NZ505179A - Immune suppressive food product comprising polypeptide fragments of allergens - Google Patents
Immune suppressive food product comprising polypeptide fragments of allergensInfo
- Publication number
- NZ505179A NZ505179A NZ505179A NZ50517991A NZ505179A NZ 505179 A NZ505179 A NZ 505179A NZ 505179 A NZ505179 A NZ 505179A NZ 50517991 A NZ50517991 A NZ 50517991A NZ 505179 A NZ505179 A NZ 505179A
- Authority
- NZ
- New Zealand
- Prior art keywords
- milk
- allergen
- allergens
- immune
- food product
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2/00—Peptides of undefined number of amino acids; Derivatives thereof
-
- 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
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/20—Milk; Whey; Colostrum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Cell Biology (AREA)
- Developmental Biology & Embryology (AREA)
- Biomedical Technology (AREA)
- Virology (AREA)
- Zoology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biotechnology (AREA)
- Pulmonology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Medicines Containing Plant Substances (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
A method for desensitizing a human subject to an allergen wherein the method comprises orally administering to the subject a food product, in an amount and for a time sufficient to produce an allergic response-suppressive effect in the subject against the allergens. The food product comprises allergic response-suppressive amounts of active; non-antibody polypeptides form the milk of milk-producing, immunized animals wherein the animals have been immunized against the allergens.
Description
New Zealand Paient Spedficaiion for Paient Number 505179
NEW ZEALAND PATENTS ACT, 1953
No:
Divided out of No. 314856
Date:
Dated 10 May 1991
COMPLETE SPECIFICATION
METHODS FOR PRODUCING AND USING AN IMMUNE SUPPRESSIVE PRODUCT
We, STOLLE MILK BIOLOGICS, INC. a corporation organised and existing under the laws of the State of Ohio, United States of America, located at 6954 Cornell Road, Cincinnati, Ohio 45242, United States of America, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:
(followed by page -la-)
INTELLECTUAL PROPERTY OFFICE
-la-
Field of the Invention
This invention is broadly related to the discovery of polypeptide fractions in milk which contain peptides derived from allergens administered to a milk-producing animal. These fractions are useful in suppressing allergic responses in humans and animals.
The invention provides methods for preparing immune suppressive products containing such fractions and to the use of such products in suppressing allergic responses in humans.
BACKGROUND OF THE INVENTION
The allergic reaction in man and animals has been extensively studied and the basic immune mechanisms involved are well known. The generic name for molecules that cause an allergic reaction is allergen. There are numerous species of allergens. Common examples include plant pollens, bee venom, house dust, animal dander, and a wide array of food proteins. Many allergens are protein or polypeptide in nature, as proteins and polypeptides are generally more antigenic than carbohydrates or fats. The allergic reaction occurs when tissue-sensitizing immunoglobulin of the IgE type reacts with foreign allergen. The IgE antibody is bound to mast cells and/or basophils, and these specialized cells release chemical mediators of the allergic reaction when stimulated to do so by divalent antigens bridging the antibody molecules. Histamine, platelet activating factor, arachidonic acid metabolites, and serotonin are among the best known mediators of allergic reactions in man.
The symptoms of the allergic reaction vary, depending on the location within the body where the IgE reacts with the antigen. If the reaction occurs along the respiratory epithelium the symptoms are sneezing, coughing and asthmatic reactions. If the interaction occurs in the digestive tract, as in the case of food allergies, abdominal pain and diarrhea are common. Systematic reactions, for example following a bee sting, can be severe and often life threatening.
The preferred, but frequently impossible, method of relieving allergies is allergen avoidance. Failing that, there are two medical approaches to allergy control, both with an approximate 60 to 85% efficacy rate (Aas K., Allergy 37:1-14 (1982)). The most common approach to the medical treatment of allergies is to treat the symptom. Drugs known
to block the effects of the chemical mediators of the allergic reactions, including antihistamines, are used to control the severity of the allergic symptoms. These drugs, however, do nothing to prevent the allergic reaction and the liberation of the chemical mediators, and do nothing to prevent or diminish allergic responses to subsequent allergen exposure.
Another approach is to prevent the allergic reaction by desensitizing the allergic host. This is accomplished by giving repeated small doses of the reactive allergen. The treatment usually involves injecting the allergens under the skin. Treatment with reactive allergens, more appropriately called immunotherapy, is believed to increase the concentration of antibodies of the IgG type against the allergen. The IgG antibody competes with the IgE antibody for allergen binding, and this competitive antibody somehow neutralizes, arrests, or blocks the action of the tissue sensitizing IgE antibody, although a distinct correlation between blocking antibody and amelioration of symptoms has not been definitely proven (Mailing, H.J., (ed.), Immunotherapy Position Paper, Allergy (Supp.) 6, 43:9-33 (1988)}. This rationale, although generally accepted, is not fully understood, and does not reflect the complex interactions and events that accompany the IgG response. For example, other effects of immunotherapy that may be involved with relief of symptoms include suppression of IgE, increase in blocking IgA and IgG in secretions, reduced basophil reactivity/sensitivity, and reduced lymphocyte responsiveness to allergens. All of these changes may not occur in every patient, and those related to actual symptom relief have not been conclusively defined (Norman, P.S., J. Allergy Clin. Immunol. 75:531-545 (1985)).
Immunotherapy using reactive allergen is dangerous because the sensitized host is actually treated with the
molecules capable of eliciting an allergic response. The treatment is started with extremely low does to avoid inducing a severe reaction. The antigen concentration required for 50% histamine release from peripheral basophils of an allergic individual varies 10,000 fold from patient to patient (Norman, P.S., J. Allergy Clin. Immunol. 75:531-545 (1985)). If no adverse reaction occurs, higher doses are given. The injection may cause severe allergic reactions and extreme care must be taken. Only experienced doctors can administer this treatment because if a severe reaction occurs immediate medical treatment must be given to control the symptoms of the allergic reaction. Desensitization is an expensive, painful, and time consuming process (Aas K., Allergy 37:1-14 (1982)), therefore, only the most severe allergies are treated by this method (Mailing, H.J., ed., Immunotherapy Position Paper, Allergy (Supp.) 6, 43:9-33 (1988)).
Modifying allergens to eliminate their allergenicity, or ability to induce an IgE-mediated response, while preserving their immunogenicity, or their ability to elicit the protective IgG response, has been under investigation for years. Polymerized antigens have been evaluated with the theory that they would display reduced antigenicity due to concealed antigenic determinants, a lower molecular concentration hence decreased bridging opportunity on a weight basis, and slower diffusion through the tissues (Patterson R., J. Allergy Clin. Immunol. 68:85-90 (1981)). Allergen conjugates have been studied with a variety of allergens in attempts to selectively inhibit the formation of IgE antibodies while normal IgM and IgG responses to the antigen occurred (Lee, W.Y. et al., Imm. Rev. 41:200-217 (1978)). Conjugates with a glutamic acid/lysine copolymer may be acting specifically on IgE lymphocytes, on suppressor and/or helper T cells, or a combination of mechanisms may be
in effect (Liu, F.T. et al., Proc. Natl. Acad. Sci. USA 75:1430-1434 (1979)).
Modifications that decrease the size of the allergen in efforts to eliminate their allergenicity have also been attempted. It has been proposed that limited proteolysis may actually reveal suppressor determinants on allergen molecules (Mowatt A.M., Immunology 55:253-260 (1985)).
Polypeptide fractions of allergens and the use of enzymes to break down the parent proteins is not new (King, T.P., Advances in Immunology 23:77 (1976)). U.S. patent number 4,469,677 teaches the use of polypeptide fractions prepared from allergens for desensitization of allergic humans and animals. The polypeptide fractions are prepared by digesting allergens with proteolytic enzymes. Following the enzymatic digestion procedure, the enzymes and residual parent allergens must be removed from the polypeptide subfractions. The specific structure of the polypeptide fractions is dependent on the enzymes used for the digestive process. However, this is a synthetic process that requires preselection of the enzymes used for the digestive process. The polypeptide fraction is produced by controlled proteolytic digestion of the polypeptide allergen. Although this represents an improvement over using the reactive antigens, the treatment still requires frequent and painful injections.
The function of the polypeptide fractions for suppressing immune function are structure dependent, see Unanue, E.R. et al., Science 235:551-557 (1977) for a review of the structure dependence of polypeptide fractions of proteins in the immune response.
The structure of the polypeptide fractions of Michael is limited because the selection of enzymes is based on a limited understanding of which enzymes are most important.
The development of oral "tolerance" is a normal phenomenon, and a necessary function in response to the
variety of foreign antigens consumed in the diet. Oral tolerance is initiated by a special class of T lymphocytes and their products, and it results in systematic suppression of the IgE-mediated hypersensitivity reaction. Variable responses of other components of the immune system have been reported to occur during induction of the tolerized state, so that the actual mechanism has not been succinctly defined.
In addition, animal studies have shown an actual enhancement of IgE production in response to intragastric administration of pollen extracts (Henderson, D.C. et al., Int. Archs. Allergy Appl. Inunun. 79:66-71 (1986)). Although this may be a dose-related phenomenon, conflicting results were reported from two studies where 20 mg ovalbumin was administered orally to parenterally immunized mice, with IgE increased in one study (Handson, D.G. et al., Int. Arch. Allergy Appl. Immun. 55:256-532 (1977)) and decreased in the other (Lafont, S. et al., J. Exp. Med. 155:1573-1578 (1982)).
Some investigators have concluded that recognition of antigenic determinants varies between parenterally and orally induced suppressor T cells. Suppressor cells resulting from feeding antigen were able to recognize different forms of the antigen, while parenterally induced suppressor T cells were specific for the molecular confirmation to which they initially responded (Mowatt, A.M., Immunology 56:253-260 (1985)). If this phenomenon is exhibited by a majority of antigens, it would further warrant the use of oral immunotherapy.
The problem with administering allergens orally to allergic subjects is that severe immune reactions may occur following treatment by this route as well. Anaphylaxis, relapse, urticaria, rectal bleeding, and anaphylactic shock have all been reported following oral immunotherapy (Platts-Mills, T.A.E., J. Allergy Clin. Immunol. 80:129-132 (1987)).
In addition, oral treatment requires significantly larger doses than parenteral therapy, due to the action of the digestive tract enzymes upon the allergens. Individual responses to the ingested antigens may vary, however, so that more or less intact allergen may be represented to the gastrointestinal mucosa from the same dose given to different subjects, increasing the risk of inappropriate dosing.
Nonallergenic fractions of allergens can be given orally without concern for severe immune reactions; however, for reasons that are not clearly understood, oral administration of the polypeptide fractions of some allergens, including those prepared in the Michaels patent (U.S. 4,469,677) are not effective in causing desensitization. Studies of the immune response to feeding other modified proteins are limited, with varying results. Collagen-induced arthritis in mice was suppressed by feeding native type II collagen but not if the denatured molecule was fed (Nag!er-Anderson, C.L. et al., Proc. Natl. Acad. Sci. USA 83:7443 (1986)). In a study of another autoimmune disease, both the disease-producing and nondisease-producing fragments and decapeptides of the myelin base protein were capable of eliciting immune suppression following oral treatment in rats (Higgins, P.J. et al., J. Immunology 140:440-445, (1988)). Results from a mouse study evaluating induction of oral tolerance with both natural and denatured ovalbumin identical suppression of delayed type hypersensitivity response to each form (Mowat, A.M., Immunology 56:253-260 (1985)).
One factor that may be involved in the failure of some molecular fragments to effectively induce immune tolerance is the low pH of the stomach, which may further modify the polypeptide fraction, abrogating its ability to induce tolerance.
Another factor involved in the failure of orally dosed allergen fragments to induce desensitization to future
exposure may be the actual nature of the fragment itself. In vitro synthesis of fragments requires specific enzymes and conditions that may or may not result in the preparation of a biologically optimal formulation. The fragment may be effective when it is acutely exposed to the immune system following intravenous administration, but may be so susceptible to modification that any alterations occurring in the gastrointestinal tract before its exposure to the appropriate immune system components may destroy its effectiveness.
A need exists, therefore, for methods of producing an oral formulation of allergen fractions that, when administered orally, is sufficiently active to induce tolerance but is not allergenic. A need also exists for methods employing such products in desensitising a human subject to an allergen. v^oPERTpx.,
X V v/
SUMMARY OF THE INVENTION
This invention embodies the discovery of a method of manufacture land method of usd of an immune-suppressive product. The generic form of the product produced by the process of this invention, is milk that contains polypeptide fractions of allergens. The specific product of the process of this invention is the milk polypeptide fraction that contains polypeptide fragments of specific allergens.
Described but not claimed is a method of the production of an allergic response-suppressive pharmaceutical composition, wherein said method comprises:
(a) administering an allergen to a milk-producing human animal;
(b) collecting the milk from the animal of part(a);
(c) filtering the milk of part (b) through a filter which excludes molecules of greater than 100,000 daltons; and
(d) collecting the effluent from the filtration of part (c) wherein said effluent contains said active fraction.
In a first aspect, the invention is directed to a method for desensitizing a human subject to an allergen wherein said method comprises orally administering to said subject a food product, in an amount and for a time sufficient to produce an allergic response-suppressive effect in said subject against said allergen, wherein said food product comprises allergic resonse-suppressive amounts of active, non-antibody polypeptides from the milk of milk-producing, immunized animals wherein said animals have been immunized against said allergens.
Preferably, said food product is selected from the group consisting of milk, skim milk, yogurt, and cheese.
The food product can be in powdered form or in liquid form. ____
/f
I <
I 11, JAN * N ;\ J ;DESCRIPTION OF THE PREFERRED EMBODIMENTS ;The invention provides methods for preparing an oral formulation for desensitization, an oral vaccine, which is of significant medical benefit to the subject who ingests it. By subject is meant a human in need of allergy desensitizing according to the method of the invention. The oral vaccine can be self administered, is less painful, and less expensive then vaccines which must be injected. The subject ingesting the oral vaccine is exposed to the allergen in a derivatized, processed form which allows such subject to acquire tolerance to such allergen. ;The milk , or an active fraction thereof, ;may be administered in any form which retains the allergic response suppressive properties of the milk, either powdered ;-10- ;or liquid. Any food product which incorporates the active fractions of such milk may also be provided, for example, ;skim milk, yogurt and cheese. ;By an "active fraction" of the milk is meant a preparation or composition which has been extracted from the milk and which retains the beneficial, allergic reaction-suppression properties of the unextracted milk which are due to the presence of derivatized, processed forms of the allergen used to immunize such animal providing such milk. ;The derivatized, processed form of the allergen is, in accordance with the method of the invention, found in the milk of a milk-producing human animal which has been immunized against the allergen. The advantaqe of administering the polypeptide fraction to a subject rather than administering the unprocessed allergen itself is that, unlike the unprocessed allergen, the allergic response suppressive polypeptide fraction of the milk is nonallergenic. Desensitization of the subject who ingests the milk occurs but there is no risk of severe allergic reactions in such subject because the allergen has been processed to a non-allergic form by the immune system in the milk-producing host. ;The allergen which is used as a source of the immune suppressant active polypeptides can be any allergen which is capable of provoking an immune system response in the human animal which processes such allergen. ;The allergen preparation may contain a mixture of allergens or only one specific allergen. Examples of allergen ;-11- ;mixtures which may be protected against by the administration of the milk preparation as described herein include mixtures of pollens of various trees and grasses, venoms from animals and insects, and food allergens. Examples of specific allergens which may be protected against by the administration of the preparation described herein include, for example, ragweed, bee venom, and wheat protein in the case of a food allergy. ;The method of manufacture of the polypeptide fraction produces a unique subfraction of the parent allergen, such subfraction exhibiting immune suppressive activity when used to treat a host allergic to such allergen. By "immune suppressive activity" is meant the ability of a composition to lessen allergic symptoms or allergic responses in an allergic subject who is administered such composition By "allergic symptoms" is meant physiological reactions or conditions which are induced in an individual in response to that individual's being exposed to substances which are allergic for that individual, such as, for example, allergy-induced congestion, headaches, breathing, itching, swelling, sneezing, wheezing, coughing, rhinorrhea, and decreased ability to smell and taste. ;The milk composition described herein, and polypeptide fractions produced therefrom according to the process of this invention, lack the allergenicity of the parent allergen (the allergen used to immunize the milk-producing animal) but possess the ability to desensitize a host administered such compositions. ;It is not necessary that the milk-producing animal be induced to, or maintained in, a hyperimmune state to produce the milk described herein. Further, it is not necessary that the milk-producing animal be induced to an antibody-producing state to produce the milk because the active compositions do not rely on antibodies to provide their protective and suppressive activity. It is only ;necessary that the allergen-administered human animal be provided with time sufficient to process such allergen into a form which is secreted in the milk of the animal. ;Because immune cell processing of the allergen is one of the earliest steps in the immune response, milk containing the active polypeptides described herein may be obtained relatively soon after administering the allergen, for example, 24 hours to a week after allergen administration. ;Any amount of the allergen which results in the appearance of the active polypeptides described herein in the milk of such animal may be administered to the milk-producing human animal. If the amount of such active polypeptides in the milk of the allergen-administered animal is too low to provide efficacious benefits to a subject in need of desensitization, ;such active polypeptides may be provided to the subject in a more concentrated form. Such concentration is obtainable using techniques known in the art, for example, by salt precipitation, evaporation or lyophil ization of the compositions of the invention. ;Active polypeptide-containing preparations may be combined from more than one allergen-administered animal, and from more than one species of allergen-administered animal so as to provide the subject who is in need of desensitization with a composition containing a variety of polypeptide subfractions from different genetic heritages. ;Although inducing a milk-producing animal to an antibody producing state or to a hyperimmune state is not necessary, neither is it detrimental to the milk described herein and continuous production of milk containing the active polypeptides may be achieved by repeatedly administering the allergen to the milk-producing human host. ;-13- ;Without meaning to be held to this theory, since the processing mechanism of the immune system is not fully understood, it is thought that the foreign protein or polypeptide is ingested or phagocytized by special cells of the immune system, the most noteworthy of which are the macrophage and neutrophil. After administration to a milk-producing animal, enzymes within the immune cell break down or derivatize the protein or polypeptide allergen into forms herein interchangeably termed "processed" forms or "subfractions" of the allergen. ;The immune cell-produced subfractions are unique and cannot be produced outside of the natural host. The uniqueness is based first on the structure of the parent allergen and second on the combination of enzymes contained in the mammalian host's allergen processing cells. The enzyme combination which is expressed in the mammalian allergen processing cells are genetically determined; other species each have a unique combination of enzymes. For example peptide fractions of allergens processed by the immune cells of the bovine species are similar, but not identical, to polypeptide fractions processed by the immune cells of other species. It is because of this genetic specificity that the polypeptides produced by the process of this invention are unique and different from polypeptides produced by any other method. ;Special immune cells called helper cells assist the macrophage in presenting the processed antigens to T and B lymphocytes. The passage of the allergen subfraction with and/or from the macrophage through the blood and across the mammary gland and into the milk may further modify the structure of the allergen polypeptide found in milk. This natural biological method of processing environmental antigens and transporting natural immune suppressants into the milk provides a mechanism whereby the dairy cow transfers immune ;-14- ;protective factors to the calf through milk. These milk immune factors protect the nursing young of such animals against allergic reactions. Nature, through the process of evolution, has found a method for the mother of the species to sample the environment for potential allergens. The immune system then transforms the environmental allergens into the factors that protect against allergic reactions. The mother passes the immune protective factors to the nursing infant through milk. The essence of the discovery of the invention is that man can utilize this natural biological process to transform known allergens into immune protective polypeptide fractions that have utility for preventing and treating allergic reactions. ;The milk immune suppressive factor is a polypeptide subfraction found in milk and not the antibodies found in milk. Although it is probable that antibodies are useful in treating allergies, milk antibody is not the immune suppressive product. ;The milk of human animals treated by the process of"this* invention contains specific and unique polypeptide subfractions of the allergens used to treat the host. The same milk lacks the intact or underivatized parent allergen. The uniqueness of these polypeptide fractions results from specific enzymatic breakdown by specialized immune cells of the host. Blood and mammary tissue enzymes may also play a role in modifying the chemistry of the allergens before entry into the milk. Milk containing these unique nonreactive polypeptides is useful as an oral immune treatment for inducing protection and/or tolerance when fed to other species including man. The milk allergen polypeptide fractions, when isolated from the milk, are useful for suppressing allergic reactions against the representative parent allergens.
The allergen may be administered to the milk-producing human animal by various routes of administration including oral,
rectal, vaginal, intramuscular injection, subcutaneous injection, intradermal injection, transcutaneous administration, etc. While, any route of treatment can be used for administering the allergen, the preferred route of treatment is by intramuscular injection of the allergen into the host. The allergen, upon entry into the body of the milk-producing animal, is processed by the immune system of the milk-producing host.
Treatment of the allergic individual or animal with the compositions in accordance with the"invention effects protection in that individual or animal against the parent allergen without danger of side effects that may occur when the parent molecule is used. Examples of protein or polypeptide allergens that can be processed by the mammalian milk system of mammals include pollen allergens of weeds, grasses and trees, animal venoms and poisons, and various food allergens.
Theoretically, any allergen can be processed by the mammalian, macrophage system to produce immune suppressive polypeptide subfractions.
The process of this invention is advantageous because it uses the full spectrum of processing enzymes available in the allergen processing cell of the mammalian immune system. A second advantage of the process of this invention is that the full spectrum of polypeptide fractions is contained in the immune suppressive milk product and the immune suppressant allergen fractions, when contained in a natural milk vehicle, are orally active. The process of this invention, does not require selection of specific enzymes to degrade the allergen in vitro or regulation of the enzymatic digestive process, nor does the process of this invention require separation of the enzymes and residual parent molecules from the reaction system. The entire antigen processing occurs naturally within the body of the milk-producing animal. The genetics of the
a§
mammal selects the enzymes and the natural metabolism of the mammal maintains reaction conditions at an optimal level for antigen processing.
The peptide fractions described herein may be monitored, purified and isolated by any technique or combination of techniques wherein such peptides retain their bioactivity, that is, wherein such peptides retain the ability to suppress allergic responses. Such techniques are known in the art and include, but are not limited to, chromatographic techniques, including adsorption chromatography, gel chromatography and especially, gel chromatography through a dextran, polyacrylamide, or agarose matrix, ion-exchange chromatography, for example, utilizing a strong cationic exchanger such as, for example, SP-Sephadex (which contains a sulfopropyl functional group derivatized to a dextran), AG 50 (which contains a sulfonic acid derivatized to styrene-divinyl-benzene), and Bio-Rex 40 (which contains a sulfonic acid functional group derivatized to a phenolic matrix); weak cationic exchangers, such as, for example, CM-Sepharose (which contains a carboxymethyl functional group derivatized to a dextran), Bio-Rex 70 (which contains a carboxylic functional group derivatized to a phenolic matrix); strong anionic exchangers, such as, for example, QAE-Sephadex (which contains a di ethyl - (2-hydroxypropyl)-aminoethyl functional group derivatized to a dextran), AG 1 (which contains a tetramethylammonium ion functional group derivatized to styrene-divinyl-benzene); weak anionic exchangers, such as, for example, DEAE-Sephadex (which contains a diethylaminoethyl functional group derivatized to a dextran, AG-3 (which contains a tertiary amino functional group derivatized to an epoxyamine matrix); medium strength cationic exchangers, such as, for example, CM-cellulose (which contains a carboxymethyl functional group derivatized to cellulose), P-cel (which contains a phospho- functional group derivatized to
cellulose); and medium strength anionic exchangers, such as, for example, DEAE-cell ul ose (which contains a diethylaminoethyl functional group derivatized to cellulose), PEI-cellulose (which contains a polyethyleneimine functional group derivatized to cellulose, DEAE(BND)-cellulose (which contains a benzoyl ated-naphthoylated, diethyl aminoethyl functional group derivatized to cellulose), PAB cellulose (which contains a p-aminobenzyl functional group derivatized to cellulose); and, exchangers which provide a mixture of functional groups, such as, for example, AG501 (which contains two functional groups, sulfonic acid and tetramethylammonium ion derivatized to a styrene-divinyl benzene matrix). In addition, high pressure liquid chromatography, may be used to separate the peptides.
Other compounds may be conjugated, either chemically or by genetic engineering, to the active polypeptides so as to enhance or provide additional properties to such polypeptide-containing compositions, especially properties which enhance the active polypeptide's ability to promote relief of an allergen's effects in a subject in need of immune suppressive treatment.
Amounts and regimens for the administration of the immune suppressive compositions can be determined readily by those with ordinary skill. Generally, the dosage of the active peptide-containing composition will vary depending upon considerations such as: type of allergen employed; age of the subject being treated; health of the subject being treated; type of allergy being treated; kind of concurrent treatment, if any; physiological tolerance to the compositions of the invention; frequency of treatment and the nature of the effect desired; gender; duration of the symptoms; and, counterindications, if any, and other variables as may be adjusted, as desired, by the individual's physician. Dosage
can be administered in one or more applications to obtain the desired results.
The compositions can be administered in any appropriate pharmacological carrier for administration. They can be administered in any form that effects prophylactic, palliative, preventative or curing conditions of allergic reactions in humans.
Preparations of the active polypeptide-containing compositions for parenteral administration includes sterile aqueous or non-aqueous solvents, suspensions and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oil, fish oil, and injectable organic esters. Aqueous carriers include water, water-alcohol solutions, emulsions or suspensions, including saline and buffered medical parenteral vehicles including sodium chloride solution, Ringer's dextrose solution, dextrose plus sodium chloride solution, Ringer's solution containing lactose, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers, such as those based upon Ringer's dextrose and the like.
The immune suppressive compositions may also be administered by means of pumps, or in sustained-release form.
Administration in a sustained-release form is more convenient for the patient when continuous repeated administration for prolonged periods of time are indicated.
The active polypeptide-containing compositions can be employed in dosage forms such as tablets, capsules, powder packets, or liquid solutions for oral administration.
The pharmaceutical compositions are manufactured in a manner which is in itself known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, lyophilizing or similar processes.
Having now generally described the invention, the following examples further describe the materials and methods used in carrying out the invention. The examples are not intended to limit the invention in any manner.
Immunization of Cows and Collection of Immune Milk
The immunogen for the preparation of the milk product for allergy symptom alleviation comprises a mixture of commercial allergen extracts purchased as 1:100 wt:vol preparations and pooled in the following ratios:
EXAMPLES
Example 1
ALLERGEN
Volume (ml)
Alternaria tenuis Aspergillus niger Monilia albicans Hormodendrum hordei Lambs quarter House dust
Helminthosporium Sat. Russian thistle Careless weed Spiny pigweed Mugwort, common Ragweed, slender Ragweed, southern Ragweed, false Ragweed, short Ragweed, giant Pigweed, redroot Trichophyton mentag Goldenrod Palmer's ameranth Sage, prairie Curvularia spisifera Pullularia pullulans Mucor plumbeus Fusarium moniliforme GS Mold Mix #2 GS 10 Tree Mix Rhizopus nigricans
10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 30 30 30 30 30 30 30
The pooled mixture is diluted with an equal volume of sterile saline. Cows are injected intramuscularly with 5 ml of the preparation at 2 week intervals during normal lactation, and the milk is collected and powdered. Milk is collected beginning 24 hr. post treatment.
Example 2 Fractionation of Milk Fractions Containing Processed Allergens
Twenty liters of fresh milk from hyperimmunized cows were run through a cream separator (DeLaval Model 102) to remove the fat.
The resulting sixteen liters of skimmed milk was ultrafiltered to remove the high molecular weight species (over 100,000 daltons) using a hollow fiber diafiltration/ concentrator. The concentrator is equipped with two 100,000 daltons molecular weight cut-off cartridges. The skimmed milk was run at the pump speed of 80 on the meter and inlet and outlet pressure of 30 psi and 25 respectively.
Twelve liters of the filtrate (<100,000 daltons) coming out of the cartridges at the flow rate of four liters per hour was frozen or 1yophi1ized for storage.
The same methods may be used to fractionate the milk from non-hyperimmunized cows."
Example 3
Desensitization of Allergic Subjects
Human volunteers consumed approximately 1/2 cup of the immune milk powder reconstituted with 8 oz of water. Two hundred volunteers ranged in age from 4 to 87 years, and drank the milk for 1 to 172 months. Of 168 subjects with allergies who submitted responses indicating the status of their condition, 138 (82.1%) indicated that they had improved while drinking the milk. Ninety-four percent of subjects reporting benefits stated their improvement occurred within I month of starting to drink the milk. Specific effects reported included less congestion, fewer or no headaches, easier breathing, less itching, swelling, sneezing, wheezing, coughing, rhinorrhea, and an enhanced ability to smell and taste. Many subjects reported a recurrence of symptoms of milk consumption was stopped, and several subjects discontinued allergy immunotherapy after drinking the milk.
Having now fully described the invention, it will be understood by those with skill in the art that the scope may be performed within a wide and equivalent range of conditions, parameters and the like, without affecting the spirit or scope of the invention or any embodiment thereof.
Claims (5)
1. A method for desensitizing a human subject to an allergen wherein said method which comprises orally administering to said subject a food product, in an amount and for a time sufficient to produce an allergic response-suppressive effect in said subject against said allergen, wherein said food product comprises allergic response-suppressive amounts of active, non-antibody polypeptides from the milk of milk-producing, immunized animals wherein said animals have been immunized against said allergens.
2. The method of claim 2, wherein said food product is selected from the group consisting of milk, skim milk, yoghurt and cheese.
3. The method of claim 2, wherein said food product is in powdered form.
4. The method of claim 2, wherein said food product is in liquid form.
5. A method as defined in claim 1 for desensitizing a human subject to an allergen substantially as herein described with reference to any example thereof. END OF CLAIMS ERfp 'O Uj 1 h 2002
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US54841990A | 1990-07-05 | 1990-07-05 |
Publications (1)
Publication Number | Publication Date |
---|---|
NZ505179A true NZ505179A (en) | 2002-06-28 |
Family
ID=24188777
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NZ238117A NZ238117A (en) | 1990-07-05 | 1991-05-10 | Non-antibody-containing fraction of milk and its use in food products, vaccines and for allergic suppression |
NZ505179A NZ505179A (en) | 1990-07-05 | 1991-05-10 | Immune suppressive food product comprising polypeptide fragments of allergens |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NZ238117A NZ238117A (en) | 1990-07-05 | 1991-05-10 | Non-antibody-containing fraction of milk and its use in food products, vaccines and for allergic suppression |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0646017A1 (en) |
JP (1) | JP3054194B2 (en) |
AU (1) | AU648800B2 (en) |
CA (1) | CA2086101C (en) |
NZ (2) | NZ238117A (en) |
WO (1) | WO1992000756A1 (en) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AUPP494798A0 (en) | 1998-07-29 | 1998-08-20 | Pacific Biolink Pty Limited | Protective protein formulation |
GB0002386D0 (en) * | 2000-02-02 | 2000-03-22 | Novartis Nutrition Ag | Therapeutic composition |
US7060687B2 (en) | 2001-02-07 | 2006-06-13 | Genmont Biotechnology Co. | Live vaccines for allergy treatment |
US20020197268A1 (en) * | 2001-06-08 | 2002-12-26 | Hsu Ching-Hsaing | Allergen-containing milk for allergy treatment |
US6770280B1 (en) | 2001-11-15 | 2004-08-03 | Humanetics Corporation | Treatment of menorrhagia, hypermenorrhea, dysmenorrhea and menstrual migraines by the administration of an antibacterial milk product |
US20100129377A1 (en) * | 2007-04-16 | 2010-05-27 | Friesland Brands B.V. | Milk derived antigen-specific antibodies, methods of preparation and uses thereof |
NL1033696C2 (en) * | 2007-04-16 | 2008-10-20 | Friesland Brands Bv | Obtaining an antigen specific antibody from milk derived from a non-human mammal that has not been immunized with the antigen prior to collecting the milk for delivering an antibody of a ruminant |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3128230A (en) * | 1961-04-04 | 1964-04-07 | Sunbury Milk Products Co | Milk having antibodies therein and process for producing same |
US3376198A (en) * | 1965-07-21 | 1968-04-02 | Collins Products Inc | Method of producing antibodies in milk |
US4732757A (en) * | 1978-02-06 | 1988-03-22 | Stolle Research And Development Corporation | Prevention and treatment of rheumatoid arthritis |
US4284623A (en) * | 1979-11-09 | 1981-08-18 | Beck Lee R | Method of treating inflammation using bovine milk |
USRE33403E (en) * | 1982-06-03 | 1990-10-23 | Stolle Research & Development Corporation | Method for treating disorders of the vascular and pulmonary systems |
US4879110A (en) * | 1983-10-27 | 1989-11-07 | Stolle Research And Development Corporation | Antihypertensive hyperimmune milk, production, composition, and use |
US4636384A (en) * | 1982-06-03 | 1987-01-13 | Stolle Research & Development Corporation | Method for treating disorders of the vascular and pulmonary systems |
US5242691A (en) * | 1982-06-03 | 1993-09-07 | Stolle Research & Development Corporation | Anti-inflammatory factor, method of isolation, and use |
US4956349A (en) * | 1983-10-27 | 1990-09-11 | Stolle Research & Development Corporation | Anti-inflammatory factor, method of isolation, and use |
AU590711B2 (en) * | 1982-10-13 | 1989-11-16 | Biowhittaker, Inc. | Stable allergenic extracts and methods |
-
1991
- 1991-04-26 WO PCT/US1991/002923 patent/WO1992000756A1/en not_active Application Discontinuation
- 1991-04-26 JP JP3509229A patent/JP3054194B2/en not_active Expired - Fee Related
- 1991-04-26 AU AU78916/91A patent/AU648800B2/en not_active Ceased
- 1991-04-26 EP EP91909691A patent/EP0646017A1/en not_active Withdrawn
- 1991-04-26 CA CA002086101A patent/CA2086101C/en not_active Expired - Fee Related
- 1991-05-10 NZ NZ238117A patent/NZ238117A/en unknown
- 1991-05-10 NZ NZ505179A patent/NZ505179A/en active IP Right Revival
Also Published As
Publication number | Publication date |
---|---|
AU648800B2 (en) | 1994-05-05 |
JP3054194B2 (en) | 2000-06-19 |
AU7891691A (en) | 1992-02-04 |
NZ238117A (en) | 1996-01-26 |
CA2086101C (en) | 2002-11-19 |
JPH05508397A (en) | 1993-11-25 |
WO1992000756A1 (en) | 1992-01-23 |
EP0646017A1 (en) | 1995-04-05 |
CA2086101A1 (en) | 1992-01-06 |
EP0646017A4 (en) | 1993-07-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1051494B1 (en) | Methods and reagents for decreasing allergic reactions | |
US5196193A (en) | Antivenoms and methods for making antivenoms | |
US5772999A (en) | Method of preventing, countering, or reducing NSAID-induced gastrointestinal damage by administering milk or egg products from hyperimmunized animals | |
CN101247826A (en) | Biodegradable nanoparticle having T-cell recognizable epitope peptide immobilized thereon or encapsulated therein | |
JP3195631B2 (en) | Method for producing specific chicken egg antibody | |
JPH06510768A (en) | Vaccine for treating IgE-mediated allergic reactions containing part of the constant region of IgE | |
EP3522921B1 (en) | Prevention of allergy | |
US5529786A (en) | Process and product for treatment of rheumatoid arthritis | |
KR910005409B1 (en) | Process for preparing specific antibody containing substance from eggs | |
US5863561A (en) | Immune suppressive product | |
JP2003521524A (en) | Oral delivery of allergens in milk | |
DE69737191T2 (en) | Anti-inflammatory composition of egg, process for isolation and use | |
JP4554728B2 (en) | Pharmaceutical or food composition for the treatment of a medical condition associated with graft rejection or allergy or autoimmune reaction | |
CA2086101C (en) | Immune suppressive product from milk | |
KR20180027582A (en) | Production method of egg yolk having high AF-16 content | |
US20020119159A1 (en) | Combinations of antigen and mucosal binding component for inducing specific immunological tolerance | |
US6054124A (en) | Immune suppressive product | |
CA2317813A1 (en) | Composition and method for treatment and prevention of arthritis and/or autoimmune diseases | |
US7879977B2 (en) | Methods and reagents for decreasing clinical reaction to allergy | |
JPH0669962B2 (en) | Oral immunoglobulin | |
Yonemasu et al. | Antigenic specificities of delayed hypersensitivity in mice to dinitrophenylated proteins | |
Christensen et al. | The oral immunogenicity of BioProtein, a bacterial single-cell protein, is affected by its particulate nature | |
JPH07138187A (en) | Oral tolerogen, oral therapeutic agent for rheumatoid arthritis and functional food | |
Alam et al. | Production and properties of histamine-releasing factor of guinea pigs. | |
CN1557836A (en) | Preparation and use for immunosuppressive polypeptides |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PSEA | Patent sealed | ||
S35A | Application for proceedings under section 35 (restoration of lapsed patents) | ||
RENW | Renewal (renewal fees accepted) | ||
S35R | Proceedings under section 35 (restoration of lapsed patents): patent restored |