or PBS.
  • FIG.5B is a histogram showing LFN ⁇ production in CD4+ T cells purified from draining lymph nodes of TNP-KLH-immunized wild type and IL21-21R-/- mice restimulated by antigen.
  • the invention provides methods and compositions for modulating T helper cell differentiation, development and activity by modulating the interaction between IL-21 and an IL- 21 receptor.
  • LL-21 or agents that increase IL-21 or IL-21 receptor levels in a cell population, are added to a population of T helper cells to suppress FN ⁇ levels in a population of Thp or Thl cells.
  • IL-21, or agents that increase IL-21 levels can also be used to promote Th2 development, or to potentiate Th2-mediated immune responses and/or to suppress Thl development.
  • a method for modulating one or more of: IFN ⁇ activity, expression, secretion, or processing, in a T cell e.g., a T cell precursor cell (a Thp cell), or a Thl cell (e.g., a differentiating Thl cell or an effector Th cell), or a T cell population thereof, is provided.
  • a T cell e.g., a T cell precursor cell (a Thp cell), or a Thl cell (e.g., a differentiating Thl cell or an effector Th cell), or a T cell population thereof.
  • the method includes:
  • the subject method can be used on cells in culture, e.g. in vitro or ex vivo.
  • immune cells e.g., T cells as described herein
  • the contacting step can be effected by adding one or more LL-21 modulators (e.g., an IL-21 agonist or antagonist), to the culture medium.
  • the method is performed on cells (e.g., immune or T cells as described herein) present in a subject, e.g., as part of an in vivo (e.g., therapeutic or prophylactic) protocol.
  • a method for reducing or inhibiting the activity or level of IFN ⁇ in a cell e.g., a T cell (e.g., a T cell precursor cell (a Thp cell), or a Thl cell (e.g., a differentiating Thl cell or an effector Th cell)), or a cell population thereof is provided.
  • the method includes (optionally) identifying a cell, e.g., a T cell, or a cell population, e.g., a T cell population, in which reduction or inhibition of the activity or level of IFN ⁇ is desired; and contacting said cell or cell population with an amount of an IL-21 agonist, sufficient to reduce or inhibit the activity or level of IFN ⁇ in said cell or cell population.
  • the 11-21 agonist specifically inhibits IFN ⁇ levels or activity, e.g., it does not reduce or inhibit the activity or level of other cytokines such IL-2 or TNF ⁇ .
  • the IL-21 agonist inhibits production of IFN ⁇ by an IFN ⁇ -producing cell, e.g., an IFN ⁇ -producing Thl cell.
  • the invention provides a method for reducing IFN ⁇ levels or activity in a subject. The method includes (optionally) identifying a subject in which reduction of IFN ⁇ levels or activity is desired; and administering to said subject an amount of an EL-21 agonist sufficient to reduce the levels or activity IFN ⁇ .
  • IFN ⁇ can be measured using techniques known in the art, for example, intracellular cytokine staining, or an ELISA technique to determine levels in cell supernatants.
  • the IL-21 agonist can be an IL-21 polypeptide, a human LL-21 polypeptide, or an active fragment thereof (e.g., a human IL-21 polypeptide comprising the amino acid sequence shown as SEQ ID NO:2, or encoded by a nucleotide sequence shown as SEQ ID NO: 1, or a sequence substantially homologous thereto).
  • the IL-21 agonist is a fusion protein comprising an IL-21 polypeptide, e.g., human IL-21 polypeptide, or a fragment thereof fused to another polypeptide, e.g., an immunoglobulin polypeptide or a portion thereof (e.g., an Fc region of an immunoglobulin polypeptide); an agonist antibody to the IL-21 receptor; or a small molecule agonist.
  • the IL-21 agonist is an agent that increases the activity or level of IL-21 by, e.g., increasing expression, processing and or secretion of functional IL-21.
  • the invention additionally features a method of increasing IFN ⁇ levels or activity in a cell, e.g., a T-cell, or a cell population, e.g., a T cell population.
  • a cell e.g., a T-cell
  • a cell population e.g., a T cell population.
  • the invention includes method for increasing EFN ⁇ activity, expression, secretion, or processing, in a T cell, e.g., a T cell precursor cell (a Thp cell), or a Thl cell (e.g., a differentiating Thl cell or an effector Th cell), or a T cell population thereof.
  • a T cell precursor cell e.g., a Thp cell
  • Thl cell e.g., a differentiating Thl cell or an effector Th cell
  • the IL-21 antagonist can be, e.g., an antibody (e.g., a monoclonal or single specificity antibody) to IL-21, e.g., human LL-21, or an LL-21 receptor, e.g., human IL-21 receptor polypeptide.
  • the antibody is a human, humanized, chimeric, or in vitro generated antibody to human IL-21 or human IL-21 receptor polypeptide.
  • the antagonist includes a fragment of an IL-21 polypeptide, e.g., an IL-21 receptor binding domain of an IL-21 polypeptide.
  • the antagonist includes a fragment of an IL-21 receptor polypeptide, e.g., an IL-21 binding domain of an IL-21 receptor polypeptide.
  • the antagonist is a fusion protein comprising the aforesaid LL-21 or 11-21 receptor polypeptides or fragments thereof fused to a second moiety, e.g., a polypeptide (e.g., an immunoglobulin chain).
  • a method of increasing Th2 cell activity and/or cell number is provided.
  • the method includes (optionally) identifying a cell, e.g., a T cell (e.g., a Thp or a Th2 cell), or a cell population, where increased proliferation, survival and/or differentiation is desired; and contacting said cell or cell population with an IL-21 agonist in an amount sufficient to increase one or more of proliferation, survival and/or differentiation into, (e.g., increase differentiation of said Thp cell into a Th2 cell) a Th2 cell, thereby increasing Th2 cell activity and/or cell number.
  • a cell e.g., a T cell (e.g., a Thp or a Th2 cell)
  • an IL-21 agonist in an amount sufficient to increase one or more of proliferation, survival and/or differentiation into, (e.g., increase differentiation of said Thp cell into a Th2 cell) a Th2 cell, thereby increasing Th2 cell activity and/or cell number.
  • the IL-21 agonist is a fusion protein comprising an IL-21 polypeptide, e.g., human IL-21 polypeptide, or a fragment thereof fused to another polypeptide, e.g., an immunoglobulin polypeptide or a portion thereof (e.g., an Fc region of an immunoglobulin polypeptide); an agonist antibody to the LL-21 receptor; or a small molecule agonist.
  • an IL-21 polypeptide e.g., human IL-21 polypeptide, or a fragment thereof fused to another polypeptide, e.g., an immunoglobulin polypeptide or a portion thereof (e.g., an Fc region of an immunoglobulin polypeptide); an agonist antibody to the LL-21 receptor; or a small molecule agonist.
  • a method for modulating e.g., increasing or decreasing, Thl cell number and/or activity is provided.
  • a method of modulating, e.g., promoting or inhibiting, one or more of proliferation, survival and/or differentiation into e.g., differentiation of a T cell precursor, e.g., a Th precursor (Thp), into
  • a Thl cell e.g., differentiation of a T cell precursor, e.g., a Th precursor (Thp), into
  • immune cells e.g., T cells as described herein
  • the contacting step can be effected by adding one or more IL-21 modulators (e.g., an IL-21 agonist or antagonist), to the culture medium.
  • the method can be performed on cells (e.g., immune or T cells as described herein) present in a subject, e.g., as part of an in vivo (e.g., therapeutic or prophylactic) protocol.
  • Thl cell activity and/or cell number can be increased by increasing one or more of proliferation, survival and/or differentiation into (e.g., differentiation of a T cell precursor, e.g., a Th precursor (Thp), into), a Thl cell.
  • the method includes:
  • identifying a cell e.g., a T cell (e.g., a Thp or a Thl cell), or a cell population, where increased proliferation, survival and/or differentiation is desired; and contacting said cell or cell population with an IL-21 antagonist in an amount sufficient to increase one or more of proliferation, survival and/or differentiation into, (e.g., increase differentiation of said Thp cell into a Thl cell) a Thl cell, thereby increasing Thl cell activity and/or cell number.
  • a T cell e.g., a Thp or a Thl cell
  • an IL-21 antagonist in an amount sufficient to increase one or more of proliferation, survival and/or differentiation into, (e.g., increase differentiation of said Thp cell into a Thl cell) a Thl cell, thereby increasing Thl cell activity and/or cell number.
  • the clones can be subcloned by limiting dilution procedures and grown by standard methods. Suitable culture media for this purpose include, for example, Dulbecco's Modified Eagle's Medium and RPMI-1640 medium. Alternatively, the hybridoma cells can be grown in vivo as ascites in a mammal.
  • the monoclonal antibodies secreted by the subclones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxyapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.
  • Fully human antibodies relate to antibody molecules in which essentially the entire sequences of both the light chain and the heavy chain, including the CDRs, arise from human genes. Such antibodies are termed "human antibodies", or “fully human antibodies” herein.
  • Human monoclonal antibodies can be prepared by the trioma technique; the human B-cell hybridoma technique (see Kozbor, et al. (1983) Immunol Today 4: 72) and the EBV hybridoma technique to produce human monoclonal antibodies (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96).
  • human antibodies can be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire.
  • transgenic animals e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated.
  • human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire.
  • This approach is described, for example, in U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in Marks et al. (Bio/Technology 10, 779-783 (1992)); Lonberg et al.
  • Example 5 IL-21 inhibition of IFN ⁇ is independent of Stat6.
  • RNA from na ⁇ ve Thp cells cultured under Thl and Th2 skewing conditions in the presence and absence of IL-21 was analyzed for 12R ⁇ 2 expression by RealTime PCR.
  • Thp cells were cultured under Th 1 or Th2 skewing conditions for one week.
  • IL-21 or mock supernatant was included in indicated cultures.
  • RNA was harvested 24 hours after secondary stimulation with anti-CD3 and assessed for LL-12R ⁇ 2 expression by RealTime PCR.

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PCT/US2003/021975 2002-07-15 2003-07-15 Methods and compositions for modulating t helper (th) cell development and function Ceased WO2004007682A2 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
EA200500206A EA011686B1 (ru) 2002-07-15 2003-07-15 Способ модуляции развития и функций т-клеток-хелперов
JP2004521793A JP4776228B2 (ja) 2002-07-15 2003-07-15 Ｔヘルパー（ｔｈ）細胞の発生および機能を調節するための方法および組成物
EP03764624A EP1553982A4 (en) 2002-07-15 2003-07-15 METHOD AND COMPOSITIONS FOR MODULATING THE DEVELOPMENT AND FUNCTION OF T-HELPER CELLS (T sb H / sb)
BRPI0312738-9A BR0312738A (pt) 2002-07-15 2003-07-15 processos e composições para a modulação do desenvolvimento e da função de células t auxiliares (th)
AU2003251900A AU2003251900B2 (en) 2002-07-15 2003-07-15 Methods and compositions for modulating T helper (Th) cell development and function
MXPA05000655A MXPA05000655A (es) 2002-07-15 2003-07-15 Metodos y composiciones para modular el desarrollo y la funcion de las celulas t helper (th).
CA002491320A CA2491320A1 (en) 2002-07-15 2003-07-15 Methods and compositions for modulating t helper (th) cell development and function
IL16599004A IL165990A0 (en) 2002-07-15 2004-12-26 Methods and compositions for modulating T helper (TH) cell development and function
NO20050717A NO20050717L (no) 2002-07-15 2005-02-10 Metode og sammensetninger for modulering av T hjelpe (TH) celleutvikling og funksjon
IL195769A IL195769A0 (en) 2002-07-15 2008-12-07 Methods and compositions for modulating t helper (th) cell development and function

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US39616002P 2002-07-15 2002-07-15
US60/396,160 2002-07-15
US40300102P 2002-08-12 2002-08-12
US60/403,001 2002-08-12

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WO2004007682A3 WO2004007682A3 (en) 2004-12-29

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US7731946B2 (en) 2010-06-08
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CN1688340A (zh) 2005-10-26
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