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WO1990008161A1 - Modulation par peptides mediateurs de la reconnaissance d'antigenes par les lymphocytes t, utilises comme moyens d'affectation de reactions immunitaires - Google Patents

Modulation par peptides mediateurs de la reconnaissance d'antigenes par les lymphocytes t, utilises comme moyens d'affectation de reactions immunitaires Download PDF

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Publication number
WO1990008161A1
WO1990008161A1 PCT/US1990/000085 US9000085W WO9008161A1 WO 1990008161 A1 WO1990008161 A1 WO 1990008161A1 US 9000085 W US9000085 W US 9000085W WO 9008161 A1 WO9008161 A1 WO 9008161A1
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WIPO (PCT)
Prior art keywords
peptide
lys
leu
thr
replacing
Prior art date
Application number
PCT/US1990/000085
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English (en)
Inventor
David D. ECKELS
Jack Gorski
Jonathan R. Lamb
Jonathan Rothbard
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The Blood Center Of Southeastern Wisconsin
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Publication date
Application filed by The Blood Center Of Southeastern Wisconsin filed Critical The Blood Center Of Southeastern Wisconsin
Priority to KR1019900702013A priority Critical patent/KR910700259A/ko
Publication of WO1990008161A1 publication Critical patent/WO1990008161A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • 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
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • the responsiveness of the cellular immune system is determined by an array of highly polymorphic, so-called
  • class II molecules encoded by genes comprising the major histocompatibility complex (MHC) expressed in the membranes of macrophages and other antigen-presenting cells (APCs) , B-lymphocytes (B cells) , monocytes and some T-lymphocytes (T cells) .
  • MHC major histocompatibility complex
  • Class II MHC molecules are transmembrane glycoproteins of APCs that bind peptide fragments of foreign proteins so that they can be presented to CD4 + (helper) T cells. Receptors on the surface of a CD4 + T cell thus form ternary complexes with the class II molecule and the peptide fragment. This leads, in turn, to the activation of the T cells and the subsequent development of an immune response.
  • a given T cell is specific for a peptide and is MHC- restricted as well, in the sense that the T cell recognizes the peptide only when the latter is bound to a particular class II molecule.
  • Class II MHC molecules are therefore directly involved in mediating the immune response of mammals, for example, in the context of transplant rejection (since it is the binding of an antigen of the allograft by a class II molecule that can initiate such rejection) and of reactions to an environmental allergen.
  • Class II molecules are also thought to play a role in the etiology of "autoimmune" diseases, like rheumatoid arthritis, ankylosing spondylitis, pemphigus vulgaris, insulin-dependent diabetes mellitus and multiple sclerosis, in which the body's immune system attacks self protein antigens.
  • autoimmune diseases
  • Mixed results have attended past efforts to develop ways of alleviating the respective effects of transplant rejection and various autoimmune disorders.
  • the use of different immunity-suppressing agents such as cyclosporin, the corticosteroids and other cytotoxic drugs, suffers the drawback of nonspecificity, i.e., the agent is typically toxic to other systems and may place a patient at risk of cancer and other disorders.
  • a method for affecting immune responses in a mammalian subject comprising the step of administering to the subject a replacing peptide capable of occupying an MHC binding site in lieu of an endogenous peptide, wherein the replacing peptide is administered to the subject in an amount sufficient to modulate T-cell recognition of an MHC class II molecule:endogenous peptide complex.
  • the replacing peptide is a derivative of influenza virus hemagglutinin protein.
  • a pharmaceutical composition for affecting immune responses in a mammalian subject comprising an amount of a replacing peptide capable of occupying an MHC binding site in lieu of an endogenous peptide, wherein the amount of the replacing peptide is effective to modulate T-cell recognition of an MHC class II molecule:endogenous peptide complex.
  • a therapeutic amount of such a replacing peptide in the manufacture of a medicament for use in a method for affecting immune responses in a mammalian subject, that method being characterized by an administration to the subject of an amount of the replacing peptide sufficient to modulate T-cell recognition of an MHC class II molecule:endogenous peptide complex.
  • Figure 1 is a graphical representation of peptide- mediated modulation of alloreactive T-cell clones, pursuant to the present invention.
  • HLA-DRl-specific, alloreactive T- cell clones were stimulated with varying concentrations of irradiated, DR1 + lymphoblastoid "stimulator" cells that had been pre-incubated with a synthetic peptide derived from influenza virus hemagglutinin protein.
  • Negative controls consisted of lymphoblastoid cells alone and clone alone in tissue culture medium supplemented with 10% pooled human plasma. After a 48-hour incubation period, each microwell was pulsed overnight with 1.0 ⁇ Ci 3 HTdR (specific activity 6.7 Ci/mM) . Radiolabel incorporation was measured by liquid scintillation spectroscopy and expressed as the mean counts per minute (CPM) of triplicate cultures.
  • CPM mean counts per minute
  • Figure 2 is a series of bar graphs illustrating the relative capacity of a number of synthetic peptides, in accordance with the present invention, to inhibit (2a) and enhance (2b) T-cell proliferation responsive to allostimulation.
  • Class II molecules consist of two non-covalently linked peptide chains ( ⁇ and ⁇ ) which traverse the plasma membrane, each chain having two domains on the outside of the cell. Both chains can be polymorphic, although there is more structural variation in the ⁇ chains. In any event, the variation in class II molecules between individuals can mean that a given replacing peptide will be effective in counteracting a particular immune response for some individuals but not others. To accommodate this exigency, different combinations of replacing peptides can be identified empirically on the basis of relative abilities to modulate responses restricted by different class II allelic products.
  • peptides suitably used as replacing peptides in accordance with the present invention are those that comprise the amino-acid sequence Cys-Pro-Lys- Tyr-Val-Lys-Gln-Asn-Thr-Leu-Lys-Leu-Ala-Thr-Gly, which represents the residues 306 through 320 of influenza virus hemagglutinin (HA) protein. It has been found that synthetic polypeptides containing this sequence and, optionally, additional amino-acid residues can modulate immune responses in the manner described above and, hence, are appropriate candidates for replacing peptides in a clinical context.
  • HA hemagglutinin
  • polypeptides containing a variant of the aforementioned sequence obtained, for example, by deleting one or two residues from at least one end of the sequence.
  • a variant is one that includes the sequence Lys-Tyr-Val-Lys-Gln-Asn- Thr-Leu-Lys-Leu-Ala-Thr, as are sequences derived therefrom via one-, two- or three-residue substitutions in the variant sequence.
  • the replacing peptide it is important for the replacing peptide to be present in a therapeutically-effective concentration in vivo.
  • concentrations will be on the order of 100 micromolar in magnitude, but a suitable concentration for a given treatment will be determined in practice on a case-by-case basis.
  • the replacing peptide can administered systemically, for example, via intravenous or intraperitoneal injection in physiologic saline or other physiologically compatible carrier, or (in the context of a transplant) by bringing the foreign tissue into infiltrating contact with a physiologically compatible solution containing the replacing peptide.
  • administration may be optimally accomplished by localized injection at the site where symptoms of the disorder are manifest, e.g., at a joint affected by inflammation associated with rheumatoid arthritis.
  • the present invention is further described below by reference to the following illustrative examples.
  • Example 1 Modulation of T-cell recognition with an HLA- DRl-restricted peptide representing a portion of influenza virus hemagglutinin (HA) protein.
  • HLA- DRl-restricted peptide representing a portion of influenza virus hemagglutinin (HA) protein.
  • TLCs peripheral blood lymphocytes
  • PBLs peripheral blood lymphocytes
  • PBLs selected as stimulators were HLA-DR- serotyped by direct complement-mediated cytotoxicity after an enriching for B cells on solid-phase antihuman immunoglobulin, according to Grier et al. Tissue Antigens 10: 236-37 (1977) .
  • Priming combinations included cells bearing HLA-DRl through DRw8 antigens, and was effected against alloantigens associated with two complete haplotypes.
  • Responder and stimulator cells were each adjusted to 1 x 10 6 / ⁇ n..l in medium containing 10% human plasma, combined 1:1 in 2-ml aliquots and placed into sterile, round- bottom tests tubes.
  • T-cell growth factor or TCGF interleukin-2
  • primed lymphoblasts were cloned by limiting dilution, in the presence of TCGF and a fresh alloantigenic challenge, according to the technique of Eckels and Hartzman, Hum.Immunol. 3: 337-43 (1981). Thus, primed cells were diluted to
  • Positive wells were transferred to 96-well U-bottom trays containing 1 x 10 5 /well irradiated stimulator cells in 0.1 ml medium plus 10% human plasma. After three days in the absence of TCGF, 0.1 ml of complete medium supplemented with 10% human plasma plus 20% TCGF was added to each well. After a total of seven days in 96- well trays, proliferating clones were transferred in 24- well culture trays containing 1 ml/well of medium (10% human plasma, 20% TCGF) and 1 x 10 6 / ⁇ l irradiated stimulators (30 Gy) .
  • Clones generated in this manner were maintained on a regular schedule of 20% TCGF on day 3, followed by irradiated stimulator (feeder) cells plus 20% TCFG on day 7. Clone concentrations were kept at 2-4 x 10 5 /ml, and feeder cells were added at a final concentration of 1 x 10 6 / m l- Clones were transferred to progressively larger containers when necessary. The resulting TLCs were frozen at -180 * C before being thawed and screened in proliferation assays for their specificities on panels of allogeneic PBLs or lymphoblastoid B-cell lines (LCLs) .
  • LCLs lymphoblastoid B-cell lines
  • f tnat is: Cys-Pro-Lys-Tyr-Val-Lys-Gln-Asn-Thr-Leu-Lys-Leu-Ala-Thr- Gly (I) .
  • the proliferative response of the TLCs (1 x lo well) were determined while concentrations of HA- 06 . 320 were held constant at 30 or 100 ⁇ g/ml, and the number of LCL stimulator cells was increased (range: 2.5 x 10 4 to 20 x 10 4 cells/well) .
  • the alloreactive TLCs were added, respectively, under suboptimal stimulating conditions in which LCL cells with bound peptide would be limiting at low cell concentrations; suboptimal conditions ensured that any modulating effects of the replacing peptide would be detected.
  • LCLs were preincubated with a synthetic peptide representing residues 51 through 65 of ragweed antigen E (Glu-Val-Trp-Arg-Glu-Glu-Ala-Tyr-His- Leu-Ala-Asp-Ile-Lys-Asp) .
  • This peptide has also been shown to be restricted by HLA-DRl. See Rothbard et al. Cell 52: 515-23 (1988).
  • LCL stimulator cells were irradiated (10 4 rads) and resuspended at the above-mentioned concentrations in RPMI 1640 tissue culture medium supplemented with 10% human plasma, 2 mM glutamine, 25 mM HEPES, 50 ⁇ g gentamicin per ml, 100 ⁇ g of streptomycin per ml, 100 international units (IUs) of penicillin per ml, and 24 IUs of sodium heparin per ml. Whenever peptide was employed, it was added, at the concentrations indicated above, two to twenty-four hours prior to the addition of TLCs.
  • Responder TLCs were plated, at 1 x 10 4 cells per well, in supplemented medium.
  • Triplicate cultures 200 ⁇ l were incubated for forty-eight hours at 37 * C in 5% C0 2 /air and then pulse overnight with 1.0 ⁇ Ci titrated thymidine.
  • proliferation was measured by liquid scintillation spectroscopy and expressed as the mean counts per minute of triplicate cultures (+ SEM) .
  • LCLs (2 x 10 6 ) were aliquoted into 12 x 75 mm sterile test tubes and pelleted at 200 x g for 10 minutes. Supernatant was aspirated, the pellet was resuspended, 1 ml of 0.01% paraformal- dehyde was added, and the resulting mixture was incubated at room temperature for 20 minutes. Unsupplemented RPMI 1640 containing 10% fetal calf serum was chilled to 4°C and used to wash the fixed cells three times. Cells were finally resuspended at appropriate concentrations in supplemented medium containing 10% human plasma.
  • APCs abrogates enhancement indicates an internalization of the replacing peptide by the presenting cells. In any event, abrogation cannot be attributed to a modification of the DR1 molecule because paraformaldehyde-fixed APCs can present HA 306 _ 320 to TLC HA1.7 with the same efficiency as do unfixed accessory cells.
  • Example 2 Modulation of T-cell recognition with other peptide derivatives of HA protein.
  • the peptides shown below in Table 2 were tested for immune-modulating activity.
  • the experimental paradigm employed was the one described in Example 1, except that only one peptide concentration (100 ⁇ g/ml) and a single cell density (LCLs at 25 x 10 3 / ell) were used.
  • Each tested peptide was a derivative of the HA protein, i.e., each peptide was obtained by modifying an isolated portion of HA, and was comprised of
  • Lys-Tyr-Val-Lys-Gln-Asn-Thr-Leu-Lys-Leu-Ala-Thr (II) produced by deleting the first two and the last amino- acid residues from HA 306 . 320 ; or
  • TLC AL63.14 in ordinary medium was inhibited by a number of the tested HA derivatives (see Figure 2a) .
  • the T-cell clone AL63.65 which was characterized by an increased proliferative response in Example 1, displayed a qualitatively similar enhancement in the presence of several tested HA derivatives, as shown in Figure 2b.
  • peptide No. 1 was unusual among the tested HA-derivative peptides for being several orders of magnitude more effective than HA itself (data from antigen-specific assay not shown) .
  • no such large difference separated peptide No. 1 from the other tested peptides in the capacity to inhibit or enhance T- cell proliferation responsive to allostimulation.
  • replacing peptides to modulate immune responses should be effective in the particular context of modulating allergic responses, in that peptides would be identified empirically that replace allergenic peptides at the class II-molecular binding site.
  • T-cell clones specific for allergenic peptides would be generated to use, and putative replacing peptides would be assayed, in competitive inhibition experiments as described above.
  • any T cell-mediated immune response involving MHC-restricted peptide recognition should be modulable pursuant to the present invention.

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Abstract

Un groupe potentiellement large de peptides endogènes est utilisé comme médiateur dans le reconnaissance d'antigènes par des lymphocytes T restreints par le complexe d'histocompatibilité majeur (dit ''MHC''), et cette reconnaissance peut être modulée au moyen de peptides qui remplacent ces peptides endogènes au niveau du site de liaison sur la molécule de classe II qui agit en interaction avec le récepteur de lymphocytes T. Les peptides de remplacement peuvent ainsi être utilisés pour réguler des réactions immunitaires chez des mammifères, en influençant la reconnaissance d'un halloantigène ou d'un autoantigène par les lymphocytes T, par exemple dans les domaines du traitement d'un trouble immunitaire, de la suppression du rejet d'allogreffe ou de l'affectation d'une réaction allergénique.
PCT/US1990/000085 1989-01-12 1990-01-11 Modulation par peptides mediateurs de la reconnaissance d'antigenes par les lymphocytes t, utilises comme moyens d'affectation de reactions immunitaires WO1990008161A1 (fr)

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KR1019900702013A KR910700259A (ko) 1989-01-12 1990-01-11 T-세포 인지성 펩티드 변형에 의해 면역반응에 영향을 주는 방법

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992002543A1 (fr) * 1990-08-01 1992-02-20 Cytel Corporation Nouveaux peptides immunosuppresseurs
WO1993005011A1 (fr) * 1991-08-29 1993-03-18 Sandoz Ltd. Nouveaux immunosuppresseurs
FR2722207A1 (fr) * 1994-07-07 1996-01-12 Inst Nat Sante Rech Med Methode pour generer une population de cellules presentant a leur surface une forte densite d'un pepride exogene specifique associe azx molecules du cmh; population de cellules
EP0759771A1 (fr) * 1995-03-07 1997-03-05 President And Fellows Of Harvard College Identification des auto-antigenes et des non auto-antigenes intervenant dans les affections auto-immunes
US5679640A (en) * 1991-02-12 1997-10-21 Cytel Corporation Immunosuppressant peptides
WO1998006861A2 (fr) * 1996-08-15 1998-02-19 Agrivax Incorporated Administration d'antigenes tolerogeniques via des plantes comestibles ou des produits derives de plantes
US6333031B1 (en) * 1996-03-08 2001-12-25 Reception, Inc. Receptor derived peptides as modulators of receptor activity
US7084247B2 (en) 2004-03-11 2006-08-01 Peptimmune, Inc. Identification of self and non-self antigens implicated in autoimmune diseases

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1984000687A1 (fr) * 1982-08-23 1984-03-01 Scripps Clinic Res Antiserums de la grippe a large spectre

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1984000687A1 (fr) * 1982-08-23 1984-03-01 Scripps Clinic Res Antiserums de la grippe a large spectre

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 102, 1985, (Columbus, Ohio, US), A. NESTOROWICZ et al.: "Antibodies Elicited by Influenza Virus Hemagglutinin Fall to Bind to Synthetic Peptides Representing Putative Antigenic Sites", see page 434* Abstract 147208g, & Mol. Immunol. 1985, 22 (2), 145-54* *
CHEMICAL ABSTRACTS, Vol. 111, 1989, (Columbus, Ohio, US), J.B. ROTHBARD et al.: "Recognition of the HLA Class II-Peptide Complex by T-Cell Receptor: Reversal of Major Histocompatibility Complex Restriction of a T-Cell Clone by a Point Mutation in the Peptide Determinant", see pages 569-570* Abstract 132041j, & Philos. Trans. R. Soc. London, B 1989, 323 (1217), 553-64* *
CHEMICAL ABSTRACTS, Vol. 111, 1989, (Columbus, Ohio, US), R.A. EFRENCH et al.: "Class II-Restricted T-Cell Clones to a Synthetic Peptide of Influenza Virus Hemagglutinin Differ in their fine Specificities and in the Ability to Respond to Virus", see page 548* Abstract 95062u, & J. Virol. 1989, 63 (7), 3087-94* *
Nature, Vol. 300, 4 November 1982, MacMillan Journals, J.R. LAMB et al.: "Human T-Cell Clones Recognize Chemically Synthesized Peptides of Influenza Haemagglutinin", pages 66-69 *
Proc. Natl. Acad. Sci. USA, Vol. 85, November 1988, D.D. ECKELS et al: "Peptide-Mediated Modulation of T-Cell Allorecognition", pages 8191-8195 *
The Journal of Immumology, Vol. 142, No. 5, 1 March 1989, The American Association of Immunologists, (US), C.R.A. HEWITT et al.: "Human T Cell Clones Present Antigen", pages 1429-1436 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992002543A1 (fr) * 1990-08-01 1992-02-20 Cytel Corporation Nouveaux peptides immunosuppresseurs
US5679640A (en) * 1991-02-12 1997-10-21 Cytel Corporation Immunosuppressant peptides
WO1993005011A1 (fr) * 1991-08-29 1993-03-18 Sandoz Ltd. Nouveaux immunosuppresseurs
FR2722207A1 (fr) * 1994-07-07 1996-01-12 Inst Nat Sante Rech Med Methode pour generer une population de cellules presentant a leur surface une forte densite d'un pepride exogene specifique associe azx molecules du cmh; population de cellules
WO1996001891A1 (fr) * 1994-07-07 1996-01-25 Institut National De La Sante Et De La Recherche Medicale (Inserm) Methode pour generer une population de cellules presentant a leur surface une forte densite d'un peptide exogene specifique associe aux molecules du cmh; population de cellules
EP0759771A1 (fr) * 1995-03-07 1997-03-05 President And Fellows Of Harvard College Identification des auto-antigenes et des non auto-antigenes intervenant dans les affections auto-immunes
EP0759771A4 (fr) * 1995-03-07 1999-12-29 Harvard College Identification des auto-antigenes et des non auto-antigenes intervenant dans les affections auto-immunes
US7255861B1 (en) 1995-03-07 2007-08-14 President And Fellows Of Harvard College Preparations for inducing immunotolerance and uses therefor
US6333031B1 (en) * 1996-03-08 2001-12-25 Reception, Inc. Receptor derived peptides as modulators of receptor activity
WO1998006861A2 (fr) * 1996-08-15 1998-02-19 Agrivax Incorporated Administration d'antigenes tolerogeniques via des plantes comestibles ou des produits derives de plantes
WO1998006861A3 (fr) * 1996-08-15 1998-05-14 Agrivax Inc Administration d'antigenes tolerogeniques via des plantes comestibles ou des produits derives de plantes
US7084247B2 (en) 2004-03-11 2006-08-01 Peptimmune, Inc. Identification of self and non-self antigens implicated in autoimmune diseases

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AU4948890A (en) 1990-08-13
KR910700259A (ko) 1991-03-14

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