EP0154625A4 - Hybridoma zellinie die den allergie mindernden faktor erzeugt. - Google Patents

Hybridoma zellinie die den allergie mindernden faktor erzeugt.

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Publication number
EP0154625A4
EP0154625A4 EP19840901879 EP84901879A EP0154625A4 EP 0154625 A4 EP0154625 A4 EP 0154625A4 EP 19840901879 EP19840901879 EP 19840901879 EP 84901879 A EP84901879 A EP 84901879A EP 0154625 A4 EP0154625 A4 EP 0154625A4
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EP
European Patent Office
Prior art keywords
sfa
ige
molecule
cells
cell line
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Application number
EP19840901879
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English (en)
French (fr)
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EP0154625A1 (de
Inventor
David H Katz
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Individual
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Individual
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Publication of EP0154625A1 publication Critical patent/EP0154625A1/de
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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
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • 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
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • 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 immune response to a given antigen is in most cases several distinct types of immune responses supported by multiple cell types of the reticuloendothelial system.
  • humoral immunity is mediated by antibodies produced by B lymphocytes
  • cellular immunity is mediated by specially sensitized T lymphocytes.
  • the interaction of these cells and others is further modulated by various mediators.
  • Cells that have been stimulated by antigens have been shown to produce antigen-specific mediators, or lymphokines, that regulate humoral and cell-mediated immune responses in both a positive and negative manner, as well as non-antigen-specific mediators that are associated with delayed hypersensitivity and B and T lymphocyte collaboration to produce antibodies.
  • Antigens although classically defined as substrates capable of stimulating the production of antibodies that will react specifically with a particular antigen, also include molecules that will induce an immune response, that is, a complex biologic process that includes the proliferation of lymphoid cells and the subsequent synthesis of recognition molecules, such as antibodies or cellular receptors.
  • the antibodies produced by antigen stimulation have been classified according to their physiochemical properties and have been grouped in 10 immunoglobulin (Ig) categories, called isotypes, which presently include five (5) classes.
  • IgE immunoglobulin
  • the IgE system plays perhaps one of the most important defense roles against certain exogenous agents, particularly those which gain access through mucoepithelial and epithelial linings such as the respiratory and gastrointestinal tracts and skin.
  • the IgE system is particularly unique in that the biological effects of IgE antibodies are extraordinarily amplified through widely distributed cells which possess IgE-specific Fc receptors(FcRe). Since IgE molecules bind specifically and avidly to such Fc receptors displayed on the surface membranes of tissue-fixed mast cells and circulating basophils, and since such cells are actually little factories of potent pharmacological mediators, only a small number of IgE molecules are required to exert the biological effects for which this system was designed.
  • IgE antibody responses could be sufficient to provide protection to the individual without resulting in undesirable and/or deleterious reactions.
  • mice A very useful experimental model, largely in mice, that has helped reveal some of the crucial steps in the regulatory mechanisms controlling IgE synthesis has been the ability to selectively enhance IgE antibody production by exposure of mice to low dose whole body irradiation. More importantly, irradiation-enhanced IgE responses of genetically low responder inbred mice can be modulated selectively by the circulating proteins SFA and EFA.
  • IgE IgE-mediated allergic diseases, diseases that constitute a major health problem with consequenses that not only effect the physical well-being of one out of every three individuals, but also impose a substantial economic impact on both individuals and society alike.
  • Diseases linked to the IgE system include, for example, the generalized anaphylactic reaction and other allergic states such as hayfever, asthma and urticaria.
  • SFA is one of the critical mediators in the IgE system, and that, according to the present invention, it can be isolated and economically feasibly produced using either hybridoma technology or recombinant DNA technology, potentially makes available new therapies that can be tailored to recapture the fine tuning of the regulatory network controlling IgE synthesis so that ample, but not excessive, quantities of this important protective lymphokine are produced.
  • SFA therapy using the inventive concepts set forth herein, over conventional therapy are dramatic. Since the SFA molecule is the natural protein the human body uses to down regulate IgE synthesis and to dampen the allergic response in vivo, SFA therapy should have little or no side effects. SFA inhibits only IgE responses and the amount of SFA can be clinically titrated to reduce the IgE levels so that they still contribute to natural immunity (which appears to be essential for life) without being dramatically overproduced or directed against innocuous antigens, thus leading to allergic reactions. Also, the effects of SFA treatment on the production of IgE directed against defined antigens appears to be very long lasting.
  • mice which are treated with SFA have dramatically reduced antigen stimulated IgE responses even one year (half a lifetime) after treatment.
  • antigen stimulated IgG responses remain normal.
  • SFA appears to be able to dampen the allergic response to any allergen so that patients could be clinically desensitized to virtually any existing allergy, or to new allergies as they arise.
  • a hybridoma T cell line (1C1) was produced by fusing SFA-producing human PBL's with JURKAT cell line JKOT. mRNA was isolated from the 1C1 cell line and identified by its ability to direct SFA synthesis in Xenopus laevis oocytes. A sensitive biological assay for SFA was developed using a combination of Lyt-1 cells and the inhibition of FcRe positive cells.
  • the present invention comprises a hybridoma cell line characterized by the production of SFA, and, more particularly, a cell line comprising a fusion of cells from JURKAT human T cell leukemia and SFA-producing human peripheral blood lymphocytes.
  • the SFA or SFA-containing supernatant of the cell line is at least 50% effective in inhibiting FcRe expression in dilutions exceeding ltl,000, and, more characteristically, in dilutions of 1:10,000 to 1:10 6 .
  • the major protein produced by the cell line is the protein SFA further comprising a molecule of molecular weight of approximately 15,000 to 30,000 daltons, having no IgE-binding properties, that is selective in activity for the IgE antibody system, that inhibits IgE antibody synthesis, that inhibits igE-mediated FcRe induction on lymphocytes, that is non-antigen-specific, whose activity is not strain or species-dependent, and that selectively stimulates Lyt-1 cells to produce SEM.
  • the invention comprises the hybridoma cell line 1C1, i.e. the hybridoma cell line comprising a mRNA molecule comprising a RNA sequence coding for SFA.
  • the mRNA translational product is the protein SFA comprising a molecule of molecular weight of approximately 15 ,000 to 30,000 daltons, having no IgE-binding properties, that is selective in activity for the IgE antibody system, that inhibits IgE antibody synthesis, that inhibits IgE-nediated FcRe induction on lymphocytes, that is non-antigen-specific, whose activity is not strain or species-dependent, and that selectively stimulates Lyt-1 cells to produce SEM.
  • the invention includes a process for the detection or determination of SFA comprising treating a culture of mouse splenocytes with a measured amount of soluble monoclonal antibody to the Lyt-2 cells, the addition of SFA or SFA containing supernatant to a pre-determined final concentration, the addition of mouse anti-DNP, and the determination of the percentage of FcRe positive cells using a rosette-forming assay as compared to control cultures without SFA.
  • the invention comprises the product of the cell line and process described. DESCRIPTION OF THE DRAWINGS
  • Figure 1 depicts the ability of PWM to stimulate IgE synthesis in vitro from 10 different human donors as assayed by two different techniques.
  • Figure 2 depicts the selective suppression of human IgE synthesis in vitro by human SFA.
  • Figure 3 depicts the inhibitory activities of SFA and EFA on FcRe induction, and shows that SFA and EFA do not have Ige-binding properties.
  • Figure 4 compares the ability of SFA produced by conventional mouse ascities, hybridoma cell line ICl, and hybridoma cell line ICl mRNA translation product, to inhibit in vitro FcRe induction and in vivo IgE synthesis.
  • CFA complete Freund's adjuvant (Difco Laboratories, Detroit, MI).
  • DNP 2,4-dinitrophenyl.
  • EFA enhancing factor of allergy.
  • EIR IgE-induced regulants.
  • Fc crystallizable fragment of IgE. FCSi fetal calf serum.
  • FcRe IgE specific Fc receptors.
  • GAHG goat anti-human IgG.
  • HAT hypoxanthine, aminopterin, and thymidine.
  • IgE imraunoglobulin E.
  • Lyt-1 T lymphocytes.
  • Lyt-2 T lymphocytes.
  • MEM minimum essential medium.
  • MLR mixed lymphocyte reaction.
  • MNC mononuclear cells.
  • PBL peripheral blood lymphocytes.
  • PEG polyethylene glycol
  • PMC peripheral mononuclear cells.
  • PWM pokeweed mitogen.
  • RiA radioimmunoa ⁇ say.
  • SFA suppressive factor of allergy.
  • SRBC sheep red blood cells.
  • TNBS 2, 4, 6-trinitrobenzene sulfonic acid (ICN
  • TNP Trinitrophenyl
  • This invention involves the production of SFA, or an SFA-like molecule, having the ability to modify human IgE synthesis, and the isolation of mRNA that translates for an SFA or SFA-like molecule capable of modifying IgE synthesis. More particularly, this invention involves the formation of a hybridoma that produces SFA, and the isolation of the mRNA from the hybridoma that is responsible for the expression of the protein SFA.
  • RIA radioimmunoassay
  • GHE high-titer goat anti-human IgE
  • PS high-titer goat anti-human IgE
  • DZA IgE
  • the production of GAHE was prepared by hyperimmunizing a goat with 100 micrograms of IgE (PS or DZA) emulsified in complete Freunds Adjuvant (CFA) (Difco Laboratories, Detroit, MI) every three weeks over a time period of 11 months. Bleedings were accumulated at varying intervals during this immunization schedule and over a several-month period thereafter.
  • the GAHE serum was screened by a quantitive binding analysis.
  • the Ig fraction of the GAHE was obtained by precipitating it twice with amonium sulfate at final concentrations of 40% and 30% saturation.
  • the recovered Ig fraction of GAHE was depleted of anti-light chain antibodies by absorption with normal human serum coupled to Sepharose 4B (Pharmacia, Uppsala, Sweden).
  • the absorbed GAHE was used as the coating protein in the RIA.
  • purified anti-human IgE antibodies were isolated from the normal human serum-absorbed GAHE proteins by affinity chromatography on lgE(PS)-coupled Sepharose 4B and elution with 0.1M glycine-HCl buffer, pH 2,3. Affinity-purified GAHE was labeled with Iodine-125 by solid-state lactoperoxidase.
  • the iodinated GAHE was then separated from free Iodine-125 by passage over a G-25 column (PD-10, Pharmacia).
  • the specific activities of labeled GAHE ranged from 9 to 18 X 10 6 CPM/microgram. Labeling was generally performed once a week.
  • a conventional solid-phase RIA system was employed to measure IgE levels in culture supernatants (Zollinger, et al . , 1976).
  • FIG. 1 A summary of results obtained with peripheral blood cells from ten different donors stimulated with varying doses of PWM is presented in Figure 1.
  • PS or DZA the GAHE reagent
  • the values shown in the upper panel were obtained with anti-human IgE that had been affinity purified on the same IgE myeloma protein, PS, as that used for hyperimmunization to raise the goat antiserum; the values depicted in the lower panel were those obtained on the same culture supernatant fluids using anti-human IgE that had been affinity-purified on a completely unrelated IgE myeloma protein, DZA, than that used for immunization.
  • SFA is obtained from two-way human mixed lymphocyte reactions (MLR), in which mononuclear cells (MNC), were suspended at 1 X 10 6 cells/ml in culture medium.
  • MLR mononuclear cells
  • One milliliter from each of two unrelated donors was placed in a 2ml culture well.
  • the cultures were placed in 5% CO 2 humidified atmosphere at 37°C for eight days, at which times the supernatants were harvested by centrifugation and stored at -20°C.
  • FcRe induction by in vitro exposure to IgE can be modulated, and quite selectively, by both SFA (Chen, S.-S., et al.,1981) and EFA (Katz, et al.,1983b).
  • SFA Choten, S.-S., et al.,1981)
  • EFA Kerz, et al.,1983b.
  • the percentage of FcRe positive cells is detected by conventional rosette assay techniques. Basically, TNP-derivatized sheep red blood cells (SRBC) were prepared by reaction with TNBS as described by Rittenberg and Pratt (1969).
  • the IgE-coated TNP-SRBC were prepared by incubating the red cell suspension (1% in MEM) with subagglutinating amounts of DNP-specific antibodies in the range of 1 to 10 micrograms/ml. The mixture was incubated for 30 minutes in a 37°C. water bath, followed by washing twice with MEM. The IgE-coated red cells were brought to a 1% suspension in rosetting medium (MEM supplemented with 1% FCS and pennicillin/streptomycin) . Rosettes were prepared by adding 50 microliters of lymphocytes (2.5 X 10 6 cells) to 12 X 75-mm Falcon tubes that contained 100 microliters of appropriate indicator cells.
  • rosetting medium MEM supplemented with 1% FCS and pennicillin/streptomycin
  • the cell mixtures were incubated in a 37°C water bath for 15 minutes and centrifuged at 500 rpm for 5 minutes. The pellets were incubated unperturbed for an additional 30 minutes at 4°C and were subsequently gently resuspended either with a 100 microliter Eppendorf or by vortexing. The cells were incubated at 4°C overnight, and Trypan blue (0.3 ml) was added to each tube just before enumeration of the rosettes; the viability of cultured cells was routinely 60% or more.
  • a rosette-forming cell is defined as a lymphocyte that is tightly surrounded by at least three indicator cells.
  • the pass-through fraction recovered from such columns was utilized as SFA and the material eluted from Con A-Sepharose (by ⁇ -D-methyl mannoside) was used as EFA.
  • a portion of the respective SFA and EFA-enriched fractions was further subjected to affinity chromatography on IgE-coupled Sepharose. Two ml of each of the factors was adsorbed on 2 ml of Ige-Sepharose constructed with 5,25 mg affinity-purified IgE per gram Sepharose 4B. After 24 hrs., the cells exposed (or not) to the various agents were washed and assayed for FcRe expression by rosette formation with DNP-specific igE-coated TNP-SRBC.
  • EIR a induces FcRe expression in B cells
  • EIR T induces FcRe expression in T cells. Therefore, when unfractionated spleen cells are exposed to IgE resulting in the induction of both T and B cells which express FcRe on their surface membranes, B cells must be present for IgE to induce FcRe expression in
  • EIR T was produced by FcRe positive B cells that had been stimulated by ElR ß .
  • SFA then triggers Lyt-1 T cells to synthesize and secrete a final suppressive effector molecule (SEM) which has the ability to (1) directly inhibit B cell expression of FcRe induced by exposure to IgE, and (2) to suppress IgE antibody synthesis both in the in vivo mouse model and in the in vitro human system.
  • SEM final suppressive effector molecule
  • EFA is involved in this regulatory scheme by its ability to stimulate FcRe expression in Lyt-2 positive T cells causing the secretion of a final enhancing effector molecule (EEM) which, like SEM, is capable of directly inhibiting FcRe expression by B cells following exposure to IgE, and is responsible for marked enhancement of IgE synthesis in vivo or in vitro.
  • EEM final enhancing effector molecule
  • SFA requires Lyt-1 positive T cells
  • EFA in contrast, requires Lyt-2 positive T cells in order to effectively inhibit IgE-mediated FcRe induction in vitro.
  • human peripheral blood lymphocytes were isolated by standard techniques, and cultured with PWM in RPMI 1640 medium plus 10% FCS (Microbiological Associates, Walkersville, MD) for seven days. PBL's were washed and fused with Jurkat cell line clone JKOT which is resistant to thioguanine and ouabain and is sensitive to HAT. Fusion was accomplished with polyethelyne glycol (PEG) in a solution containing 50% PEG and 50% 150 mM Hepes buffer.
  • PEG polyethelyne glycol
  • the cells were placed in 0.1 ml PEG solution for one minute at 37° C, then diluted with RPMI into 5 ml, washed once, then plated into RPMI plus 10% FCS, plus HAT. These cultures contained murine thymocytes as feeder cells. The population of hybridomas constructed were then screened by standard techniques to isolate the individual clones producing SFA.
  • SFA is produced, it should be noted that SFA is not specie ⁇ -dependent; animal sources are believed to be effective in the human system, and human SFA is likewise effective in most, if not all,animal systems.
  • the SFA that is produced by the hybridoma ICl was assayed with respect to its ability to inhibit FcRe induction in vitro, and also its ability to inhibit in vivo IgE synthesis in the mouse, according to the techniques described above.
  • the hybridoma produced SFA was also compared with conventional human SFA, produced as described above. As depicted in Figure 4, as can be seen by comparing group II to group I, conventional human SFA blocked both in vitro IgE-mediated FcRe induction and in vivo IgE antibody synthesis, as expected. Importantly, supernatant fluids from the relevant hybridoma ICl are likewise effective in blocking both bioas ⁇ ay indicators.
  • the mRNA from hybridoma ICl was subsequently isolated according to technique as described by Berger and Birkenmeier (1979).
  • the ability of the mRNA preparations to direct the synthesis of SFA was determined by microinjection into stage V-VI Xenopus laevis oocytes, according to the procedure described by Gurdon, et al., (1971). Typically, 20-30 nanograms of mRNA in 20-30 microliters were injected/oocyte .
  • Oocytes were incubated in modif ied Barth ' s medium supplemented with 100 units/ml pennicillin-100 raicrograms/ml streptomycin, 10 mM-Hepes, 1 mM phenylmethylsulfonyl fluoride and 0.1% Bovine serum albumin.
  • Viable oocytes were selected 16-18 hours after injection and incubated at 5 oocytes/well in 96-well microtiter dishes (100 microliters of the above medium/well) for a further 40-48 hours at room temperature at which time the culture medium was removed and assayed for SFA activity according to the procedures described above.
  • the translation product of mRNA extracted from this hybridoma line shows identical biological activities as the hybridoma produced SFA, as depicted in Figure 4 by group IV.
  • the invention has application as a therapeutic for diseases linked to the IgE system that are generally manifested by allergic reactions, such as hayfever and asthma, or by the anaphylactic reaction.
  • allergic reactions such as hayfever and asthma
  • SFA is a natural body regulant of IgE synthesis and control of the allergic response, little or no side effects would result from its therapeutic use.
  • SFA can be administered in amounts sufficient to reduce the overproduction of IgE that leads to the allergic reactions, while not eliminating IgE levels necessary to contribute to the natural immunity. Also, the effects of SFA are long-lasting, eliminating the need for continuous therapy,

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  • Medicinal Chemistry (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
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EP19840901879 1983-08-18 1984-04-16 Hybridoma zellinie die den allergie mindernden faktor erzeugt. Withdrawn EP0154625A4 (de)

Applications Claiming Priority (2)

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US52439583A 1983-08-18 1983-08-18
US524395 1983-08-18

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EP0154625A1 EP0154625A1 (de) 1985-09-18
EP0154625A4 true EP0154625A4 (de) 1987-09-02

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EP (1) EP0154625A4 (de)
JP (1) JPS60502202A (de)
AU (1) AU576499B2 (de)
CA (1) CA1215918A (de)
DK (1) DK175485D0 (de)
NO (1) NO851539L (de)
WO (1) WO1985000750A1 (de)

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* Cited by examiner, † Cited by third party
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FR2598917B1 (fr) * 1986-05-21 1988-08-19 Pasteur Institut Nouvelle lymphokine suppressive de l'activation plaquettaire, son procede d'isolement et de purification et medicaments la contenant

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4361550A (en) * 1979-12-04 1982-11-30 Ortho Pharmaceutical Corporation Complement-fixing monoclonal antibody to human suppressor T cells and methods of preparing same
US4376110A (en) * 1980-08-04 1983-03-08 Hybritech, Incorporated Immunometric assays using monoclonal antibodies
US4411993A (en) * 1981-04-29 1983-10-25 Steven Gillis Hybridoma antibody which inhibits interleukin 2 activity
US4434156A (en) * 1981-10-26 1984-02-28 The Salk Institute For Biological Studies Monoclonal antibodies specific for the human transferrin receptor glycoprotein

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 97, no. 13, 27th September 1982, page 455, abstract no. 108228x, Columbus, Ohio, US; T. KISHIMOTO et al.: "Characterizations of T cell-derived immunoregulatory molecules from murine or human T hybridomas", & LYMPHOKINES (N.Y.) 1982, 5, 129-60 *
NATURE, vol. 292, 27th August 1981, pages 844-845, Macmillan Journals Ltd, Chesham, Bucks, GB; C. GRILLOT-COURVALIN et al.: "Establishment of a human T-cell hybrid line with suppressive activity" *
See also references of WO8500750A1 *
THE JOURNAL OF IMMUNOLOGY, vol. 121, no. 5, November 1978, pages 2113-2117, The Williams & Wilkins Co., Baltimore, US; T. WATANABE et al.: "Regulation of antibody response in different immunoglobulin classes. V. Establishment of T hybrid cell line secreting IgE class-specific suppressor factor" *

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NO851539L (no) 1985-04-17
EP0154625A1 (de) 1985-09-18
JPS60502202A (ja) 1985-12-19
AU2822684A (en) 1985-03-12
AU576499B2 (en) 1988-09-01
DK175485A (da) 1985-04-18
DK175485D0 (da) 1985-04-18
WO1985000750A1 (en) 1985-02-28
CA1215918A (en) 1986-12-30

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