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WO1996028176A1 - Composition destinee a induire la tolerance orale et utilisation de ladite composition - Google Patents

Composition destinee a induire la tolerance orale et utilisation de ladite composition Download PDF

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Publication number
WO1996028176A1
WO1996028176A1 PCT/EP1996/001004 EP9601004W WO9628176A1 WO 1996028176 A1 WO1996028176 A1 WO 1996028176A1 EP 9601004 W EP9601004 W EP 9601004W WO 9628176 A1 WO9628176 A1 WO 9628176A1
Authority
WO
WIPO (PCT)
Prior art keywords
quail
egg
composition
eggs
induction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP1996/001004
Other languages
English (en)
Inventor
Dominique Rigal
Claude Pinon
Jean-Claude Truffier
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Truffier Francis
Original Assignee
Truffier Francis
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Truffier Francis filed Critical Truffier Francis
Priority to AU50042/96A priority Critical patent/AU5004296A/en
Publication of WO1996028176A1 publication Critical patent/WO1996028176A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/495—Transforming growth factor [TGF]
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/57—Birds; Materials from birds, e.g. eggs, feathers, egg white, egg yolk or endothelium corneum gigeriae galli
    • 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
    • A61K39/0005—Vertebrate antigens
    • A61K39/0008—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • composition for oral tolerance induction and use thereof are provided.
  • the present invention relates to the use of quail's egg or quail's egg lyophilisate as an adjuvant for induction of oral tolerance (OT).
  • OT oral tolerance
  • OT Oral tolerance, or systemic unresponsiveness to ingested antigen, was first described at the turn of the century. It is usually effected by oral administration of minimal and very progressively increasing doses of antigen under medical surveillance favouring the systemic unresponsiveness to the ingested antigen.
  • OT may thus be employed to treat or cure allergies, auto-immune diseases, pathological situations where auto-immunity is an aggravating factor, induction of tolerance prior to organ transplants, etc.
  • OT could be induced in several experimental animal models but its induction varied e.g. with: the structure of the antigen and its sensitivity to proteolysis the dose of antigen ingested the chronology of administration the method and duration of administration the species and strains of the animals employed the age and sex of the animals the mode of feeding.
  • the present invention provides a solution to this problem by providing an adjuvant for the induction of OT which improves the outcome of the treatment, i.e. which enhances the effect on OT, and gives it the required reliability.
  • EP 0 032 344 describes a therapeutic effect with quail's egg lyophilisate in the treatment of immuno-allergic diseases it is silent with respect to the induction of oral tolerance.
  • composition of the invention therefore provides for a composition for enteral administration comprising a quail's egg lyophilisate, characterized in that the quail's egg lyophilisate is produced in the presence of 5 to 40% by weight of carbohydrate, based on the weight of the quail's egg content, (hereinafter referred to as composition of the invention)
  • Quail's eggs or the composition of the invention are used in combination with an antigen for which an immune response of the tolerance type, i.e. systemic unresponsiveness, is to be achieved, in order to enhance the OT-inducing effect.
  • the antigen can be administered prior to the administration of the adjuvant, subsequently or simultaneous with the adjuvant.
  • the antigen is mixed together with the composition of the invention and administered simultaneously.
  • the invention further provides for the use of quail's eggs or of a composition of the invention in the preparation of a medicament or nutritional formulation for the enhancement of induction of oral tolerance in mammals.
  • the mammals are humans.
  • the invention also provides a method for enhancing the OT-inducing effect of an antigen in a mammal, which comprises administering enterally, prior to, subsequent to or simultaneous with the antigen to which an immune response of the tolerance type is to be achieved, an amount of quail's egg or of a composition of the invention which is effective for enhancing the OT-inducing effect of the antigen.
  • Quail's egg as used herein refers to egg white and/or yolk, OT-inducing components of egg white and/or yolk or mixtures thereof.
  • quail's egg refers to egg white and yolk, i.e. whole egg content.
  • Any quail's eggs may be used according to the invention.
  • Typical examples of eggs suitable as an adjuvant for the induction of OT include those from the following quail types: Coturnix-coturnix, Coturnix-delagorguei, Coturnix- novaeZealandiae, Coturnix-chinensis, Coturnix-coturnix japonica, Excalfactoria and strain MINA B.
  • the eggs may be fertilized or unfertilized, fertilized eggs being preferred.
  • MINA B is a cross of the wild quail Coturnix-coturnix-coturnix and the quail Coturnix-coturnix-japonica.
  • MINA B is a cross of the wild quail Coturnix-coturnix-coturnix and the quail Coturnix-coturnix-japonica.
  • eggs of other quail species have revealed the same properties as the fertilized eggs of MINA B, this effect was never obtained with eggs of chickens, ducks, guinea fowl or pheasants.
  • the dosage of the composition of the invention for humans per day is preferably from 2 to 12 g. It is normally administered as cure of nine consecutive days followed by nine consecutive days without treatment and an optional further cure of nine consecutive days.
  • the corresponding dosage of fresh quail's egg is from 1 to 6 eggs per day.
  • Antigen as used herein refers to soluble or particulate antigen such as allergens, auto-antigens, allo-antigens, xeno-antigens, proteins, glycoproteins, cells such as red blood cells, bacteria, viruses, etc.
  • the dosage of antigen to be employed to obtain the desired effect will depend on the particular treatment and the desired oral tolerance. Such dosages are known or can be established by the skilled person in a manner known per se for conventional treatment with antigen to induce OT.
  • the amount of antigen to be administered lies in the range of from 1 ng to 1 g, preferably from 1 mg to 500 mg, particularly preferred about 100 mg.
  • the antigen may be administered enterally such as by oral feeding or intragastric feeding or by inhalation.
  • OT is also used herein when reference is made to administration of antigen by inhalation or intragastric feeding because OT is a term known in the art and describes the same effect that is observed with the present invention.
  • OT administration of antigen and quail's egg or the composition of the invention should be started at least five days before the challenge with the immune response inducing agent, whereby the duration of administration may vary.
  • induction of OT can be effected after treatment according to the invention for three weeks, however, improvements of the clinical condition may already be observed after one week.
  • Induction of OT can further be enhanced through the "idiotypic network" if auto ⁇ antibodies are administered in combination with the quail's egg or the composition of the invention in combination with the antigen as set out above.
  • auto-antibodies a higher rate of induction of OT is achieveable.
  • the dosage of auto ⁇ antibodies having an enhancing effect on induction of OT is within the range of 1 ⁇ g to 10 mg per day during 1 to 10 days.
  • the autoantibodies can be administered prior to, subsequent to or simultaneous with the quail's egg or the composition of the invention in combination with the antigen, whereby mixing the quail's egg or composition of the invention with antigen and auto-antibody and administering all these ingredients simultaneously is preferred.
  • TGF beta 1 Transforming Growth Factor
  • the invention further provides the use of quail's eggs or of a composition of the invention in the preparation of a medicament or nutritional formulation for the induction of production of lymphokines with immunosuppressive properties.
  • composition of the invention can be prepared by lyophilisation of egg contents according to known methods.
  • Some preferred methods of lyophilisation are as follows:
  • the batches of eggs are steeped in an antiseptic solution, broken en masse, filtered, centrifuged, and mixed with carbohydrates in a proportion of 5 to 40% (w/w), preferably 5 to 20% (w/w).
  • Suitable examples of carbohydrates that may be used in this application are disaccharides such as maltose, trehalose or lactose, monosaccharides such as glucose, fructose, galactose or carbohydrate mixtures such as honey.
  • the carbohydrate is preferably saccharose or honey.
  • the mixture may then optionally be pasteurized at a temperature not exceeding 37°C.
  • Lyophilization is carried out with a freezing stage which should not drop below -42°C, at a rate of cooling of 5°C/min, at a pressure of 0.01 torr.
  • An alternative consists in freezing the egg contents abruptly with liquid nitrogen. Drying should be effected at less than 25°C at a pressure of 0.003 to 0.006 torr. Afterwards, the powder is divided into sachets of 6 g which corresponds to 3 eggs.
  • the quail's eggs are separated into white and yolk according to a manual or industrial procedure especially adapted to quail's eggs and egg white and yolk are mixed separately with the carbohydrates. Then the whites are lyophilised according to a standard procedure and the yolks are lyophilized by freezing in liquid nitrogen. Drying should be effected at less than 25°C at a pressure of 0 003 to 0.006 torr. Afterwards, the powder is divided into sachets of 6 g which corresponds to 3 eggs.
  • a standard procedure for lyophilising the egg whites is e.g. as follows: the egg whites are put into a petri dish whereby the thickness of the egg layer should not exceed 2 cm, then the petri dish is put in a -80°C-freezer overnight, whereafter it is transferred to a dryer chamber where for the primary drying of 24 hours the condenser temperature is -45°C and the chamber pressure 0.01 torr and for the secondary drying of 6 to 12 hours the shelf temperature is +5°C and the pressure 0.01 torr.
  • the invention further provides for a process for manufacturing quail's egg Iyophilisates comprising the steps of: a) separating egg contents from eggshells, b) adding 5 to 40% (w/w) of carbohydrate and mixing it with the egg contents, c) freezing and drying the mixture.
  • composition of the invention may be formulated into conventional enteral administration forms, such as granules, tablets, capsules, liquids, powders, etc.
  • enteral administration forms such as granules, tablets, capsules, liquids, powders, etc.
  • a physiologically acceptable formulation form such as a capsule or tablet form
  • Typical pharmacologically acceptable formulation forms for oral administration will further comprise pharmacologically acceptable diluents, carriers, vitamins, spices, pigments and/or other adjuvants well known to the skilled person to be suitable for incorporation into such formulation and preferably also antigen.
  • the composition of the invention is administered in powder form as this form is most convenient to mix the lyophilisate with the appropriate antigen.
  • the egg contents are frozen abruptly with liquid nitrogen and dried at less than 25°C at a pressure of 0.003 to 0.006 torr. Afterwards, the powder is divided into sachets of 6 g which corresponds to 3 eggs.
  • Balb/c mice do not produce OT to soluble antigens, whereas it is very easy to induce OT with C3H mice.
  • Human transferrin was used as antigen.
  • 5 Balb/c mice (group A) were given orally 20 mg of transferrin dissolved in 1 ml of isotonic salt serum at 0.9% on day 0.
  • the anti-transferrin antibody titre is evaulated by a passive haemagglutination technique according to the method of Johnson et al (Int Arch Allergy 1968, 33, 511-520).
  • a group B of 5 Balb/c mice underwent the same treatment, but were given the transferrin by digestive means, i.e. enterally, with 100 mg of a mixture of quail's egg lyophilisate before challenge with transferrin on day 15.
  • a control series of 5 mice were given orally 20 mg of bovine albumin with quail's egg lyophilisate; then on day 15 they were given 1 mg of transferrin mixed in 100 ⁇ l of complete Freund's adjuvant (CFA) by injection, finally on day 30 the anti-transferrin antibody titre is evaulated as set out above (group C).
  • CFA complete Freund's adjuvant
  • Another control group D of 5 Balb/c mice underwent the same treatment as group A but were given fresh chicken's egg instead of quail's egg lyophilisate.
  • mice The same experimental pattern was carried out with C3H mice (groups E, F, G, H) and OF1 mice (groups I, J, K, L).
  • mice were used in order to show that the induction of a OT with the quail's egg was independent of genetic background.
  • the hapten used is DNCB (2,4-dinitrochlorobenzene) obtained from Sigma. This hapten is diluted in a mixture of acetone/olive oil (4 vol / 1 vol). To induce a state of hypersensitivity of contact, after shaving the backs of the mice, a 5% solution of DNCB was applied thereto on day 0. Then, the reaction was revealed 5 days later by application to the ear of a 1% suspension. Finally, the reaction is read 48 hours later by measuring the thickness of the ear with a micrometer. The controlateral ear serving as a control. Under these conditions, a specific DHC is observed, which may be easily evaluated.
  • DNCB 2,4-dinitrochlorobenzene
  • OT was induced by the ingestion of 500 ⁇ l of a 1.25% suspension of DNCB with or without 100 mg of quail's egg 7 days before immunisation.
  • the following table summarises the results of the groups of 5 mice. The values indicate the difference in thickness in mm between the test ear and the reference ear.
  • AIHAi autoimmune haemolvtic anaemia
  • the intraperitoneal injection of 10 8 rat erythrocytes once per week for 4 to 5 weeks causes AIHA of the mouse with the presence of auto-antibodies and anti rat- erythrocyte xeno-antibodies.
  • This AIHA occurs with 100% of the animals (group A). If 10 9 rat erythrocytes are ingested 3 days before each of the injections, a reduction in the number of animals affected by AIHA is obtained (60%) with titres a little lowered (group B).
  • Balb/c mice are resistant to the induction of OT according to standard procedures. They even have an anaphylactic shock at the moment of ingestion of the antigen if, first of all, they have been immunised with it. In a series of experiments, it was demonstrated that the antigen (human transferrin) mixed with the quail's egg induces OT in these mice. On the other hand, the same ingestion with immunised animals no longer induces anaphylactic shock.

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Abstract

Composition pour administration entérale, qui comporte un lyophilisat d'÷uf de caille, caractérisée par le fait que ledit lyophilisat est produit en présence de 5 à 40 % en poids d'hydrate de carbone, sur la base de la teneur en ÷uf de caille en poids. La présente invention concerne l'utilisation d'÷uf de caille ou de ladite composition dans la préparation d'un médicament ou d'une composition nutritionnelle destinée à induire la tolérance orale chez les mammifères, l'÷uf de caille ou ladite composition améliorant la tolérance orale.
PCT/EP1996/001004 1995-03-09 1996-03-08 Composition destinee a induire la tolerance orale et utilisation de ladite composition Ceased WO1996028176A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU50042/96A AU5004296A (en) 1995-03-09 1996-03-08 Composition for oral tolerance induction and use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR9502958A FR2731353A1 (fr) 1995-03-09 1995-03-09 Utilisation de l'oeuf de caille ou de ses derives ajoute a un antigene comme adjuvant de l'induction d'une tolerance par voie orale ou aerienne pour le traitement des maladies a composantes immunitaires
FR95/02958 1995-03-09

Publications (1)

Publication Number Publication Date
WO1996028176A1 true WO1996028176A1 (fr) 1996-09-19

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PCT/EP1996/001004 Ceased WO1996028176A1 (fr) 1995-03-09 1996-03-08 Composition destinee a induire la tolerance orale et utilisation de ladite composition

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FR (1) FR2731353A1 (fr)
WO (1) WO1996028176A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2810550B1 (fr) * 2000-06-27 2004-10-08 Medibrevex Nouvelle formes galeiques solubles d'oeufs de caille a usage medicamenteux pour lavage oculaire et nasale et leurs procedes de fabrication
FR2811898B1 (fr) * 2000-07-18 2003-12-12 Medibrevex Formes galeniques medicamenteuses homeopathiques d'allergenes impregnes sur un support biologiquement actif pour desensibilisation specifique par voie sublinguale et leur procede de fabrication
FR2813531B1 (fr) * 2000-09-06 2003-02-14 Medibrevex Formes galeniques d'oligoelements incorpores dans un excipient biologiquement actif d'homogenat d'oeufs de caille et leur procede de fabrication

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2356426A1 (fr) * 1976-06-29 1978-01-27 Truffier Jean Claude Fraction ovomucoide du blanc de l'oeuf de caille, ayant des proprietes antiproteasiques
EP0032344A2 (fr) * 1979-12-28 1981-07-22 Jean-Claude Truffier Lyophilisat d'oeuf de caille pour le traitement des maladies immuno-allergiques
FR2489690A1 (fr) * 1979-05-07 1982-03-12 Coturnix Procede d'obtention de la fraction ovomucoide et d'un extrait d'ovomucoide de l'oeuf de caille, produits ainsi obtenus et leur application a titre de medicament
WO1989011297A1 (fr) * 1988-05-27 1989-11-30 Centocor, Inc. Preparation lyophilisee pour la stabilisation de produits a base d'anticorps

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2356426A1 (fr) * 1976-06-29 1978-01-27 Truffier Jean Claude Fraction ovomucoide du blanc de l'oeuf de caille, ayant des proprietes antiproteasiques
FR2489690A1 (fr) * 1979-05-07 1982-03-12 Coturnix Procede d'obtention de la fraction ovomucoide et d'un extrait d'ovomucoide de l'oeuf de caille, produits ainsi obtenus et leur application a titre de medicament
EP0032344A2 (fr) * 1979-12-28 1981-07-22 Jean-Claude Truffier Lyophilisat d'oeuf de caille pour le traitement des maladies immuno-allergiques
WO1989011297A1 (fr) * 1988-05-27 1989-11-30 Centocor, Inc. Preparation lyophilisee pour la stabilisation de produits a base d'anticorps

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J. BENVENISTE: "GUÉRIR L'ALLERGIE.", LA RECHERCHE, vol. 10, no. 104, October 1979 (1979-10-01), PARIS FR, pages 1012 - 1013, XP002005328 *

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FR2731353A1 (fr) 1996-09-13
AU5004296A (en) 1996-10-02

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