WO1995013288A1 - Proteines de membrane de surface et leur effet sur la reponse immunitaire - Google Patents

Proteines de membrane de surface et leur effet sur la reponse immunitaire Download PDF

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Publication number
WO1995013288A1
WO1995013288A1 PCT/US1994/012985 US9412985W WO9513288A1 WO 1995013288 A1 WO1995013288 A1 WO 1995013288A1 US 9412985 W US9412985 W US 9412985W WO 9513288 A1 WO9513288 A1 WO 9513288A1
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Prior art keywords
peptide
cells
protein
binding
hla
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PCT/US1994/012985
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English (en)
Inventor
Carol Clayberger
Alan M. Krensky
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The Board Of Trustees For The Leland Stanford Junior University
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Priority to AU10939/95A priority Critical patent/AU1093995A/en
Priority to EP95901851A priority patent/EP0730604A4/fr
Priority to JP7514017A priority patent/JPH09508617A/ja
Publication of WO1995013288A1 publication Critical patent/WO1995013288A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56966—Animal cells
    • G01N33/56977—HLA or MHC typing
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the field of this invention is modification of immune response.
  • CD4 and CD8 participated in the MHC TCR complex by binding a loop of the MHC, enhancing the stability of the complex.
  • other interactions were uncovered, apparently not directly associated with the T-cell receptor/MHC complex, where CD28 and B7 were found to bind.
  • CD28 and B7 were found to bind.
  • T-cell Because of the crucial role that the T-cell plays at the center of a major component of the immune system, it remains of great importance to be able to understand how T-cells are selected, activated or tolerized. By understanding the role that various participants play in T-cell activation, there will be opportunities to regulate the immune system, either enhancing the immune response, where one is dealing with vaccines, pathogens, neoplasia, or the like, or diminishing the immune response, where one is dealing with autoimmunity or organ transplantation.
  • a number of immunosuppressants have been shown to have specific cellular proteins as targets. Cyclosporin A binds to cyclophilin, FK506 to FK binding protein, and deoxyspergualin to both Hsc70 and Hsp70. Hsp 70 has been shown to be a member of a multigene family, having at least one constitutively expressed cognate, Hsc70. The effect of DSG seems to be specific for antigen presenting cells; interfering with antigen presentation and/or processing. The action of immunosuppressants is mediated by their cellular binding proteins, and there is, therefore, interest in identifying targets and other agents binding to the targets which will provide modulation of the immune response.
  • the proteins are characterized by being associated with T cell activation and binding to the HLA-B2702 ⁇ l helix peptide, and are immunologically cross-reactive with the heat shock protein cognate, Hsc70.
  • the proteins, fragments thereof and nucleic acids encoding the proteins and oligonucleotides are provided, as well as antibodies which bind thereto.
  • T-cell activation may be modulated.
  • T cells are surface membrane proteins associated with T-cell activation in mammalian T-cells, which proteins bind to the HLA-B2702 ⁇ l helix peptide, nucleic acid encoding such proteins or fragments thereof, and agents for modulating the signal transduction associated with the proteins in the modulation of activation of T-cells.
  • the protein of interest is referred to as p74. It is a surface membrane protein which is expressed in T cells and a limited number of other cells. It can be readily isolated by extracting a lysate of T cells with the peptide of the ⁇ l -helix of HLA- B2702, namely the RENLRIALRY sequence, peptide extensions thereof, or dimers thereof, particularly palindromic dimers, having the amino acid sequence YRLAIRLNERRENLRIALRY.
  • the affinity of p74 for the HLA-B2702 palindrome is at least about 10" M.
  • the extraction may occur with the peptide on a surface, such as particles, microtiter well walls, etc.
  • p74 is a protein found in a limited number of cells, particularly activated CTLs, the T cell tumor PEER, and the EBV transformed cell line JY, in effect, lymphoid T and B cells.
  • the p74 protein can be obtained by lysis with an amphoteric detergent, such as CHAPS.
  • the lysate may then be combined with a peptide or protein having an appropriate Bw4 epitope, for example, HLA-B 2702.84-75-84 palindromic peptide.
  • a peptide or protein having an appropriate Bw4 epitope for example, HLA-B 2702.84-75-84 palindromic peptide.
  • the lysate may be passed through the column, followed by elution with lysis buffer or other convenient buffer. Effective elution can be achieved using relatively high pH, conveniently in the range of about 11-12. See, for example, (Ey (1978) I mmuno chemistry 15:429-436).
  • a different detergent may be used as described by Mescher et al. (1983) Meth. Enzymol. 92:86-109.
  • washes may be any convenient buffer solution, varying in salt content. The washing should not adversely affect the complex between the peptide and p74. In this way successive enrichments may be employed to provide for a protein composition having at least about 50 weight % of total protein as p74 protein, preferably at least about 75 weight %, more preferably at least about 90 weight %, up to 100 % pure.
  • Hsc70 heat shock protein cognate
  • Antibodies directed against Hsc70 react with p74.
  • Various affinity purification methods are known in the art. Antibodies may be bound to beads or another insoluble support, and combined with the cellular lysate. The bound protein is washed free of the unbound lysate. The bound protein is eluted from the antibody by a number of methods, e.g. heat, salt gradients, mild detergents, etc.
  • gel electrophoresis of the lysate may be performed, where the Bw4 epitope containing peptide, suitably labeled, may be used to identify the presence of p74.
  • the Bw4 peptide may be labeled with fluorescer, radioisotope, or the like, non-specifically bound peptide washed away, and the appropriate band developed.
  • binding can be accomplished in solution, using a suitably labeled soluble form of the peptide, e.g. N-terminal biotinylation, etc.
  • the complexed cells may then be lysed as described above. After lysis, the complexes may be isolated by means of the label, e.g. biotin, isolated by means of avidin bound to a solid surface. Alternatively, the label- complementary binding member complex may be preformed and used to extract specific protein binding to the peptide as described above. The samples may then be washed extensively, boiled in SDS and separated using SDS-PAGE gel electrophoresis.
  • p74 Prior to the affinity purification or gel electrophoresis, one may enrich for the desired p74 protein by using the peptide sequence of the B7.84-75-84 palindrome, YGRLNRLSERRESLRNLRGY, to remove any proteins which bind to that sequence, as distinct from the B2702.84-75-84 palindrome sequence to which the p74 binds. In this manner, p74 may be greatly enriched and obtained substantially free of other proteins.
  • the subject proteins may be obtained from any mammalian species, such as rodent, bovine, canine, primate, particularly human, or the like.
  • the sequence of the proteins may be readily determined in accordance with conventional ways.
  • the protein purified as described above may be sequenced using conventional sequence equipment.
  • the purified protein may be cleaved, using mild proteolytic degradation, cyanogen bromide, or other mode of cleavage, to provide fragments under about 20 amino acids.
  • the fragments may then be fractionated e.g. reverse phase-HPLC or preparative SDS-PAGE and electroelution, and the fragments sequenced.
  • the sequences of the fragments may then be used to deduce the sequence of the respective protein.
  • degenerate probes may be produced from the known amino acid sequence of the proteins.
  • DNA probes of at least about 15 nucleotides, usually of at least about 20 nucleotides, one may screen a cDNA library of cells known to express the proteins, particularly T-cells. Those cDNAS which bind to the probes may then be isolated and sequenced. Where the sequence encodes the appropriate peptide sequence, if the isolated cDNA is not a complete cDNA, the isolated cDNA may be used as a probe to isolate a complete cDNA which encodes the entire protein. If desired, the cDNA gene may then be used to isolate the genomic gene in accordance with conventional techniques. (See, for example, Molecular Cloning: A Laboratory Manual, 2nd ed., J. Sambrook, E. F. Fritsch, T. Maniatis, CSHL, Cold Spring Harbor, NY, 1989).
  • the gene or fragments thereof may be used for probing cells to determine whether a subject protein is expressed, when in the cell cycle the protein is expressed, and at what level of differentiation it may be expressed, and quantitate the amount of message RNA during activation or deactivation of T-cells.
  • the gene may be introduced into an expression vector for expression in a wide variety of hosts, both prokaryotic and eukaryotic.
  • the expression vector may include downstream from the polylinker, a transcriptional and translational termination regulatory region, functional in the expression host.
  • the gene may be inserted into the vector after linearization of the vector with a restriction enzyme which cuts at a convenient site in the polylinker.
  • the expression vector may also include a gene which allows for selection of hosts comprising the expression vector.
  • these genes will provide for antibiotic resistance, but may also serve to complement an auxotrophic host, or other mode of selection.
  • the vector may also include an origin for episomal maintenance or the vector may allow for integration into the expression host.
  • the vector may be introduced into the expression host by any convenient means, including electroporation, fusion, calcium precipitated DNA, transfection, etc., the particular mode employed not being critical to this invention and depending upon the choice of expression host.
  • the expression construct can also be used in the elucidation of T-cell activation.
  • These constructs may be used, for example, in complementation studies. For example, cells lacking one or both of the subject proteins, as well as other surface member proteins associated with T-cell activation, may be modified so as to express one or both of the subject proteins. The effect of p74 binding on various pathways in the cell may then be studied. These studies may also examine the effect of mutations on the activity of p74.
  • a ligand or other binding molecule for the extracellular portion binds to the extracellular portion.
  • various receptors with known ligands such as the EGF receptor, IL2 receptor, insulin receptor, CD4, or the like, where binding of the protein, particularly crosslinking on the surface, will result in signal transduction.
  • a natural ligand or antibodies to the receptor so as to provide for the signal transduction.
  • a soluble form of p74 may be constructed by deletion of the transmembrane region.
  • the soluble protein is used as a competitor for the native protein, thereby modulating the cellular immune response.
  • the expression constructs may also be used to produce fusion proteins, where p74 may be fused to a marker, such as ⁇ -gal, CAT, lacZ, and the like.
  • the fusion proteins may serve as markers for translational expression, for production of antibodies, in assays, or the like.
  • the fusion proteins may serve to aid in the purification of a source of p74, where p74 or truncated portion thereof may be joined to a sequence which allows for purification in the Qiagen process or other process.
  • p74 binds to HLA-B 2702.75-84, particularly as the palindromic dimer, and not to HLA-B7 75-84 or its palindromic dimer. It is associated with the process of T-cell activation. Binding to p74 can result in inhibition of cytolysis by CTL as well as CTL differentiation. By employing agents which bind to the p74 of CTL, the immune response can be significantly inhibited. Alternatively, by inhibiting binding agents, either naturally occurring or synthetic to p74, CTL activity may be maintained, other aspects necessary for CTL activity being present. For inhibition of CTL activity, peptides having the Bw4 epitope may be employed in an amount sufficient to inhibit differentiation or cytolysis of target cells.
  • antibodies may be employed which bind to p74, where the antibody may provide for activation or inhibition. Depending upon the antibody, it may inhibit binding of an agent to p74 allowing for activation of the CTL, it may provide for activation of the CTL in conjunction with other interactions of surface member proteins or other signals being transduced into the cell, or it may independently inactivate the CTL through the binding of p74.
  • Whole antibodies need not be used, binding fragments thereof, such as Fab, F(ab')2, Fv, or the like, or other binding entities, either naturally occurring or synthetic.
  • p74 when bound to the B2702 peptide results in a large calcium influx in nontransformed T cells. The magnitude and kinetics are essentially the same as that induced by anti-CD3 antibodies, supporting the conclusion that the rise in intracellular calcium is involved in the development of anergy. This response appears to be specific to the B2702.75-84 peptide.
  • Soluble p74 may be prepared by truncating the respective gene and removing the transmembrane sequence and the intracellular sequence. The truncation can be achieved in accordance with conventional methods, using restriction enzymes, primer repair, exonucleases, or synthesis of the extracellular portion of the protein.
  • the soluble p74 may be used for a variety of purposes.
  • the soluble p74 may be used in diagnostic assays to determine the presence and amount of p74 in a sample, may be used for screening compounds which bind to p74 in accordance with conventional binding assays, for prophylactic or therapeutic purposes (i.e. to inhibit binding of agents to the native protein, as well as in research to elucidate the mechanism of T cell activation.
  • Soluble p74 may be used for identifying APCs which bind to p74 as well as agents which interfere with such binding. Using labeled p74, cells binding to p74 can be readily detected by magnetic separation, fluorescence, etc. Soluble p74 may also be used to modulate CTL response in vivo or in vitro in a mixture of T cells and antigen presenting cells, such as macrophages and B cells.
  • Antibodies to the subject proteins may be prepared in accordance with conventional methods.
  • p74 native or soluble form, may be used as an immunogen, being injected intravascularly, intraperitoneally, intramuscularly, subcutaneously, or the like normally in conjunction with an adjuvant, into an appropriate mammal, e.g. mouse, rat, guinea pig, or the like.
  • an adjuvant e.g. an adjuvant
  • an appropriate mammal e.g. mouse, rat, guinea pig, or the like.
  • booster injections will be employed to enhance the specificity of the antisera.
  • the immunized host may then be sacrificed, the spleen isolated and splenocytes immortalized by any convenient means, e.g. fusion with a hybridoma.
  • the hybridomas may then be grown using limiting dilution and screened for binding characteristics with p74, as appropriate. Hybridomas which show binding affinity for p74, may then be expanded and the supernatant used for isolation of monoclonal antibodies, or the hybridomas used for the preparation of ascites fluid as a source of monoclonal antibodies. The hybridomas may then be further subcloned and screened to identify antibodies which have a desired binding affinity. These antibodies may be then be further screened with T-cells having p74 under conditions where the physiological effect of the antibodies can be determined. For procedures for preparing monoclonal antibodies, see Antibodies: A Laboratory Manual, Eds., Ed Harlow and David Lane, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 1988.
  • the antibodies may be modified by replacing constant regions and framework regions of the antibody with sequences utilized by the host to be treated.
  • Techniques for isolating the variable regions of the heavy and light chains and fusing them to variable regions native to the host, as well as substitution of framework regions native to the host, have been described in numerous publications. See, for example, EPA 173,494 and WO92/16562.
  • the subject therapeutic agents may be prepared as formulations in pharmaceutically acceptable media, for example saline, PBS, in glucose, generally at a pharmacologically effective dose, the concentrations of which will be determined empirically in accordance with conventional procedures for the particular purpose.
  • the formulations may include bactericidal agents, stabilizers, buffers or the like.
  • the amount administered to the host will vary depending on what is being administered, the purpose of the administration, such as prophylaxis or therapy, whether inhibition or activation is desired, the state of the host, the manner of administration, and the like.
  • the peptides may be encapsulated, introduced into the lumen of liposomes, prepared as a colloid, modified by binding to stable peptides, such as the constant region of IgG, or polyalkyleneoxy groups, or other conventional techniques.
  • p74 The role of p74 in the mixed lymphocyte reaction, B cell activation, and other cellular or compound interactions may be investigated.
  • the p74 or biologically active fragment thereof may be added to the culture medium in from about 1 to 500 ⁇ g per 1 x 10 ⁇ cells, where inhibition of T cell activation is studied.
  • p74 may be used for screening novel compounds for agonist or antagonist activity to CTL activation.
  • the affinity of the candidate compound for p74 By carrying out a competition between the complex involving p74 and the labeled agent with the compound being analyzed, and determining the rate of release of the labeled agent from p74, one can measure the affinity of the candidate compound for p74. Alternatively, one may use CTLs where the peptide or other agent competes for binding to the protein with the candidate compound and measure the effect of the candidate compound on CTL differentiation or cytolytic activity as compared to a standard, where the candidate compound is not present.
  • HLA-B2702/05.145- 169 RKWEAARVAEQLRAYLEGECVEWLR HLAB38.6084 WDRNTQICKTNTQTYRENLRIALRY The effect of the above sequences on lysis of long-term CTL specific for HLA-A2, -B2705, -Bw46, -Bw62, and -Cw4 was determined, including CTL specific for HLA-B27 and the HLA-Cw4. None of the peptides inhibited or enhanced lysis with the exception of the B2702.60-84 peptide. This peptide blocked lysis by all CTL, regardless of their HLA specificity. This effect was due to interaction with the CTL and not the target cell as shown by pre-treatment experiments.
  • B27.145-169 164,245 PBL from a normal donor (HLA-A3; B-7, 38: Cw4; DR4,6) were cultured with ty (HLA-A2; B7; DR4,6) or HOM2 (HLA-A3; B27) in the presence of 10-100 ⁇ g/ml peptide. After 6 days, lysis was tested on 51 Cr-labeled CIR cells expressing either
  • HLA-B2702/05.60-69 WDRETQICKA The peptide corresponding to residue 60-69 of HLA-B2702/05 had no effect on the assays described above.
  • the peptide corresponding to residue 75-84 of HLA-B2702 blocked all Class I specific CTL responses, whereas the peptide corresponding to the same region of HLA-B2705 did not.
  • the plastic binding procedure was as follows: peptide (100 ⁇ g/ml) was dissolved in PBS and 50 ⁇ l was added to round bottom microtiter wells or 5-10 ⁇ l to petri dishes. After 60 minutes at 37°C or overnight at 4°, the solution was removed and the plates washed twice in RPMI-1640 supplemented with 10% fetal bovine serum. Cells were added and incubated at 4° for 30 minutes. Binding to petri dishes was determined by inspecting the dishes under a microscope following gentle agitation. Binding to microtiter wells was determined after centrifugation at 500 rpm for 3 minutes. Cells which did not bind formed a small pellet at the bottom of the well whereas cells that did bind did not form a pellet.
  • B2702.84-79/79-84, B2702.84-75T/75-84T, B7.60-84, and B7.84-75/75-84 peptides were conjugated to biotin-(CH) ⁇ 2-for use with strepavidin-agarose (SAA) to isolate the peptide receptor from 35s-methionine and cysteine labeled cells.
  • SAA strepavidin-agarose
  • biotinylated peptide was complexed to the SAA and allowed to bind to labeled cells at 4°C for 30 minutes. The cells were washed free of excess complex and lysed by addition of CHAPS containing lysis buffer. This method preferentially precipitates material from the cell surface.
  • cell lysates were prepared in CHAPS lysis buffer and the lysate was incubated with biotinylated peptide/SAA complexes for 30 minutes at 4°C followed by extensive washing. This method preferentially precipitates intracellular material.
  • the 70 and 74 kD bands were subsequently shown to be reactive with antibodies specific for members of the heat shock protein family.
  • Biotin-conjugated B2702.84-75/75-84 or B7.84-75/75-84 peptides were used to precipitate proteins from CTL. Following separation by SDS-PAGE, proteins were electrophoretically transferred to a nylon membrane and the Western blot was probed with a monoclonal antibody specific for Hsp70. It is seen that the antibody reacts specifically with the p74 protein. Isoelectric focusing on the p74 protein as well as on the Hsc70 after precipitation with either peptide or anti-Hsc70 mAb shows an identical molecular weight and isoelectric points.
  • the B2702 peptide also binds to the heat inducible form, commonly referred to as Hsp70, although the binding to the Hsc70 is much more pronounced. Both forms are expressed on the cell surface and are upregulated following treatment of cells at 43° for one hour. Expression of the Hsc70 protein correlates with peptide induced calcium increase and the induction of unresponsiveness.
  • Binding of the B2702 peptide to nontransformed T cells was found to result in a large calcium influx, having a magnitude and kinetics comparable to that induced by anti-CD3 antibodies, in support of the peptide binding to a surface membrane protein and being involved in the development of anergy.
  • Other Class I HLA ⁇ l helix derived peptides did not induce this response under comparable conditions.
  • the correlation between the peptide induced increase in calcium and precipitation of the 70 and 74 kD bands from the surface for a number of different cell types is shown in Table I.
  • the largest increase in intracellular calcium is observed in the human CTL, PBL, Jurkat, and rat spleen cells. With the exception of Jurkat, these cells also express the highest levels of the 70 and 74 kD bands. Six ⁇ g of p70 and p74 have been purified.
  • the B2702.84-75/75-84 peptide did not cause a Ca 2+ flux in the human T cell lines Peer, HUT-78, HSB; human Epstein Barr virus transformed B cell lines, including JY and 721.221; the natural killer cell line YT2C2; or several pre-erythrocytic cell lines, including K562 and HEL. Neither the B2702.75-84 peptide nor the inverted repeat B7.84-75/75-84 peptide initiated Ca 2+ mobilization in any of the cells tested.
  • the threonine substituted peptides which failed to cause unresponsiveness in T cells, were also unable to promote Ca 2+ mobilization.
  • the maximum intracellular Ca 2+ level induced by the B2702.84-75/75-84T and B2702.84-75T 75-84 peptides was only 10-30% of that achieved with the unsubsrituted B2702.84-75/75-84 peptide.
  • the double substituted B2702.84-75T/75-84T peptide did not initiate any Ca 2+ flux.
  • IP3 is one messenger molecule that links surface receptor activation to the release of Ca 2+ from internal stores by binding to a receptor on the endoplasmic reticulum.
  • the level of IP3 in cells is elevated following the activation of either G protein linked receptors or by tyrosine kinase linked receptors.
  • the other major mechanism is Ca 2+ induced Ca 2+ release (CICR).
  • cADPR cyclic adenosine diphosphate ribose
  • NAD + nicotinamide adenine dinucleotide
  • T cell activation Another early event in T cell activation is a change in the patterns of phosphorylation of many proteins. Therefore, it was determined whether the peptides that inhibited T cell function affected protein phosphorylation or the level of intracellular calcium. None of the peptides examined thus far has had any effect on the pattern of tyrosine phosphorylation observed by Western blot analysis in whole lysates from T cells.
  • B2702 has a novel pattern of activity, as compared to the known immunosuppressants, cyclosporin A, FK506, rapamycin and deoxyspergualin.
  • ADDRESSEE FLEHR, HOHBACH, TEST, ALBRITTON & HERBERT
  • Tyr Arg Leu Ala lie Arg Leu Asn Glu Arg Arg Glu Asn Leu Arg lie 1 5 10 15
  • Trp Asp Arg Glu Thr Gin lie Cys Lys Ala Lys Ala Gin Thr Asp Arg 1 5 10 15
  • Tyr Arg Leu Ala lie Arg Leu Asn Glu Arg Arg Glu Asn Leu Arg lie 1 5 10 15
  • Trp Asp Arg Glu Thr Gin He Cys Lys Ala Lys Ala Gin Thr Asp Arg 1 5 10 15
  • Trp Asp Arg Glu Thr Gin He Cys Lys Ala Lys Ala Gin Thr Asp Arg 1 5 10 15
  • Trp Asp Arg Glu Thr Gin Lys Tyr Lys Arg Gin Ala Gin Thr Asp Arg 1 5 10 15

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Abstract

La protéine p74 se rencontre dans les lymphocytes T et d'autres cellules. Lorsqu'elle est liée à certains agents, elle produit une inhibition de l'activité cytolytique et de la différenciation des lymphocytes T cytotoxiques. La p74 peut être isolée des lymphocytes T et d'autres cellules à l'aide d'un peptide HLA-B2702.84-75-84 palindromique, par la liaison d'affinité d'un lysat cellulaire.
PCT/US1994/012985 1993-11-10 1994-11-10 Proteines de membrane de surface et leur effet sur la reponse immunitaire WO1995013288A1 (fr)

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Application Number Priority Date Filing Date Title
AU10939/95A AU1093995A (en) 1993-11-10 1994-11-10 Surface membrane proteins and their effect on immune response
EP95901851A EP0730604A4 (fr) 1993-11-10 1994-11-10 Proteines de membrane de surface et leur effet sur la reponse immunitaire
JP7514017A JPH09508617A (ja) 1993-11-10 1994-11-10 表面膜タンパク質および免疫応答に対するそれらの影響

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US15049393A 1993-11-10 1993-11-10
US08/150,493 1993-11-10

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US7094413B2 (en) 2002-01-24 2006-08-22 Sangstat Medical Corporation Combined therapy for treatment of HIV infection
US7498309B2 (en) 2003-11-29 2009-03-03 Sangstat Medical Corporation Pharmaceutical compositions for bioactive peptide agents

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US5888512A (en) * 1987-01-30 1999-03-30 Board Of Trustees Of The Leland Stanford Junior University Lymphocyte activity regulation by HLA peptides

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Title
BIOLOGICAL ABSTRACTS, Vol. 87, No. 2, issued January 1991, HAIRE et al., "Mitogen-Induced Preferential Synthesis of Proteins During the G0 to S Phase Transition in Human Lymphocytes", see page 182, col. 2, the abstract no. 14222; & EXPERIMENTAL CELL RESEARCH, 1988, 179(1), 65-78. *
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES USA, Vol. 91, issued March 1994, CIAVARRA et al., "Heat Stress Induces hcs70/Nuclear Topoisomerase I Complex Formation In Vivo: Evidence for hcs70-Mediated ATP-Independent Reactivation In Vitro", pages 1751-1755. *
See also references of EP0730604A4 *

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US7011834B1 (en) * 1987-01-30 2006-03-14 The Board Of Trustees Of Leland Stanford Junior University Immunomodulating dimers
US6162434A (en) * 1995-05-03 2000-12-19 Sangstat Medical Corporation Cytomodulating peptide for inhibiting lymphocyte activity
EP0939643A1 (fr) * 1996-05-22 1999-09-08 The Board Of Trustees Of The Leland Stanford Junior University Composes immunomodulateurs comprenant des isomeres d d'acides amines
EP0939643A4 (fr) * 1996-05-22 2003-04-16 Univ Leland Stanford Junior Composes immunomodulateurs comprenant des isomeres d d'acides amines
JP2001504451A (ja) * 1996-09-18 2001-04-03 ヴィルドナー，ゲルヒルト 自己免疫疾患の診断薬と治療薬となるペプチド類
WO1998046633A1 (fr) * 1997-04-11 1998-10-22 Sangstat Medical Corporation Cytomodulation de peptides lipophiles aux fins d'une modulation de l'activite du systeme immunitaire et de la suppression de l'inflammation
US6696545B1 (en) 1997-04-11 2004-02-24 Sangstat Medical Corporation Cytomodulating lipophilic peptides for modulating immune system activity and inhibiting inflammation
US7267822B2 (en) 1997-04-11 2007-09-11 Genzyme Corporation Cytomodulating lipophilic peptides for modulating immune system activity and inhibiting inflammation
US7094413B2 (en) 2002-01-24 2006-08-22 Sangstat Medical Corporation Combined therapy for treatment of HIV infection
US7498309B2 (en) 2003-11-29 2009-03-03 Sangstat Medical Corporation Pharmaceutical compositions for bioactive peptide agents

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CA2176208A1 (fr) 1995-05-18
JPH09508617A (ja) 1997-09-02
EP0730604A1 (fr) 1996-09-11
EP0730604A4 (fr) 1998-01-07
AU1093995A (en) 1995-05-29

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