DK158138B - METHOD OF PREPARING IMMUNOGLOBULIN-IGG-CONTAINING MILK OR FROM DERIVED PRODUCT TO TREAT RHEUMATOID ARTHRITIS - Google Patents
METHOD OF PREPARING IMMUNOGLOBULIN-IGG-CONTAINING MILK OR FROM DERIVED PRODUCT TO TREAT RHEUMATOID ARTHRITIS Download PDFInfo
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Description
iin
DK 158138 BDK 158138 B
Den foreliggende opfindelse angår en fremgangsmåde til fremstilling af immunoglobulin-IgG-holdig mælk eller herudfra afledt produkt til behandling af rheumatoid arthritis, ved hvilken fremgangsmåde der anvendes en vaccine, som er fremstillet ud fra kulturer af bakte-5 riestammer, der er dyrket i passende dyrkningsmedier, hvorefter bakterierne er blevet dræbt, indhøstet, vasket, lyofiliseret og suspenderet i en til injektion passende vehikel.The present invention relates to a method for producing immunoglobulin IgG-containing milk or derived product for the treatment of rheumatoid arthritis, using a vaccine prepared from cultures of bacterial strains grown in appropriate culture media, after which the bacteria have been killed, harvested, washed, lyophilized and suspended in a vehicle suitable for injection.
For et antal år siden var det almindeligt antaget, at rheumatoid 10 arthritis havde en infektiøs ætiologi. Denne opfattelse er ikke vel anset idag, endskønt de betændelsesagtige aspekter og væsentlige manifestationer ved rheumatoid arthritis - synovitis (ledbetændelse) og granulomatøse læsioner, feber, tachycardia, leukocytose, lympha-denopati og lejlighedsvis splenomegali, den accelererede erythrocyt-15 sedimentationshastighed og andre forandringer hos "akut-fase-reak-tanter" - alle er kompatible med en infektiøs proces. Kompetente og gentagne bakteriologiske studier har ikke været i stand til på overensstemmende måde at udvinde et enkelt infektiøst agens fra blod, synovial væske (ledvæske), synovial væv (ledvæv) eller subkutane 20 noduli (underhudsknuder). Forsøg på at overføre sygdommen ved injektion af ledvæske fra patienter med rheumatoid arthritis i led på andre humane individer har været uden succes. Subkutane noduli har ikke været i stand til at overleve efter en homolog transplantation (Bauer, W., Clark, W.S. og Dienes, L, The Practitioner, 166: 25 5 (1961)).A number of years ago, it was widely believed that rheumatoid 10 arthritis had an infectious etiology. This view is not well considered today, although the inflammatory aspects and essential manifestations of rheumatoid arthritis - synovitis and granulomatous lesions, fever, tachycardia, leukocytosis, lymphadenopathy and occasional splenomegaly, the accelerated erythrocyte duct and other sedation disorders "acute-phase reactants" - all compatible with an infectious process. Competent and repeated bacteriological studies have not been able to recover in a consistent manner a single infectious agent from blood, synovial fluid (articular fluid), synovial tissue (articular tissue) or subcutaneous nodules (subcutaneous nodules). Attempts to transmit the disease by injection of joint fluid from patients with rheumatoid arthritis into the joints of other human subjects have been unsuccessful. Subcutaneous nodules have been unable to survive after a homologous transplant (Bauer, W., Clark, W.S. and Dienes, L, The Practitioner, 166: 25 (1961)).
En infektiøs proces synes at fremme sygdommens indtræden ved rheumatoid arthritis hos et betydeligt antal patienter og kan udøve en skadelig virkning på forløbet af sygdommen, når den allerede er ind-30 trådt. Der er statistisk sandsynlighed for dette kliniske indtryk (Lewis-Fanning, E., Ann. Rheum. Dis.. Supplement 9 (1950)).An infectious process seems to promote the onset of the disease in rheumatoid arthritis in a significant number of patients and can exert a detrimental effect on the course of the disease when it has already occurred. There is statistical probability of this clinical impression (Lewis-Fanning, E., Ann. Rheum. Dis. Supplement 9 (1950)).
Der er blevet gjort mange forsøg på at frembringe en sygdom i dyr svarende til rheumatoid arthritis. Endskønt et antal forskellige 35 bakterier kan frembringe arthritis i dyr, er de ikke i stand til at reproducere de kliniske og patologiske træk ved rheumatoid arthritis, navnlig de seivvedvarende karakteristika ved den proliferative arthritis. En arthritis, der har nogen lighed med den humane lidelse, er blevet frembragt i mus med pleuro-pneumonialignendeMany attempts have been made to produce a disease in animals similar to rheumatoid arthritis. Although a number of different bacteria can produce arthritis in animals, they are unable to reproduce the clinical and pathological features of rheumatoid arthritis, in particular the persistent characteristics of proliferative arthritis. An arthritis that bears some resemblance to the human disorder has been produced in mice with pleuro-pneumonia-like
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2 organismer (Sabin, A.B., Science, 89: 228 (1939)) og i svin med Erysipelothrix rhusiopathiae (Sikes, D., Neher, G.M., og Doyle, L.P., Am. J. Vet. Res.. 16 (1955)). Det er blevet postuleret, at disse organismer initierer en hypersensitivitetsmekanisme (Sikes, 5 D., Neher, G.M., og Doyle, L.P., Am. J. Vet. Res.. 16 (1955)).2 organisms (Sabin, AB, Science, 89: 228 (1939)) and in pigs with Erysipelothrix rhusiopathiae (Sikes, D., Neher, GM, and Doyle, LP, Am. J. Vet. Res. 16 (1955) ). It has been postulated that these organisms initiate a hypersensitivity mechanism (Sikes, 5 D., Neher, G.M., and Doyle, L.P., Am. J. Vet. Res. 16 (1955)).
Forskere af rheumatoid arthritis fortsætter ikke desto mindre med at blive indfanget af visse genopdukkende temaer, der formoder forbindelser mellem infektioner og ledlidelser. F.eks. er gonorré i stand 10 til at frembringe ikke blot typisk gonorré-arthritis men også lejlighedsvis at indlede en kronisk arthritis, der udvikler sig til typisk rheumatoid arthritis. Der foreligger ingen statistik om den hyppighed, hvormed dette indtræder, så man kan ikke vide, hvor megen vægt man kan lægge på sammenhængen. Tonsillitis (betændelse i 15 mandlerne) eller pharyngitis (betændelse i svælget) kan også efterfølges af en polyarthritis, som først synes at være rheumatisk feber, men som udvikler sig til rheumatoid arthritis. Akutte virusinfektioner, især rubella hos unge kvinder, kan efterfølges af vedvarende polyarthritides, der involverer de små led såvel som de 20 store; disse arthritides har almindeligvis et forløb på adskillige måneder med vedvarende ledlidelse, der ligner rheumatoid arthritis, inden de gradvist aftager.Researchers of rheumatoid arthritis nonetheless continue to be captured by certain reappearing themes that presume links between infections and joint disorders. Eg. is gonorrhea capable of producing not only typical gonorrheal arthritis but also occasionally initiating a chronic arthritis that develops into typical rheumatoid arthritis. There are no statistics on the frequency with which this occurs, so you cannot know how much weight you can put on the context. Tonsillitis (inflammation of the 15 tonsils) or pharyngitis (inflammation of the pharynx) may also be followed by a polyarthritis, which at first appears to be rheumatic fever, but which develops into rheumatoid arthritis. Acute viral infections, especially rubella in young women, may be followed by persistent polyarthritides involving the small joints as well as the large ones; These arthritides usually have several months of persistent joint resemblance to rheumatoid arthritis before gradually subsiding.
Selvom kronisk infektion med et ukendt agens forbliver en populær 25 antagelse som ætiologi for rheumatoid arthritis, findes der ingen publicerede data til støtte for denne formodning. Nogle af sygdommens udforskere nærer formodning om, at hvis infektion er en faktor, er det måske ikke en infektion med en specifik type mikroorganismer, men snarere infektion med et bredt spektrum af banale mikroorganis-30 mer i forbindelse med et ændret værtsrespons frembragt af de infektioner, der er ansvarlige for sygdommen. Den foreliggende opfindelse er baseret på denne teori om oprindelsen til rheumatoid arthritis.Although chronic infection with an unknown agent remains a popular assumption as the etiology of rheumatoid arthritis, no published data exists to support this presumption. Some of the researchers of the disease have the presumption that if infection is a factor, it may not be an infection with a specific type of microorganism, but rather an infection with a broad spectrum of banal microorganisms in connection with a changed host response produced by the infections. who are responsible for the disease. The present invention is based on this theory of the origin of rheumatoid arthritis.
Endskønt en infektiøs ætiologi aldrig er blevet fastslået, synes 35 adskillige af den senere tids opdagelser relevante som støtte for denne teori.Although an infectious etiology has never been established, 35 of several recent discoveries seem relevant in support of this theory.
Nogle af disse er følgende:Some of these are the following:
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3 1. Patienter med rheumatoid arthritis har lavere IgAværdier end normalt; IgA er den klasse af immunoglobuliner, der findes i mave-tarmkanalens sekreter.3 1. Patients with rheumatoid arthritis have lower IgA values than normal; IgA is the class of immunoglobulins found in the secretions of the gastrointestinal tract.
5 2. Immunoglobulin A fremkommet som respons på immunisering via spytkirtlerne findes i serum kolostrum og mælk såvel som i spyttet. Det formodes, at IgA transporteres til disse forskellige væsker via mave-tarmkanal en og det lymfatiske system (Michelok, S.M., Rolman, A.F.R., og McGhee, J.R., Proc. Soc.2. Immunoglobulin A produced in response to immunization via the salivary glands is found in serum colostrum and milk as well as in saliva. It is believed that IgA is transported to these various fluids via the gastrointestinal tract and the lymphatic system (Michelok, S.M., Rolman, A.F.R., and McGhee, J.R., Proc. Soc.
10 Exptl. Biol. Med.. 148; 1114 (1975)).10 Exptl. Biol. Med .. 148; 1114 (1975)).
3. Efter en tarmomføringsoperation ved morbus obesicas udvikler nogle patienter symptomer, som faktisk er identisk med rheumatoid arthritis. Udbruddet af arthritis ledsages af fremkomsten 15 i blodserum af cirkulerende kryoproteiner, der er proteiner, som udfældes eller danner gel ved henstand ved køleskabstemperatur, i nogle tilfælde også ved noget højere temperatur, og som atter går i opløsning ved 37°C sammensat af IgG, IgM, IgA, komplementkomponenter C3, C^, C5 og IgGantistof mod E. coli og 20 B. fragil is. Fjernelse af tarmomføringen resulterer i fuld stændig forsvinden af symptomerne (Woods, J.R., La Mont, J.T.,3. Following a bowel resection operation in morbus obesicas, some patients develop symptoms that are actually identical to rheumatoid arthritis. The onset of arthritis is accompanied by the emergence in blood serum of circulating cryoproteins, which are proteins that precipitate or gel upon standing at refrigerator temperature, sometimes even at somewhat higher temperatures, and again dissolve at 37 ° C composed of IgG, IgM, IgA, complement components C3, C1, C5 and IgG antibody to E. coli and 20 B. fragile ice. Removal of the intestinal tract results in the complete disappearance of the symptoms (Woods, J.R., La Mont, J.T.,
Maur, E., Isselbacher, K.J., New Enol. J. Med.. 294: 121 (1976)).Maur, E., Isselbacher, K. J., New Enol. J. Med .. 294: 121 (1976)).
25 4. En type af Diplostreptococcus agalactiae tilhørende streptococ- gruppen B er blevet inddraget som et ætiologisk agens ved rheumatoid arthritis (Svartz, N., Acta. Med. Scand., 192: 231 (1972)). Denne streptococ er til stede i det meste, kommercielt tilgængelige, pasteuriserede mælk, men ikke i immun mælk.4. A type of Diplostreptococcus agalactiae belonging to the streptococ group B has been implicated as an etiologic agent in rheumatoid arthritis (Svartz, N., Acta. Med. Scand., 192: 231 (1972)). This streptococ is present in most commercially available pasteurized milk but not in immune milk.
30 5. En prædisposition for rheumatiske lidelser synes at være arvelig via de histokompatible antigener (HL-A). Disse antigener bestemmer sandsynligvis værtsorganismens respons på infektiøse agenser.30 5. A predisposition to rheumatic disorders appears to be hereditary via the histocompatible antigens (HL-A). These antigens are likely to determine the host organism's response to infectious agents.
35 På basis af disse indicier konkluderes det, at rheumatoid arthritis har en infektiøs oprindelse, at infektionen finder sted i fordøjelseskanalen, at et antal forskellige bakteriestammer er involveret i infektionen, at infektionen sandsynligvis opstår som følge af enOn the basis of these indications, it is concluded that rheumatoid arthritis has an infectious origin, that the infection takes place in the digestive tract, that a number of different bacterial strains are involved in the infection, that the infection is likely to occur as a result of an infection.
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4 fejl i værtsorganismens immunforsvarsmekanisme, og at den mest effektive måde at behandle sygdommen på er at reetablere immunbeskyttelsen mod det infektiøse agens i fordøjelseskanalen.4 defects in the host organism's immune defense mechanism, and that the most effective way to treat the disease is to reestablish immune protection against the infectious agent in the digestive tract.
5 Basalt er der to måder, som kan anvendes til behandling af infektion: Immunmetoden, som involverer enten aktiv eller passiv immunisering mod det infektiøse patogen, og anvendelsen af antibiotika, såsom penicillin, tetracyclin, ampicillin, o.l. Antibiotika er ikke specifikke i deres virkning, og de dræber et bredt spektrum af 10 gavnlige såvel som skadelige bakterier. På den anden side er immunmetoden højst specifik. Baktericide antistoffer frembragt mod en specifik bakteriestamme reagerer kun med denne stamme og har ingen skadelige virkninger på andre typer bakterier. Desuden er antistoffer - modsat antibiotika -naturlige legemsprodukter, som ikke har 15 kendte bivirkninger. Da formålet med opfindelsen er at kontrollere infektion med en specifik bakteriegruppe uden at skade gavnlige bakterier i fordøjelseskanalen, er immunmetoden den valgte fremgangsmåde.Basically, there are two ways that can be used to treat infection: the immune method, which involves either active or passive immunization against the infectious pathogen, and the use of antibiotics such as penicillin, tetracycline, ampicillin, and the like. Antibiotics are not specific in their effect and they kill a wide spectrum of 10 beneficial as well as harmful bacteria. On the other hand, the immune method is highly specific. Bactericidal antibodies produced against a specific bacterial strain react only with this strain and have no deleterious effects on other types of bacteria. In addition, antibodies - as opposed to antibiotics - are natural body products that do not have 15 known side effects. Since the object of the invention is to control infection with a specific bacterial group without damaging beneficial bacteria in the digestive tract, the immune method is the method of choice.
20 Der findes to forskellige metoder til at opnå immunbeskyttelse på.There are two different methods of obtaining immune protection.
Aktiv immunisering er en metode, ved hvilken værtsorganismen immuniseres aktivt med en vaccine, der stimulerer værtsorganismens immunsystem til produktion af beskyttende antistoffer mod faktorer, der er indeholdt i vaccinen. Aktiv immunisering indtræder under natur-25 lige forhold, når værtsorganismen udsættes for infektiøse patogener.Active immunization is a method by which the host organism is actively immunized with a vaccine that stimulates the host organism's immune system to produce protective antibodies against factors contained in the vaccine. Active immunization occurs under natural conditions when the host organism is exposed to infectious pathogens.
Passiv immunisering er en metode, ved hvilken antistoffer, der er opnået fra et individ, som er blevet immuniseret aktivt, gives til et andet individ. Ved denne metode overføres de beskyttende antistoffer fra den immune værtsorganisme til modtageren. Passiv immun-30 beskyttelse er midlertidig og varer kun så længe som de passivt erhvervede antistoffer fortsat er til stede i modtagerens organisme.Passive immunization is a method by which antibodies obtained from one subject that has been actively immunized are given to another subject. In this method, the protective antibodies are transferred from the immune host organism to the recipient. Passive immune protection is temporary and only lasts as long as the passively acquired antibodies continue to be present in the recipient's organism.
F.eks. kan antistoffer, der er opnået fra heste, som er blevet immuniseret mod tetanustoxin, gives til mennesker, som er blevet inficeret med tetanus, til opnåelse af en midlertidig immunbe-35 skyttel se mod det toxin, der produceres af tetanus-bakterier.Eg. For example, antibodies obtained from horses that have been immunized against tetanus toxin can be given to humans infected with tetanus to provide a temporary immune response to the toxin produced by tetanus bacteria.
I beskrivelsen til et tidligere patent (USA patent nr. 3.626.057) er der beskrevet en fremgangsmåde til fremstilling af tetanusantitoxin i mælk. Dette patentskrift lærer, at koen kan immuniseres aktivt modIn the disclosure of a previous patent (U.S. Patent No. 3,626,057), a process for the preparation of tetanus antitoxin in milk is described. This patent teaches that the cow can be actively immunized against
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5 tetanustoxin, at antistoffer frembragt af koen mod toxinet kan opnås fra koens mælk, og at disse antistoffer kan anvendes til behandling af dyr, som er blevet inficeret med tetanusbakterier, på en sådan måde, at antistofferne neutraliserer toxinet. Patentskriftet lærer, 5 at den passive administration af antistoffer neutraliserer det livstruende toxin, som frembringes af bakterierne, og derved tilvejebringer midlertidig immunitet mod toxinet.5 tetanus toxin, that antibodies produced by the cow against the toxin can be obtained from the cow's milk, and that these antibodies can be used to treat animals that have been infected with tetanus bacteria in such a way that the antibodies neutralize the toxin. The patent teaches that the passive administration of antibodies neutralizes the life-threatening toxin produced by the bacteria, thereby providing temporary immunity to the toxin.
Passiv immunisering adskiller sig fra aktiv immunisering derved, at 10 immunbeskyttelsen er midlertidig og kun varer så længe som de beskyttende antistoffer er til stede. Aktiv immunisering er mere permanent, fordi værtsorganismens immunsystem fortsætter med at producere beskyttende antistoffer ved tilstedeværelsen af det stimulerende antigen.Passive immunization differs from active immunization in that the immune protection is temporary and only lasts as long as the protective antibodies are present. Active immunization is more permanent because the host organism's immune system continues to produce protective antibodies in the presence of the stimulating antigen.
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Den senere tids undersøgelser inden for området fordøjelseskanal s-immunologi har vist eksistensen af en lokal immunmekanisme i fordøjelseskanalen. Dette immunsystem i fordøjelseskanalen producerer en speciel type antistof, der virker kontrollerende på bakterielle 2o angreb i fordøjelseskanalens hulrum. Antistoffet, der kaldes sekre-tionsimmunoglobulin eller IgA, produceres som respons på lokal, aktiv immunisering af fordøjelseskanalens slimhinde med antigenet. Sekretionsimmunsystemet i fordøjelseskanalen virker forhindrende på koloniseringen og formeringen af skadelige bakteriearter i dette 25 miljø. Det antages, at svigt hos det lokale immunsystem i fordøjelseskanalen tillader ukendte, skadelige bakterier at etablere sig, og at disse bakterier forårsager rheumatoid arthritis. Ifølge denne teori opstår rheumatoid arthritis som følge af en svigtende evne hos det lokale immunsystem i fordøjelseskanalen til at producere og 3Q sekretere beskyttende antistoffer mod skadelige bakterier. Den manglende evne hos værtsorganismen til at reagere på aktiv immunisering udelukker således denne metode som en fremgangsmåde til behandling af rheumatoid arthritis.Recent studies in the field of digestive tract immunology have shown the existence of a local immune mechanism in the digestive tract. This immune system in the digestive tract produces a special type of antibody that acts to control bacterial 2o attacks in the digestive tract cavity. The antibody, called secretion immunoglobulin or IgA, is produced in response to local, active immunization of the digestive tract mucosa with the antigen. The secretory immune system of the digestive tract prevents the colonization and propagation of harmful bacterial species in this environment. It is believed that failure of the local immune system in the digestive tract allows unknown, harmful bacteria to establish and that these bacteria cause rheumatoid arthritis. According to this theory, rheumatoid arthritis arises from a failing ability of the local immune system in the digestive tract to produce and 3Q secrete protective antibodies against harmful bacteria. Thus, the inability of the host organism to respond to active immunization precludes this method as a method of treating rheumatoid arthritis.
35 Den foreliggende opfindelse angår således en fremgangsmåde af immunoglobulin-IgG-holdig mælk eller herudfra afledt produkt til behandling af rheumatoid arthritis, ved hvilken fremgangsmåde der anvendes en vaccine, som er fremstillet ud fra kulturer af bakteriestammer, der er dyrket i passende dyrkningsmedier, hvorefterThus, the present invention relates to a method of immunoglobulin IgG-containing milk or derived product for the treatment of rheumatoid arthritis, using a vaccine prepared from cultures of bacterial strains grown in appropriate culture media, after which
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6 bakterierne er blevet dræbt, indhøstet, vasket, lyofiliseret og suspenderet i en til injektion passende vehikel, hvilken fremgangsmåde er ejendommelig ved, at vaccinen, der fremstilles ud fra bakteriekulturer af følgende mikroorganismer: 5 ORGANISME ATCC NR.6 the bacteria have been killed, harvested, washed, lyophilized and suspended in a vehicle suitable for injection, the method being characterized in that the vaccine prepared from bacterial cultures of the following microorganisms: 5 ORGANISM ATCC NO.
Staphylococcus Aureus 11631Staphylococcus Aureus 11631
Staphylococcus epidermidis 155Staphylococcus epidermidis 155
Streptococcus pyogenes, A. type 1 8671 10 - type 3 10389 type 5 12347 type 8 12349 type 12 11434 type 14 12972 15 - type 18 12357 type 22 10403Streptococcus pyogenes, A. type 1 8671 10 - type 3 10389 type 5 12347 type 8 12349 type 12 11434 type 14 12972 15 - type 18 12357 type 22 10403
Aerobacter aerogenes 884Aerobacter aerogenes 884
Escherichia coli 26Escherichia coli 26
Salmonella enteritidis 13076 20 Pseudomonas aeruginosa 7700Salmonella enteritidis 13076 20 Pseudomonas aeruginosa 7700
Klebsiella pneumoniae 9590Klebsiella pneumoniae 9590
Salmonella typhimurium 13311Salmonella typhimurium 13311
Haemophilus influenzae 9333Haemophilus influenzae 9333
Streptococcus viridans 6249 25 Proteus vulgaris 13315Streptococcus viridans 6249 25 Proteus vulgaris 13315
Shigella dysenteriae 11835Shigella dysenteriae 11835
Streptococcus, gruppe B Diplococcus pneumoniae Streptococcus mutans 30 Corynebacterium, Acne, type 1 og 2, ugentligt injiceres intramuskulært i sunde køer i fire på hinanden følgende uger og derefter to gange månedligt, at hver injektionStreptococcus, group B Diplococcus pneumoniae Streptococcus mutans 30 Corynebacterium, Acne, types 1 and 2, are injected intramuscularly weekly into healthy cows for four consecutive weeks and then twice monthly for each injection.
OISLAND
omfatter 20 x 10 bakterieceller, at mælken fra de immuniserede køer 35 fra den fjerde uges begyndelse indsamles og prøves for titer til sikring af, at minimumstiteren af antistof mod hver af de af vaccinen omfattende bakterier er 1-500 bestemt ved reagensgiasagglutinationsmetoden til prøvning for antistoftiter.20 x 10 bacterial cells comprise the milk from the immunized cows 35 from the beginning of the fourth week collected and tested for titers to ensure that the minimum titer of antibody to each of the vaccine-containing bacteria is 1-500 determined by the reagent gias agglutination test for antibody titers .
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Immunoglobul intypen er vigtig at tage i betragtning, hvad angår patenterbarheden af opfindelsen, eftersom der er fem kendte immunogl obul i nklasser, der betegnes IgG, IgM, IgA, IgD og IgE (Nisonoff, A., Molecules of Immunity in Immunobiology. (Editors Good R.A. og 5 Fisher, W.) Sinauer Associates, Stamford, Connecticut (1971)). Hver immunoglobul intype adskiller sig strukturelt (Waldman, T., Blaese, R.M. og Strobe, W., Plasma Protein Metabolism. (Editors Rothschild, M. og Waldman, Academic Press, side 269 (1970)) og har en forskellig biologisk funktion i legemet (Waldman, T., Immune Mechanisms on 10 Secretory Surfaces, Post Grad. Med.. 50: 78 (1971), og Franklin, E.C., Proo. Al 1 erg.. bind 8, side 57 (1964)). Desuden er der en påfaldende variation i lokaliseringen af immunoglobul i nerne i legemet. F.eks. adskiller fordelingen klart immunoglobul i nklasserne IgA og IgG. Det mest påfaldende træk ved IgA er dets høje koncen-15 tration i legemets eksterne sekretioner, inklusive mave-tarmkanalens væsker. Det er klart blevet påvist, at det immunsystem, som leverer IgA til mave-tarmkanalens saft, er et særskilt system forskelligt fra det, som producerer IgG.The immunoglobulin type is important to consider for the patentability of the invention, as there are five known immunogl obul in classes designated IgG, IgM, IgA, IgD and IgE (Nisonoff, A., Molecules of Immunity in Immunobiology. (Editors Good RA and 5 Fisher, W.) Sinauer Associates, Stamford, Connecticut (1971)). Each immunoglobulin type differs structurally (Waldman, T., Blaese, R. M. and Strobe, W., Plasma Protein Metabolism. (Editors Rothschild, M. and Waldman, Academic Press, p. 269 (1970)) and has a different biological function in body (Waldman, T., Immune Mechanisms on 10 Secretory Surfaces, Post Grad. Med. 50: 78 (1971), and Franklin, EC, Proo. there is a striking variation in the location of immunoglobulin in the bodies of the body, for example, the distribution clearly separates immunoglobulin in the classes IgA and IgG, the most striking feature of IgA is its high concentration in the body's external secretions, including the gastrointestinal tract. It has been clearly demonstrated that the immune system that supplies IgA to the gastrointestinal tract juice is a distinct system different from that which produces IgG.
2o I mennesket findes IgG primært i legemets vaskulære og intracellu-lære rum (Waldman et al, 1970 (se ovenfor)), og meget lidt IgG finder vej til mave-tarmkanalens væsker. En anden vigtig forskel mellem immunoglobul inklasserne vedrører deres metaboliske hastighed.In humans, IgG is found primarily in the vascular and intracellular compartments of the body (Waldman et al., 1970 (see above)), and very little IgG finds its way into the gastrointestinal tract fluids. Another important difference between the immunoglobulin classes relates to their metabolic rate.
Uanset dets lokalisering i legemet synes nedbrydningen af hver 25 immunoglobulinklasse at være under særskilt kontrol. Den funktio nelle kataboliske hastighed varierer fra så lavt som 6,5% for IgG til så højt som 90% for IgE og med andre immunogl obul i nklasser liggende derimellem (Waldman et al, 1970 (se ovenfor)). Desuden adskiller de forskellige immunoglobul inklasser sig også hvad angår 3Q deres iver efter at bindes til antigener, og hvad angår deres evne til at kombinere med kompliment, som er en af de nødvendige elementer for at dræbe levende bakterieceller (Heremans, J.F., Les Golbulenes Serioues du Svsteme Gamma Leur Nature et Leur Patholoqie.Regardless of its localization in the body, the degradation of each 25 immunoglobulin class appears to be under separate control. The functional catabolic rate ranges from as low as 6.5% for IgG to as high as 90% for IgE and with other immunogl obul in n classes located therebetween (Waldman et al, 1970 (see above)). In addition, the different immunoglobulin classes also differ in their eagerness to bind to antigens and in their ability to combine with the compliment, which is one of the elements necessary to kill living bacterial cells (Heremans, JF, Les Golbulenes Serioues du Svsteme Gamma Leur Nature et Leur Patholoqie.
Arscia, Brusseles & Masson, Paris (1960)). Det er vigtigt at under-35 strege disse forskelle hos antistoftyperne, eftersom immunvirkninger kan variere i afhængighed af den involverede antistoftype.Arscia, Brussels & Masson, Paris (1960)). It is important to emphasize these differences in antibody types, as immune effects may vary depending on the type of antibody involved.
Den mest almindeligt antagne teori er, at de forskellige immuno-globulinklasser har udviklet sig til funktion i forskellige miljøer 8The most commonly accepted theory is that the various immunoglobulin classes have evolved to function in different environments 8
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i legemet. Det er f.eks. kendt, at der eksisterer et specielt og særskilt immunsystem til produktion af antistoffer, som virker i fordøjelseskanalens miljø. Der er desuden almindelig enighed om, at fordøjelseskanalens immunfunktioner kontrolleres specielt af IgA-5 antistoffer og ikke af IgG. Under naturlige forhold er IgA derfor den immunoglobul i nklasse, som regulerer immunkontrollen over bakterielle infektioner, der optræder i mave-tarmkanalens hulrum hos mennesket. Eftersom IgG, IgM, IgD og IgE normalt ikke findes i tarmsekreterne, er det ikke logisk at forvente, at disse antistof-10 typer ville være effektive ved behandling af infektioner i fordøjelseskanalens miljø.in the body. It is e.g. It is known that a special and distinct immune system exists for the production of antibodies that act in the digestive tract environment. Furthermore, there is general agreement that the immune functions of the digestive tract are controlled specifically by IgA-5 antibodies and not by IgG. Therefore, under natural conditions, IgA is the n-class immunoglobulin that regulates the immune control of bacterial infections that occur in the gastrointestinal tract of man. Since IgG, IgM, IgD and IgE are not normally found in the intestinal secretions, it is not logical to expect that these antibody types would be effective in treating infections in the digestive tract environment.
Det væsentligste immunoglobulin i mælk fra køer er IgG og ikke IgA (Sullivan, A.L., Pendergast, R.A., Antunes, L.J., Silverstein, A.S., 15 og Tomasi, Jr., T.B. Jour, of Immunol., bind 2, side 103, (1969)).The major immunoglobulin in cows' milk is IgG and not IgA (Sullivan, AL, Pendergast, RA, Antunes, LJ, Silverstein, AS, 15 and Tomasi, Jr., TB Jour, of Immunol., Volume 2, page 103, ( 1969)).
Mælk fra kvæg er derfor ikke en nærliggende kilde for antistof til behandling af bakterielle infektioner i menneskets fordøjelseskanal på grund af dets høje koncentrationer af IgG og lave koncentrationer af IgA.Therefore, bovine milk is not a nearby source of antibody to treat bacterial infections of the human digestive tract due to its high concentrations of IgG and low concentrations of IgA.
2020
Immuniseringsmetoden er en anden vigtig parameter at tage i betragtning ved de forskellige immunoglobul inklasser. Det er velkendt for fagfolk inden for området, at forskellige immuniseringsmetoder resulterer i den fortrinsvise produktion af forskellige antistofty-25 per. Lokal immunisering af sekretionsvæv opnået ved at udsætte vævet for antigener stimulerer f.eks. den fortrinsvise produktion og sekretion af immunoglobul iner af IgA-typen. Teknikken ved intra-mammal perfusion, som den er beskrevet i beskrivelsen til USA patent nr. 3.376.198, er et eksempel på lokal immunisering. Denne 30 metode stimulerer produktion og sekretion af IgA-antistoffer og er ikke en effektiv metode til fremstilling af IgG.The immunization method is another important parameter to consider in the various immunoglobulin classes. It is well known to those skilled in the art that various immunization methods result in the preferential production of various antibody types. Local immunization of secretory tissue obtained by exposing the tissue to antigens stimulates, e.g. the preferential production and secretion of IgA-type immunoglobulins. The technique of intra-mammal perfusion, as described in U.S. Patent No. 3,376,198, is an example of local immunization. This method stimulates the production and secretion of IgA antibodies and is not an effective method for producing IgG.
Ifølge den foreliggende opfindelse benyttes intramuskulær injektion ved fremgangsmåden ifølge opfindelsen, eftersom IgG er hovedimmuno-35 globulinet i komælk, ikke IgA, og i koen, og systemisk immunisering er den foretrukne metode til frembringelse af antistoffer af IgG-typen i mælk. Denne skelnen mellem immunoglobulin af IgG- og IgA-typen er vigtig, eftersom den lærer, at systemisk immunisering og ikke lokal immunisering er den foretrukne metode til opnåelse af mælkAccording to the present invention, intramuscular injection is used in the method of the invention, since IgG is the main immunoglobulin in cow's milk, not IgA, and in the cow, and systemic immunization is the preferred method for producing IgG-type antibodies in milk. This distinction between immunoglobulin of IgG and IgA type is important as it teaches that systemic immunization and not local immunization is the preferred method of obtaining milk.
DK 158138 BDK 158138 B
9 med høj antistoftiter. Denne skelnen lærer desuden, at de immunopro-dukter, der produceres ved den mammale perfusion ved en vaccine, er tydeligt forskellig fra det immunprodukt, der produceres ved intra-muskulær injektion med den identiske vaccine. Produktet (IgG-anti-5 stoffer) fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse er således klart forskellig fra det produkt, der opnås ved fremgangsmåden ifølge ovennævnte USA patentskrift.9 with high antibody titer. This distinction further teaches that the immunoproducts produced by the mammalian perfusion of a vaccine are distinctly different from the immune product produced by intra-muscular injection with the identical vaccine. Thus, the product (IgG antibodies) produced by the method of the present invention is clearly different from the product obtained by the method of the above-mentioned United States patent.
Immunproduktet fremstillet ved fremgangsmåden ifølge den forel ig-10 gende opfindelse er en forbedring i forhold til produktet ifølge opfindelsen i ovennævnte USA patentskrift, eftersom koncentrationen af antistoffer af IgG-typen er væsentlig højere end koncentrationen af antistoffer af IgA-typen. Der findes ingen vidnesbyrd i litteraturen til støtte for den påstand, at IgG-antistoffer kan frem-15 stilles ved intramammal perfusion af antigener. Eftersom omfanget af IgA-immunoglobuliner desuden enten er ikke-forekommende eller er ekstremt lav i komælk, er det absurd at foreslå, at læren fra ovennævnte USA patentskrift har nogen relevans i forbindelse med fordringen på den foreliggende opfindelse. Læren fra det nævnte USA 20 patentskrift leder derimod bort fra opdagelsen ifølge den foreliggende opfindelse, eftersom den forudsætter, at IgA er en biologisk aktiv faktor i komælk med potentiel terapeutisk anvendelsesmulighed.The immune product produced by the method of the present invention is an improvement over the product of the invention in the above-mentioned United States patent, since the concentration of IgG type antibodies is substantially higher than the IgA type antibody concentration. There is no evidence in the literature to support the claim that IgG antibodies can be produced by intramammal perfusion of antigens. Furthermore, since the extent of IgA immunoglobulins is either non-existent or extremely low in cow's milk, it is absurd to suggest that the teachings of the above-mentioned United States patent have any relevance to the claim of the present invention. In contrast, the teachings of the aforementioned United States patent do not depart from the discovery of the present invention since it assumes that IgA is a biologically active factor in cow's milk with potential therapeutic utility.
Ved fremgangsmåden ifølge den foreliggende opfindelse anvendes en 25 vaccine, som er fremstillet ud fra en unik kombination af bakteriearter, hvilken vaccine gives til sunde malkekøer. De opnåede immuno-globuliner fra mælken fra de immuniserede køer kan anvendes til passiv immunisering af en patient ved oral indgivelse af immunoglobu-linet, der passivt immuniserer imod et blandet spektrum af infek-30 ti øse bakterier, som holder til i mave-tarmkanalen. Denne behandling eliminerer tilstande i mave-tarmkanalen, som forårsager rheumatoid arthritis.In the method of the present invention, a vaccine prepared from a unique combination of bacterial species is used which is given to healthy dairy cows. The immunoglobulins obtained from the milk from the immunized cows can be used for passive immunization of a patient by oral administration of the immunoglobulin which passively immunizes against a mixed spectrum of infectious bacteria present in the gastrointestinal tract. This treatment eliminates conditions of the gastrointestinal tract which cause rheumatoid arthritis.
Der skal i det følgende gives en kort beskrivelse af tegningen, 35 hvor:The following is a brief description of the drawing, 35 in which:
Fig. 1 er et eksemplar af et spørgeskema, der er omtalt i beskrivelsen,FIG. 1 is a copy of a questionnaire discussed in the specification,
DK 158138 BDK 158138 B
1010
Fig. la er en fortsættelse af spørgeskemaet i fig. 1, ogFIG. 1a is a continuation of the questionnaire of FIG. 1, and
Fig. 2 er kurver, der viser resultaterne af afprøvningen udtrykt ved RF-titer afsat mod tiden over en 12 måneders periode, 5 6 måneder på immunmælk og 6 måneder på placebo.FIG. 2 are curves showing the results of the test expressed by RF titers plotted against time over a 12 month period, 5 6 months on immune milk and 6 months on placebo.
Ved en udføre!sesform for fremgangsmåden ifølge opfindelsen fremstilles en lavfedtholdig pulvermælk, der indeholder en population af naturlige antistoffer af IgG-typen, som reagerer med de bakte-10 riearter, der er anført i tabel 1.In one embodiment of the method of the invention, a low-fat powdered milk is prepared containing a population of natural IgG-type antibodies that react with the bacterial species listed in Table 1.
TABEL 1TABLE 1
Bakterielle Antigener 15 ORGANISME ^ATCC NR.Bacterial Antigens ORGANISM ^ ATCC NO.
Staphylococcus aureus 11631Staphylococcus aureus 11631
Staphylococcus epidermidis 155Staphylococcus epidermidis 155
Streptococcus pyogenes, A. type 1 8671 20 - type 3 10389 type 5 12347 type 8 12349 type 12 11434 type 14 12972 25 - type 18 12357 type 22 10403Streptococcus pyogenes, A. type 1 8671 20 - type 3 10389 type 5 12347 type 8 12349 type 12 11434 type 14 12972 25 - type 18 12357 type 22 10403
Aerobacter aerogenes 884Aerobacter aerogenes 884
Escherichia coli 26Escherichia coli 26
Salmonella enteritidis 13076 30 Pseudomonas aeruginosa 7700Salmonella enteritidis 13076 30 Pseudomonas aeruginosa 7700
Klebsiella pneumoniae 9590Klebsiella pneumoniae 9590
Salmonella typhimurium 13311Salmonella typhimurium 13311
Haemophilus influenzae 9333Haemophilus influenzae 9333
Streptococcus viridans 6249 35 Proteus Vulgaris 13315Streptococcus viridans 6249 35 Proteus Vulgaris 13315
Shigella dysenteriae 11835Shigella dysenteriae 11835
Streptococcus, gruppe B Diplococcus pneumoniae Streptococcus mutansStreptococcus, group B Diplococcus pneumoniae Streptococcus mutans
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ππ
Corynebacterium, Acne, type 1 og 2 x) American Type Culture Collection, 12301 Parklawn Dr., Rockville, Md. 20852.Corynebacterium, Acne, Type 1 and 2 x) American Type Culture Collection, 12301 Parklawn Dr., Rockville, Md. 20,852th
55
Den antibakterielle mælk indeholder alle de stoffer, der normalt findes i lavfedtholdig pulvermælk. De hovedbestanddele, der udgør den antibakterielle mælk, er vist i tabel 2.The antibacterial milk contains all the substances normally found in low-fat powdered milk. The main constituents constituting the antibacterial milk are shown in Table 2.
10 TABEL 2TABLE 2
Kvantitativ og kvalitativ analyse af antibakteriel mælkQuantitative and qualitative analysis of antibacterial milk
Proteiner 35,6% 25 Fedt 1,0%Proteins 35.6% Fat 1.0%
Carbohydrater 52 %Carbohydrates 52%
Mineraler 7,8%Minerals 7.8%
Fugtighed 3,5%Humidity 3.5%
Hver genopløst liter af 90-120 gram af 20 ikke-fedtholdig tørmælk indeholder ca: 1200 mg calcium 157% 935 mg phosphor 125% 0,3 mg thiamin 32% 1,78 mg riboflavin 140% 25 M4 m9 niacin 10% 324 kalorierEach redissolved liter of 90-120 grams of 20 non-fat dry milk contains approximately: 1200 mg calcium 157% 935 mg phosphorus 125% 0.3 mg thiamine 32% 1.78 mg riboflavin 140% 25 M4 m9 niacin 10% 324 calories
Antibakteriel mælk og normal komælk indeholder i vægtprocent omtrent de samme bestanddelskoncentrationer. Desuden er koncentrationen af 30 immunoglobulin af IgG-typen i antibakteriel mælk og normal mælk identisk. Det er derfor kun specificiteten af de antistoffer, der er indeholdt i den antibakterielle mælk, som adskiller den fra normal mælk. Ved immunoglobulinets specificitet menes det spektrum af bakteriearter, som antistofferne reagerer med.Antibacterial milk and normal cow's milk contain about the same constituent concentrations by weight. In addition, the IgG-type immunoglobulin concentration in antibacterial and normal milk is identical. Therefore, it is only the specificity of the antibodies contained in the antibacterial milk that differentiates it from normal milk. By the specificity of the immunoglobulin is meant the spectrum of bacterial species with which the antibodies react.
Antibakteriel mælk indeholder ingen medikamentelle tilsætninger eller eventuelle andre komponenter, som ikke er naturlige levnedsmiddelprodukter fra koen.Antibacterial milk contains no drug additives or any other components that are not natural cow food products.
35 n DK 158138 Β35 n DK 158138 Β
Immunmælken fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse er også anvendelig til kontrol af autoimmune lidelser, f.eks. lupus erythematosus o.1., som forårsages eller forværres af bakterielle invasioner i mave-tarmkanalen.The immune milk produced by the method of the present invention is also useful for controlling autoimmune disorders, e.g. lupus erythematosus o.1., which is caused or exacerbated by bacterial invasions of the gastrointestinal tract.
55
Det polyvalente antigen, der benyttes til frembringelse af anti-bakteriel mælk, fremstilles som følger:The polyvalent antigen used to produce antibacterial milk is prepared as follows:
Fremstilling af vaccinen 10Preparation of the vaccine 10
De i tabel 1 anførte bakteriestammer blev opnået fra American Type Culture Collection, hvilket sikrer bakteriestammernes autenticitet og den højeste renhedsstandard, der er tilgængelig. Efter modtagelsen blev hver enkelt bakteriestamme dyrket på en bl od-agarplade til 15 undersøgelse af kulturens levedygtighed og til bestemmelse af, om vækstmønsteret var typisk eller atypisk for den pågældende bakterie.The bacterial strains listed in Table 1 were obtained from the American Type Culture Collection, which ensures the authenticity of the bacterial strains and the highest standard of purity available. Upon receipt, each bacterial strain was grown on a bl od agar plate to study the viability of the culture and to determine whether the growth pattern was typical or atypical of the bacterium in question.
En enkelt koloni fra hver af undersøgelseskulturerne blev udtaget til histologisk undersøgelse for yderligere at sikre kulturens autenticitet og renhed. En enkelt koloni fra hver kultur blev 20 anvendt til inokulering af 500 ml standard-dyrkningsmedium. Der blev benyttet af American Type Culture Collection anbefalede medier til dyrkning af hver af de i tabel 1 anførte specifikke bakterier.A single colony from each of the study cultures was sampled for histological examination to further ensure the authenticity and purity of the culture. A single colony from each culture was used to inoculate 500 ml of standard culture medium. Recommended media were used by the American Type Culture Collection to grow each of the specific bacteria listed in Table 1.
Alle organismer blev inkuberet som statiske kulturer med undtagelse 25 af den 12., 13., 14. og 16. bakteriestamme i tabel 1, der blev inkuberet i en ryster til tilvejebringelse af omrystning. Identifikationen af bakteriestammerne og American Type Culture Collection's katalognumre er vist i tabel 1. Hver kultur blev dyrket i 48 timer ved 37°C. Efter inkubationen blev kulturerne dræbt ved opvarmning 30 til 60°C i to timer. Der blev benyttet prøver af de dræbte bakterier til inokulering af frisk dyrkningsmedium, som derpå blev inkuberet i 24 timer ved 37°C til bestemmelse af, at drabsprocessen var komplet.All organisms were incubated as static cultures except 25 of the 12th, 13th, 14th and 16th bacterial strains of Table 1 which were incubated in a shaker to provide shaking. The identification of the bacterial strains and the American Type Culture Collection catalog numbers are shown in Table 1. Each culture was grown for 48 hours at 37 ° C. After the incubation, the cultures were killed by heating 30 to 60 ° C for two hours. Samples of the killed bacteria were used to inoculate fresh culture medium, which was then incubated for 24 hours at 37 ° C to determine the killing process was complete.
Kun kulturer, der ved denne procedure havde vist sig sterile, blev benyttet til videre behandling. Sterile kulturer blev derpå vasket 5 35 gange i destilleret vand, og cellerne blev genvundet ved centrifugering. Bakteriecellerne blev frosset ved neddykning i flydende nitrogen og frysetørret ved lyophili seringsmetoden. Lyophili serede celler blev opbevaret i sterile småflasker, indtil de blev anvendt til frembringelse af den polyvalente vaccine. Den polyvalenteOnly cultures that had been sterile in this procedure were used for further treatment. Sterile cultures were then washed 5 times in distilled water and the cells recovered by centrifugation. The bacterial cells were frozen by immersion in liquid nitrogen and lyophilized by the lyophilization method. Lyophilized cells were stored in sterile vials until used to produce the polyvalent vaccine. The polyvalent
13 DK 158138B13 DK 158138B
vaccine blev fremstillet ved at afveje 1 gram af hver bakteriestamme. De tørre celler blev sammenblandet, og blandingen blev suspenderet i steril fysiologisk saltvand (20 gram bakterier pr. 500 ml saltvand).vaccine was prepared by weighing 1 gram of each bacterial strain. The dry cells were mixed and the mixture was suspended in sterile physiological saline (20 grams of bacteria per 500 ml of saline).
55
En prøve af den koncentrerede opløsning blev på seriemæssig måde fortyndet med saltvand til bestemmelse af den fortynding, der gav en koncentration på 4x10 celler pr. cm . Den koncentrerede polyval ente stamvaccine blev fordelt i et antal beholdere og opbevaret frossen.A sample of the concentrated solution was serially diluted with saline to determine the dilution yielding a concentration of 4x10 cm. The concentrated polyvalent vaccine was distributed in a number of containers and stored frozen.
10 Der blev i hver enkelt beholder inkluderet tilstrækkelig mængde koncentreret antigen til at immunisere 50 køer. Den endelige fortynding af koncentratet blev udført lige forud for immuniseringen.10 A sufficient amount of concentrated antigen was included in each container to immunize 50 cows. The final dilution of the concentrate was performed just prior to immunization.
Den foretrukne fremgangsmåde er at fjerne et tilstrækkeligt antal små flasker til at immunisere det antal køer, der skal behandles. De 15 små flasker fjernes f.eks. 24 timer forud for det planlagte immuniseringstidspunkt; en prøve af koncentratet fortyndes derpå i enThe preferred method is to remove a sufficient number of small bottles to immunize the number of cows to be treated. For example, the 15 small bottles are removed. 24 hours prior to the scheduled immunization time; a sample of the concentrate is then diluted in one
steril beholder til en endelig koncentration på 4x10 celler pr. ml.sterile container to a final concentration of 4x10 cells per cell. ml.
OISLAND
Det maksimale respons i køer opnås ved injektion af 20x10 bakte- 3 8 rieceller eller 5 cm af det sterile præparat, hvilket er 4x10 20 celler pr. ml, ifølge den nedenfor beskrevne immuniseringsmetode.The maximum response in cows is achieved by injection of 20x10 bacterial cells or 5 cm of the sterile preparation, which is 4x10 20 cells per cell. ml, according to the immunization method described below.
Foretrukken fremgangsmåde til immunisering af køerPreferred method for immunizing cows
Antistofproduktet fremstillet ved fremgangsmåden ifølge opfindelsen 25 frembringes ved immunisering af køer med det polyvalente antigen 3 fremstillet som beskrevet ovenfor. Køerne injiceres 5 cm af poly-The antibody product prepared by the method of the invention 25 is produced by immunizing cows with the polyvalent antigen 3 prepared as described above. The cows are injected 5 cm
OISLAND
valent antigen indeholdende 20x10 bakterieceller. Injektionen foretages intramuskulært i gluteus maximum musklen i bagbenet. Denne procedure gantages med 1 uges mellemrum i 4 på hinanden følgende 30 uger begyndende 2-3 uger forud for den forudsagte kælvningsdato.valent antigen containing 20x10 bacterial cells. The injection is done intramuscularly into the gluteus maximum muscle of the hind leg. This procedure is repeated at 1 week intervals for 4 consecutive 30 weeks starting 2-3 weeks prior to the predicted calving date.
Efter den primære immunisering gives der under anvendelse af den samme antigenkoncentration booster-injektioner hver 14. dag. Denne immuniseringsmetode giver maksimal antistoftiter.After the primary immunization, booster injections are given every 14 days using the same antigen concentration. This immunization method yields maximum antibody titers.
35 Indsamling, transport og behandling af mælken Mælken fra immuniserede køer indsamles i et moderne malkerum. Et fuldt automatiseret malkningssystem indsamler og opbevarer mælken under fuldkommen hygiejniske forhold. Malkningssystemet består af35 Collection, transport and treatment of the milk The milk from immunized cows is collected in a modern milking room. A fully automated milking system collects and stores the milk under perfectly hygienic conditions. The milking system consists of
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14 automatiserede maskiner, der med et lukket rørsystem er forbundet direkte med kølede opbevaringstanke. Hele systemet renses og steriliseres efter hver malkning til sikring af maksimale hygiejniske forhold. Det er vigtigt ved behandling af immunmælk at tage omhyg-5 gelige forholdsregler til forhindring af bakterievækst, eftersom disse bakterier kan nedsætte mælkens antistoftiter.14 automated machines connected to a refrigerated storage tank with a closed piping system. The entire system is cleansed and sterilized after each milking to ensure maximum hygienic conditions. It is important in the treatment of immune milk to take careful precautions to prevent bacterial growth, as these bacteria can decrease the antibody titers of the milk.
Mælken transporteres dagligt med mælketransportlastbiler fra de kølede opbevaringstanke til et mælkebehandlingsanlæg. På mælkebe-10 handlingsanlægget benyttes et højtemperatur-korttidssystem til pasteurisering af den antibakterielle mælk. Specielt mælkebehandlingsmaskineri tilvejebringer lynopvarmningen af en kontinuerlig strøm af mælk til 68,3°C i et tidsrum på ikke mere end 15 sekunder. Temperatur og tid er kritisk, eftersom antistof er nedbrydningsføl-15 somt overfor varme. Mælkeantistof destrueres ved temperaturer over 73,9°C, hvis det holdes der i et tidsrum på mere end 1 minut. Efter pasteuriseringen afkøles fuldmælken øjeblikkeligt, fedtet fjernes ved centrifugering, og den skummede antibakterielle fuldmælk overføres til pulverform ved en spraytørrings-proces. Spraytørrings-20 processen udføres i et stort tørringskammer, i hvilket der indblæses varm luft (176,7°C) med stor hastighed. Den skummede mælk forstøves ind i kammeret, hvor de findelte mælkepartikler tørres øjeblikkeligt, medens de falder til bunden af kammeret. Den tørrede mælk fjernes automatisk ved hjælp af mekaniske redskaber, og mælkepulve-25 ret emballeres under hygiejniske forhold. Forud for forstøvningen koncentreres den skummede mælk ved kogning i et kammer under vacuum (37,8-43,3°C). På hvert trin er det kritisk at holde mælken fri for kontaminering med bakterier, eftersom dette nedsætter antistof-titeren.The milk is transported daily with milk transport trucks from the refrigerated storage tanks to a milk processing plant. At the milk processing plant, a high temperature short-time system is used to pasteurize the antibacterial milk. In particular, milk processing machinery provides the flash heating of a continuous flow of milk to 68.3 ° C for a period of not more than 15 seconds. Temperature and time are critical since antibody is heat-degrading sensitive. Milk antibody is destroyed at temperatures above 73.9 ° C if kept for more than 1 minute. After pasteurization, whole milk is immediately cooled, the fat is removed by centrifugation and the foamed antibacterial whole milk is transferred into powder form by a spray drying process. The spray drying process is carried out in a large drying chamber in which hot air (176.7 ° C) is blown at high speed. The foamed milk is atomized into the chamber, where the finely divided milk particles are immediately dried while falling to the bottom of the chamber. The dried milk is automatically removed by mechanical tools and the milk powder is packaged under hygienic conditions. Prior to atomization, the skimmed milk is concentrated by boiling in a chamber under vacuum (37.8-43.3 ° C). At each stage, it is critical to keep the milk free of bacteria contamination as this decreases the antibody titre.
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Afprøvningsproceduretesting procedure
Immunmælk blev fremstillet med indavlede Hol stener-køer. Køerne blev immuniseret ved intramuskulær injektion med en blanding af de i 35 tabel 1 identificerede bakterieantigener. Vaccinen blev fremstillet ved den ovenfor beskrevne metode. Køernes immunologiske respons blev fremskyndet ved to ugentlige injektioner med vaccinen. Mælken fra disse køer blev samlet, fedtet fjernet, og den ikke-fedtholdige mælk blev pasteuriseret ved udsættelse for 71,1°C i 16 sekunderImmune milk was prepared with inbred Holstein cows. The cows were immunized by intramuscular injection with a mixture of the bacterial antigens identified in Table 1. The vaccine was prepared by the method described above. The cows' immunological response was accelerated by two weekly injections with the vaccine. The milk from these cows was collected, the fat removed and the non-fat milk pasteurized by exposure to 71.1 ° C for 16 seconds.
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15 efterfulgt af en spray-tørringsproces, ved hvilken mælkens temperatur ikke kom over 29,4°C. Mælken blev emballeret i "kvarte" poly-ethylenbeholdere. Kontrolmælk (placebo) var ikke-fedtholdigt pulvermælk indkøbt fra en lokal producent.15 followed by a spray drying process at which the temperature of the milk did not exceed 29.4 ° C. The milk was packaged in "quarter" polyethylene containers. Control milk (placebo) was non-fat powdered milk purchased from a local manufacturer.
55
Erythrocytsedimentationshastigheder blev bestemt på friskt indsamlet blod ved metoden af Westergren og korrigeret for hæmatocrit ifølge metoden af Wintrobe, M.M. og Langsberg, J.W., Am. J. Sci., 189:102 (1935). Rheumatoide faktortiterværdier blev bestemt efter Singer, 10 J.M. og Plotz, C.M., Am. J. Med.. 21:888 (1966) makroskopiske reagensrørstest.Erythrocyte sedimentation rates were determined on freshly collected blood by the method of Westergren and corrected for hematocrit according to the method of Wintrobe, M.M. and Langsberg, J.W., Am. J. Sci., 189: 102 (1935). Rheumatoid factor titer values were determined by Singer, 10 J.M. and Plotz, C.M., Am. J. Med .. 21: 888 (1966) macroscopic reagent tube tests.
Patienter til undersøgelsen blev accepteret på grundlag af en forhøjet erythrocytsedimentationshastighed og en positiv rheumatoid 15 faktortiter. Ni patienter blev studeret i 12 måneder, og 11 patienter blev studeret i 18 måneder. Patientgruppen var sammensat af 13 kvinder af kaukasisk race med en alder på fra 32 til 69 år med en gennemsnitsalder på 50,4 år og af 7 mænd af kaukasisk race-med en alder på fra 43 til 70 år og med en gennemsnitsalder på 58,1 år.Patients for the study were accepted on the basis of an elevated erythrocyte sedimentation rate and a positive rheumatoid 15 factor titer. Nine patients were studied for 12 months and 11 patients were studied for 18 months. The patient group was composed of 13 women of the Caucasian race with an age of 32 to 69 years with an average age of 50.4 years and of 7 men of the Caucasian race - with an age of 43 to 70 years and with an average age of 58, 1 year.
20 Middel varigheden af arthritis var 10,8 år for kvinderne og 11,0 for mændene. Patienterne blev på tilfældig måde behandlet med enten immunmælk eller ikke-immunmælk (et kommercielt produkt, der indkøbt i Dayton-området tjente som et placebo). Begge mælkeprodukter blev emballeret i identiske beholere og blev identificeret som værende 25 immunmælk eller placebo ved en blå henholdsvis rød trykfølsom mærkat, der blev fæstnet til hver beholder på det tidspunkt, hvor den blev fyldt. Mærkaterne blev fjernet lige forud for udlevering af mælken til patienterne. På intet tidspunkt vidste patienterne således, om de modtog immunmælk eller placebo. Patienterne blev på 30 tilfældig måde (bestemt ved møntkast) udvalgt til enten at modtage immunmælk eller placebo i den første 6-måneders priode. Ved afslutningen på denne periode blev de, der modtod immunmælk, anbragt på placebo, og de, der modtog placebo, blev anbragt på immunmælk i den næste 6-måneders periode.20 The mean duration of arthritis was 10.8 years for the women and 11.0 for the men. Patients were randomly treated with either immune or non-immune milk (a commercial product purchased in the Dayton area served as a placebo). Both milk products were packaged in identical containers and were identified as having 25 immune or placebo by a blue and red pressure-sensitive label, respectively, which was attached to each container at the time it was filled. The labels were removed just prior to delivery of the milk to the patients. Thus, at no time did patients know whether they were receiving immune milk or placebo. Patients were randomly selected (30 by coin toss) to receive either immuno-milk or placebo during the first 6-month period. At the end of this period, those receiving immune milk were placed on placebo, and those receiving placebo were placed on immune milk for the next 6-month period.
3535
Ved afslutningen af denne anden 6-måneders periode meldte 11 patienter sig frivilligt til at fortsætte undersøgelsen i yderligere 6 måneder. Mælketypen (immun eller placebo) blev på dette tidspunkt igen ændret, og observationerne fortsattes. Undersøgelsen omfattedeAt the end of this second 6-month period, 11 patients volunteered to continue the study for another 6 months. At this point, the milk type (immune or placebo) was again changed and observations continued. The study included
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16 således tre 6-måneders perioder med 11 patienter deltagende i tre perioder og ni deltagende i to perioder.16 thus three 6-month periods with 11 patients participating for three periods and nine participating for two periods.
Patienterne var i konsultation med månedligt mellemrum, på hvilket 5 tidspunkt der blev udleveret én måneds mælkeforsyning, et evalueringsspørgeskema blev udfyldt, og en blodprøve blev taget til bestemmelse af rheumatoid faktortiter, erythrocytsedimentationshas-tighed og hæmatocrit.Patients were consulted at monthly intervals, at which time 5 months of one month's milk supply was provided, an evaluation questionnaire was completed, and a blood sample was taken to determine rheumatoid factor titer, erythrocyte sedimentation rate and hematocrit.
10 Patienterne blev instrueret om at tage en mængde ikke-fedtholdig mælketørstof ækvivalent med én liter mælk efter maden to gange daglig. Mælketørstoffet blev frisk opløst i ½ liter ledningsvand umiddelbart inden indtagelsen kort efter opvågningen om morgenen og igen lige forud for sengetid om aftenen. De blev instrueret om at 15 konsultere deres læge som sædvanlig og at følge de af ham fore skrevne behandlingsordinationer. Medikamenter kunne indtages ad libitum eller som foreskrevet af deres almindelige læge. De blev kun bedt om at rapportere mængden af den indtagne medicin.Patients were instructed to take a quantity of non-fat milk solids equivalent to one liter of milk after food twice daily. The milk solids were freshly dissolved in ½ liter of tap water immediately before ingestion shortly after waking in the morning and again just before bedtime in the evening. They were instructed to consult their physician as usual and to follow the prescribed treatment regimens prescribed by him. Medications could be taken ad libitum or as prescribed by their general practitioner. They were only asked to report the amount of medication taken.
20 Et spørgeskema blev udfyldt af hver patient med månedligt mellemrum.20 A questionnaire was completed by each patient at monthly intervals.
Det var opdelt i seks afsnit, der omhandlede: 1) Morgenstivhedens varighed, 25 2) Graden af smerter, som optrådte i hvert af otte led, 3} Type og mængde af indtagne medikamenter med korttidsvirkning, 4) Type og mængde af indtagne medikamenter med langvarige virk- 30 ni nger, 5) Patientens evne til at udføre sine normale aktiviteter, og 6) Graden af symptomer på rheumatoid arthritis.It was divided into six sections which dealt with: 1) Duration of morning stiffness, 25 2) The degree of pain occurring in each of eight joints, 3} Type and amount of short-acting medication taken, 4) Type and amount of medication taken with long-term effects, 5) the patient's ability to perform his normal activities, and 6) the degree of symptoms of rheumatoid arthritis.
3535
De i rubrikkerne efter hvert svar viste tal angiver den værdi, der blev tillagt svaret ved evalueringen af spørgeskemaerne. Ved pointtildelingen blev der lagt vægt på, at de afsnit, der omhandlede medicineringen, afspejlede den relative anti-inflammatoriske ogThe numbers shown in the boxes after each answer indicate the value added to the answer when evaluating the questionnaires. In the point allocation, it was emphasized that the sections dealing with the medication reflected the relative anti-inflammatory and
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17 analgetiske virkning af de forskellige, benyttede medikamenter. En 324 mg aspi ri ntablet blev tillagt værdien én. Alle andre medikamenter (med undtagelse af guld, Plaquenil® (varemærke for hydroxychlor-quinolylsulfat) og cortison indsprøjtninger, der blev vurderet 5 særskilt) blev arbitrært tillagt værdier i forhold til aspirin. Alle salicylat-præparater, Tylenol®, Darvon, Motrin®, etc. blev således regnet for ækvivalente med en 324 mg aspirin-tablet og blev også tildelt værdien én. Antallet af mg Prednison blev multipliceret med fire, antallet af indtagne Indocin-kapsl er blev multipliceret med 10 2,5. For hver 64,8 mg codein blev der multipliceret med to, og antallet af indtagne Butazoladin-tabletter blev multipliceret med syv.17 analgesic effect of the various drugs used. A 324 mg aspirin tablet was added to the value one. All other drugs (with the exception of gold, Plaquenil® (trademark of hydroxychloroquinolyl sulfate) and cortisone injections rated 5 separately) were arbitrarily added to aspirin values. Thus, all salicylate preparations, Tylenol®, Darvon, Motrin®, etc. were considered equivalent to a 324 mg aspirin tablet and were also assigned the value one. The number of mg Prednisone was multiplied by four, the number of Indocin capsules taken was multiplied by 10 2.5. For each 64.8 mg of codeine, multiplied by two and the number of butazoladine tablets taken was multiplied by seven.
Middelværdien af pointtildelingen i hver kategori blev beregnet for 15 hver 6-måneders periode. Forskellen mellem middelværdierne blev derpå beregnet ved at subtrahere middelværdierne opnået under indgivelse af immunmælk fra dem, der blev opnået under indgivelse af placebo. Når resultaterne blev beregnet på denne måde, blev en forbedring i patientens tilstand i den periode, han modtog immunmælk, 20 indiceret ved negative værdier for spørgsmål 1 og 6 og ved positive værdier for alle andre spørgsmål. Middel korrigerede erythrocytsedi-mentationshastigheder (ESR) og rheumatoide faktortitere (RF) blev vist respektivt på lignende måde. De blev beregnet på en sådan måde, at positive værdier afspejlede en lavere erythrocytsedimentations-25 hastighed eller rheumatoid faktortiter under indgivelse af immun mælk. Dataerne blev behandlet statistisk, idet Goodnight et al's "Statistical Analysis System" blev benyttet (SAS Institute, Raleigh, N.C.). Beregningerne blev udført ved hjælp af en IBM, model 370/155 computer.The average of the points awarded in each category was calculated for 15 every 6-month period. The difference between the mean values was then calculated by subtracting the mean values obtained during administration of immune milk from those obtained during the administration of placebo. When the results were calculated in this way, an improvement in the patient's condition during the period he received immune milk was indicated by negative values for questions 1 and 6 and by positive values for all other questions. Mean corrected erythrocyte sedimentation rates (ESR) and rheumatoid factor titers (RF) were shown in a similar fashion, respectively. They were calculated in such a way that positive values reflected a lower erythrocyte sedimentation rate or rheumatoid factor titer during administration of immune milk. The data were processed statistically using Goodnight et al's "Statistical Analysis System" (SAS Institute, Raleigh, N.C.). The calculations were performed using an IBM model 370/155 computer.
3030
Resultaterresults
Immunmælken blev tolereret godt af alle patienter med undtagelse af én, der havde perniciøs anæmi. Denne patient klagede over diarré og 35 blev udeladt fra undersøgelsen. Nogle patienter rapporterede om en vægtforøgelse i løbet af undersøgelsen. Dette kan have sin årsag i den forøgede kalorieindtagning fra mælken eller afspejler muligvis en generel forbedring i deres fysiske tilstand.Immune milk was well tolerated by all patients except one who had pernicious anemia. This patient complained of diarrhea and 35 were left out of the study. Some patients reported a weight gain during the study. This may be due to the increased caloric intake from the milk or may reflect a general improvement in their physical condition.
1818
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DK 158138 BDK 158138 B
2020
Som vist i tabel 3 blev patienterne observeret over ialt 27 kontrolperioder (6-måneders perioder, i hvilke de modtog placebo) og 24 testperioder (6-måneders perioder, i hvilke de modtog immunmælk). Én patient havde fået en fysisk læsion af den ene ankel og fod. Smerten 5 i disse led blev ikke evalueret, hvilket forklarer det mindre antal evalueringsperioder for disse led. Erythrocytsedimentationshastig-hederne for en patient var så ekstremt anormale (afveg med mere end to standardafvigelser fra gennemsnittet af værdierne for de andre patienter), at de ikke blev medtaget. Denne udeladelse forklarer det 10 mindre antal rapporterede observationer for denne variabel.As shown in Table 3, patients were observed over a total of 27 control periods (6-month periods during which they received placebo) and 24 test periods (6-month periods during which they received immune milk). One patient had a physical lesion of one ankle and foot. The pain 5 of these joints was not evaluated, which explains the smaller number of evaluation periods for these joints. The erythrocyte sedimentation rates of one patient were so extremely abnormal (deviating by more than two standard deviations from the average of the values of the other patients) that they were not included. This omission explains the 10 smaller number of reported observations for this variable.
Middelværdierne og variationskoefficienterne (C.V.) er for hver variabel anført i tabellen. Differencerne mellem middelværdierne blev beregnet ved at subtrahere middelværdien opnået i de perioder, 15 hvor patienterne modtog immunmælk, fra den, der blev opnået i de perioder, hvor de modtog placebo. Et gunstigt respons på immunmælk indiceres ved negative værdier for morgenstivhed (spørgsmål 1) og målelig forandring (spørgsmål 6a, b og c) og ved positive værdier for alle andre variable. Der blev opnået en effektiv respons på 20 immunmælk for alle de ud fra spørgeskemaerne opnåede data. Sandsynlighederne (P) indicerer en høj grad af statistisk signifikans i hvert tilfælde. Den lille middelforskel, der blev opnået for ery-throcytsedimentationshastigheden og rheumatoid faktortiter, var ikke signifikant. Når erythrocytsedimentationshastighederne blev vurderet 25 på individuel basis, havde fire af de 20 undersøgte patienter imidlertid statistisk signifikante formindskelser, medens de modtog immunmælk.The mean values and coefficients of variation (C.V.) for each variable are listed in the table. The differences between the mean values were calculated by subtracting the mean values obtained during the periods in which patients received immune milk from those obtained during the periods when they received placebo. A favorable response to immune milk is indicated by negative values for morning stiffness (question 1) and measurable change (questions 6a, b and c) and by positive values for all other variables. An effective response to 20 immune milk was obtained for all the data obtained from the questionnaires. The probabilities (P) indicate a high degree of statistical significance in each case. The small mean difference obtained for erythrocyte sedimentation rate and rheumatoid factor titer was not significant. However, when the erythrocyte sedimentation rates were assessed on an individual basis, four of the 20 patients studied had statistically significant reductions while receiving immune milk.
Endskønt immunmælk ikke havde nogen signifikant virkning på middel-30 værdierne for rheumatoid faktortiter, afslørede en undersøgelse af de individuelle patienter interessante respons. Syv af de 20 undersøgte patienter havde negative rheumatoide faktortitere ved i det mindste én lejlighed i den periode, hvor de modtog immunmælk. Fire af dem blev negative i løbet af den periode, hvor de modtog immun-35 mælk, og deres titere blev ikke positive igen i løbet af den følgende 6-måneders periode, i hvilken de modtog kontrolmælken (placebo) som vist i fig. 2. Fortsættelse af undersøgelsen forbi denne rapporteringsperiode afslører, af 13 af 25 patienter mistede den rheumatoide faktor i deres blod.Although immune milk had no significant effect on the mean values for rheumatoid factor titers, a study of the individual patients revealed interesting responses. Seven of the 20 patients studied had negative rheumatoid factor titers on at least one occasion during the period when they received immune milk. Four of them became negative during the period in which they received immune milk and their titers did not become positive again during the following 6-month period during which they received the control milk (placebo) as shown in FIG. 2. Continuing the study past this reporting period reveals that of 13 of 25 patients lost the rheumatoid factor in their blood.
DK 158138 BDK 158138 B
2121
DiskussionDiscussion
Videnskabsmanden, der stod for denne undersøgelse, interviewede personligt hver patient med månedligt mellemrum og nedskrev deres 5 svar på spørgsmålene. Der blev gjort al mulig anstrengelse for ikke at påvirke patienternes svar. Patienterne blev indledningsvis informeret om og blev ofte mindet om, at de i visse perioder af undersøgelsen ville modtage et placebo. Det blev antaget, at denne viden ville tjene som en tilskyndelse for patienterne til at besvare 10 spørgsmålene objektivt og uden tendentiøs forudindtagethed. Patienterne blev på intet tidspunkt informeret om, hvorvidt de modtog immunmælk eller placebo.The scientist who chaired this study personally interviewed each patient at monthly intervals and wrote down their 5 answers to the questions. Every effort was made not to influence patients' responses. Patients were initially informed and were often reminded that during certain periods of the study they would receive a placebo. It was assumed that this knowledge would serve as an incentive for patients to answer the 10 questions objectively and without tendentious bias. Patients were not informed at any time whether they were receiving immune milk or placebo.
Spørgsmålet, der angår indtagen medicin "igår" (sp. nr. 3), og 15 spørgsmålet, der angår guld-, Plaquenil- og cortison-indsprøjtninger (sp. nr. 4), er objektive og er af primær vigtighed ved vurdering af de svar, der er givet på de andre spørgsmål. Disse spørgsmål er vigtige af to grunde: 20 1) Hvis immunmælken er effektiv til lindring af sygdommens symp tomer, må det forventes, at patienten vil tage færre af de medikamenter, der var tilladt ad libitum. Som gennemsnit rapporterede patienterne, at de tog fire færre aspiriner eller hermed ækvivalente pr. dag i de perioder, hvor de modtog 25 immunmælk. De rapporterede også, at de modtog færre guld-ind sprøjtninger, Plaquenil- og cortison-indsprøjtninger i disse perioder, og 2) hvis patienterne tog mindre mængder af analgetika og andre 30 medikamenter, der er nyttige i behandlingen af rheumatoid arthritis, ville man forvente, at de rapporterede om forøget ubehag, med mindre immunmælken påvirkede lidelsen på gunstig måde.The question related to the medication "yesterday" (Q. 3) and the question regarding gold, plaquenil and cortisone injections (Q. 4) are objective and are of primary importance in the assessment of the answers given to the other questions. These issues are important for two reasons: 20 1) If the immune milk is effective in relieving the symptoms of the disease, it is to be expected that the patient will take fewer of the drugs that were allowed ad libitum. On average, patients reported taking four fewer aspirins or equivalents per day. per day during the periods when they received 25 immune milk. They also reported that they received fewer gold injections, plaquenil and cortisone injections during these periods, and 2) if patients took smaller amounts of analgesics and other 30 medications useful in the treatment of rheumatoid arthritis, one would expect that they reported increased discomfort unless the immune milk affected the disorder favorably.
35 Som anført i tabel 2 blev der rapporteret om signifikant mindre ledkomplikationer i de perioder, hvor patienterne modtog immunmælk, selvom de tog færre medikamenter mod deres arthritis.35 As indicated in Table 2, significantly less joint complications were reported during the periods when patients received immune milk, even though they were taking fewer medications for their arthritis.
Patienterne begyndte på undersøgelsen med månedlige mellemrum iPatients began the study at monthly intervals i
DK 158138 BDK 158138 B
22 løbet af en 1-årig periode, og den mælkeprodukttype (immunmælk eller placebo), som de modtog indledningsvis, blev givet tilfældigt. Den observation, at der blev opnået positiv respons eller forbedring for alle spørgeskemaets parametre, og at disse middelresponsa var 5 statistisk signifikante, indicerer kraftigt, at immunmælken havde en gunstig virkning på patienterne. Denne konklusion underbygges af den iagttagelse, at 20% af patienterne udviste en statistisk signifikant (p<0.05) formindskelse af erythrocytsedimentationshastigheden, medens de modtog immunmælk.22 over a 1-year period, and the type of milk product (immune milk or placebo) that they initially received was given at random. The observation that positive response or improvement was obtained for all questionnaire parameters, and that these mean responses were statistically significant, strongly indicates that immune milk had a beneficial effect on patients. This finding is supported by the observation that 20% of patients showed a statistically significant (p <0.05) decrease in erythrocyte sedimentation rate while receiving immune milk.
1010
Resultaterne af de rheumatoide faktortitere er vanskelige at bedømme. Dette skyldes i det mindste delvis det forhold, at de rheumatoide faktorers oprindelse og rolle i ætiologi og for prognose ved rheumatoid arthritis ikke forstås. Rose, H.W., Rogan, C., Pearce, E.The results of the rheumatoid factor titers are difficult to judge. This is due, at least in part, to the fact that the origin and role of the rheumatoid factors in the etiology and prognosis of rheumatoid arthritis are not understood. Rose, H.W., Rogan, C., Pearce, E.
15 og Lipman, M.O., Proc. Soc. Exo. Biol. Hed.. 68:1 (1948) viste, at røde fåre-blodlegemer, der var blevet sensitiviseret med kanin-antistof, undergik agglutination i nærværelse af blodserum fra patienter med rheumatoid arthritis. Prøven afhænger af den specifikke reaktion mellem normal immunoglobulin (enten kanin- eller human-IgG) og 20 rheumatoide faktorer. De af rheumatoid faktor udviste specificiteter er som dem,; der ville forventes af antistof mod IgG (Epstein, W., Johnson, A.M. og Rogan, C., Proc. Soc. Exd. Biol. Med.. 91:235 (1956)). Forekomsten af rheumatoide faktorer er blevet korreleret med sygdomsgraden ved rheumatoid arthritis og kan identificeres i 25 proteiner, der udfældes i væv hos patienter med rheumatoid arthritis. Endskønt en lille procentdel af patienterne med rheumatoid arthritis ikke har positive rheumatoide faktortitere, er der almindelig enighed blandt de fleste rheumatologer om, at positive agglutinationreaktioner ikke vender tilbage til negative, selv når 30 sygdommen er i remission. DeForrest, G.K., Mucci, M.B. og Biosvert, P.L., Arth. & Rheum.. 1:387 (1958) rapporterede imidlertid om et lille antal patienter, som havde positive rheumatoide faktortitere, der efter en remission igen blev negative. Når der indtrådte et udbrud af sygdommen, blev prøven igen positiv. Aho, K., Kirpila, J.15 and Lipman, M.O., Proc. Soc. Exo. Biol. Hed. 68: 1 (1948) showed that red sheep blood cells that had been sensitized to rabbit antibody underwent agglutination in the presence of blood serum from rheumatoid arthritis patients. The test depends on the specific reaction between normal immunoglobulin (either rabbit or human IgG) and 20 rheumatoid factors. The specificities exhibited by rheumatoid factor are like those; that would be expected from antibody to IgG (Epstein, W., Johnson, A.M., and Rogan, C., Proc. Soc. Exd. Biol. Med. 91: 235 (1956)). The incidence of rheumatoid factors has been correlated with disease severity in rheumatoid arthritis and can be identified in 25 proteins that are precipitated in tissues in rheumatoid arthritis patients. Although a small percentage of rheumatoid arthritis patients do not have positive rheumatoid factor titers, most rheumatologists generally agree that positive agglutination reactions do not return to negative, even when the disease is in remission. DeForrest, G.K., Mucci, M.B. and Biosvert, P.L., Arth. & Rheum. When an outbreak of the disease occurred, the test became positive again. Aho, K., Kirpila, J.
35 og Wayner, 0., Ann. Exd. Fenn.. 37:377 (1959) bemærkede imidlertid, at de fleste patienter, hvis sygdom var blevet inaktiv, forblev serologisk positive. Det forhold, at der blev observeret negative titere hos 60% af patienterne i den foreliggende undersøgelse, og at hos halvdelen af disse forblev titerne negative i seks måneder,35 and Wayner, 0., Ann. Exd. Fenn. 37: 377 (1959), however, noted that most patients whose disease had become inactive remained serologically positive. The fact that negative titers were observed in 60% of patients in the present study and that in half of these titers remained negative for six months,
DK 158138 BDK 158138 B
23 beviser, at immunmælk påvirker en primær ætiologisk faktor, der er ansvarlig for den rheumatoide arthritis.23 evidence that immune milk affects a primary etiologic factor responsible for rheumatoid arthritis.
Immunmælkens lindrende virkning på symptomerne på rheumatoid arthri-5 tis er navnlig relevant, når den betragtes på baggrund af den i den senere tid beskrevne forbindelse mellem histokompatibilitets-anti-generne (HL-A) og modtageligheden for rheumatisk lidelse (Brewerton, D.A., Arth. & Rheum.. 19:656 (1976). Histokompatibilitet-antigener er genetisk bestemte antigener, som findes på alle humane celler. De 10 gener, som kontrollerer deres arv, kaldes histokompatibilitetsgener.The soothing effect of the immune milk on the symptoms of rheumatoid arthritis is particularly relevant when considered in light of the recently described link between the histocompatibility anti-genes (HL-A) and susceptibility to rheumatic disorder (Brewerton, DA, Arth & Rheum .. 19: 656 (1976) Histocompatibility antigens are genetically determined antigens found on all human cells. The 10 genes that control their inheritance are called histocompatibility genes.
Der kendes nu over 40 af disse genetisk bestemte antigener. De er ansvarlig for afstødning for vævstransplantationer, der er udført mellem individer bortset fra identiske tvillinger. Overfladisk ligner HL-A-antigenerne ABO-bl odtyperne derved, at de arves for 15 livstid. Deres funktion kendes endnu ikke, bortset fra i den højst kunstige situation, der frembringes ved transplantation. Det vides imidlertid, at histokompatibilitetsgenerne er tæt forbundet med immunresponsgenerne på det sjette kromosom. I denne forbindelse kan de bestemme individets immunrespons på en fremmed invadør, såsom en 20 bakterie.More than 40 of these genetically determined antigens are now known. They are responsible for rejection for tissue transplants performed between individuals other than identical twins. Superficially, the HL-A antigens are similar to the ABO-b1 types in that they are inherited for 15 lifetimes. Their function is not yet known, except in the highly artificial situation produced by transplantation. However, it is known that the histocompatibility genes are closely related to the immune response genes on the sixth chromosome. In this connection, they can determine the individual's immune response to a foreign invader, such as a bacterium.
Personer med HLAB27 synes at være særligt modtagelige for et antal rheumatiske lidelser. Det postuleres, at dette histokompatibilitetsantigen dikterer en type af immunrespons, som i nærvær af andre præ-25 disponerende faktorer fører til rheumatoid arthritis. Efter en tarminfektion med versi nia enterocolitica udvikler nogle patienter en akut periferisk arthritis (Ahvonen, P., Sievers, K. og Aho, K.,People with HLAB27 appear to be particularly susceptible to a number of rheumatic disorders. It is postulated that this histocompatibility antigen dictates a type of immune response that, in the presence of other pre-disposing factors, leads to rheumatoid arthritis. After a bowel infection with versi nia enterocolitica, some patients develop acute peripheral arthritis (Ahvonen, P., Sievers, K. and Aho, K.,
Acta. Rheum. Scand.. 15:232 (1969)). Ligeledes udvikler ca. 2% af patienterne efter en Salmonella-infektion akut periferisk arthritis 30 (Warren, C.P.W., Ann. Rheum. Dis.. 29:484 (1970)). HLAB27 blev fundet hos 43 ud af 49 patienter med yersinia arthritis og hos 15 ud af 16 med salmonella arthritis (Aho, K., Ahvonen, P., Lassus, A. et al., Arth. & Rheum.. 17:521 (1974)). Den mulighed virker tillokkende, at infektiøse agenser eventuelt kan trives i tarmkanalen uden 35 at give anledning til lokale symptomer. Hos patienter med HLAB27 fremkommer et værtsrespons, der resulterer i arthritis. Det er således ikke nødvendigt for det infektiøse agens at få adgang til leddene. Immunmælk virker gunstig på patienter med rheumatoid arthritis, fordi den indeholder antistoffer, der effektivt 5Acta. Rheum. Scand., 15: 232 (1969)). Similarly, approx. 2% of patients after a Salmonella infection acute peripheral arthritis 30 (Warren, C.P.W., Ann. Rheum. Dis. 29: 484 (1970)). HLAB27 was found in 43 of 49 patients with yersinia arthritis and in 15 of 16 with salmonella arthritis (Aho, K., Ahvonen, P., Lassus, A. et al., Arth. & Rheum .. 17: 521 ( 1974)). The possibility is attractive that infectious agents can possibly thrive in the intestinal tract without giving rise to local symptoms. In patients with HLAB27, a host response results in arthritis. Thus, it is not necessary for the infectious agent to access the joints. Immune milk is beneficial in patients with rheumatoid arthritis because it contains antibodies that effectively
DK 15 813 8 BDK 15 813 8 B
24 inaktiverer eller neutraliserer skadevoldende bakterier oq/eller deres metabolske produkter.24 inactivates or neutralizes harmful bacteria and / or their metabolic products.
10 15 20 25 30 3510 15 20 25 30 35
Claims (6)
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US87514078A | 1978-02-06 | 1978-02-06 | |
US87514078 | 1978-02-06 |
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DK49479A DK49479A (en) | 1979-08-07 |
DK158138B true DK158138B (en) | 1990-04-02 |
DK158138C DK158138C (en) | 1990-08-27 |
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DK049479A DK158138C (en) | 1978-02-06 | 1979-02-06 | METHOD OF PREPARING IMMUNOGLOBULIN-IGG-CONTAINING MILK OR FROM DERIVED PRODUCT TO TREAT RHEUMATOID ARTHRITIS |
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JP (1) | JPS54113425A (en) |
CH (1) | CH651210A5 (en) |
DE (1) | DE2904044C2 (en) |
DK (1) | DK158138C (en) |
FR (1) | FR2416015A1 (en) |
GB (1) | GB2013691B (en) |
HK (1) | HK30283A (en) |
IT (1) | IT1116524B (en) |
NL (1) | NL7900766A (en) |
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USRE33565E (en) * | 1978-02-06 | 1991-04-02 | Stolle Research And Development Corporation | Prevention and treatment of rheumatioid arthritis |
US4732757A (en) * | 1978-02-06 | 1988-03-22 | Stolle Research And Development Corporation | Prevention and treatment of rheumatoid arthritis |
ATE14269T1 (en) * | 1981-02-26 | 1985-08-15 | Unilever Nv | METHOD AND DEVICE FOR RECOVERING IMMUNOGLOBULINES. |
EP0064103B1 (en) * | 1981-04-28 | 1985-11-06 | The Stolle Research And Development Corporation | Method of obtaining an anti-inflammatory bovine milk |
JP2561234B2 (en) * | 1981-05-12 | 1996-12-04 | スト−ル・リサ−チ・アンド・デイベロップメント・コ−ポレ−ション | Anti-inflammatory agent |
JPS58154513A (en) * | 1982-03-09 | 1983-09-14 | Sendai Biseibutsu Kenkyusho | Preventive and remedying drug |
US4636384A (en) * | 1982-06-03 | 1987-01-13 | Stolle Research & Development Corporation | Method for treating disorders of the vascular and pulmonary systems |
DE3378890D1 (en) * | 1983-06-07 | 1989-02-16 | Stolle Res & Dev | Deodorant containing bacterial antibodies |
JPS6112629A (en) * | 1984-06-28 | 1986-01-21 | Lion Corp | Composition for oral cavity application |
DE3785033T2 (en) * | 1987-07-21 | 1993-10-07 | Stolle Res & Dev | Method for obtaining immunoregulatory factors by mammalian immunization. |
JP2664906B2 (en) * | 1987-08-13 | 1997-10-22 | ストール・リサーチ・アンド・デイベロップメント・コーポレーション | Improved mammalian immunization |
EP1171161A1 (en) * | 1999-04-19 | 2002-01-16 | Richard Weisbart | Treatment of adult rheumatoid arthritis by oral administration of pooled human immunoglobulin and an antacid |
CA2423805A1 (en) * | 2000-09-28 | 2002-04-04 | Richard Weisbart | Treatment of immune-mediated diseases by oral administration of plasma fractions enriched in immunoglobulin g |
PL214224B1 (en) * | 2001-01-30 | 2013-07-31 | Lauridsen Group | Methods and compositions for modulating the immune system of animals |
BR0206869A (en) * | 2001-01-30 | 2007-01-02 | Lauridsen Group Inc | method for treating an animal suffering from a disease state of immune dysfunction associated with altered levels of igg or tnf-delta, a pharmaceutical composition for treating autoimmune disorders associated with high igg and / or tnf-delta or for potentiation of vaccine protocols, and method for treating sickness associated with immune dysfunction in an animal |
JP4960632B2 (en) * | 2006-01-10 | 2012-06-27 | 学校法人北里研究所 | Composition for treating and preventing herpes simplex virus infection comprising immune milk composition as active ingredient |
JP5361132B2 (en) * | 2006-03-10 | 2013-12-04 | 国立大学法人信州大学 | An oral immunomodulator containing immunoglobulin G, a method for producing the same, and a food or drink comprising the oral immunomodulator |
JP2008179572A (en) * | 2007-01-25 | 2008-08-07 | Shinshu Univ | IMMUNOGLOBULIN Fc FRAGMENT RECEPTOR PROTEIN AND/OR PRODUCTION INHIBITOR OF IMMUNOGLOBULIN Fc FRAGMENT RECEPTOR LIKE PROTEIN, AND USE OF THE SAME |
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CH488013A (en) * | 1965-10-24 | 1970-03-31 | Immune Milk Company Of America | Process for the production of antitoxins |
DE1617769A1 (en) * | 1967-06-10 | 1971-04-01 | Rehm Eberhard | Process for the production of milk containing specific antibodies and preparations made therefrom |
JPS5136326A (en) * | 1974-09-24 | 1976-03-27 | Komatsu Seiren Co | SEIKEIGORU FUBOORU |
JPS5837285B2 (en) * | 1975-05-29 | 1983-08-15 | カブシキガイシヤ ミドリジユウジ | It is very difficult to understand the situation. |
JPS521014A (en) * | 1975-06-17 | 1977-01-06 | Stolle Res & Dev | Pharmaceutically acceptable carrier containing milk immunoglobulin |
JPS5381613A (en) * | 1976-12-28 | 1978-07-19 | Green Cross Corp:The | Remedies for enteral infection diseases |
CH627079A5 (en) * | 1977-04-15 | 1981-12-31 | Nestle Sa | Process for preparing a protein concentrate containing immunological factors of milk origin |
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1979
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- 1979-01-31 NL NL7900766A patent/NL7900766A/en not_active Application Discontinuation
- 1979-02-02 FR FR7902807A patent/FR2416015A1/en active Granted
- 1979-02-02 GB GB7903836A patent/GB2013691B/en not_active Expired
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- 1979-02-05 JP JP1215279A patent/JPS54113425A/en active Granted
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DE2904044A1 (en) | 1979-08-30 |
IT7947888A0 (en) | 1979-02-05 |
GB2013691B (en) | 1982-08-18 |
DE2904044C2 (en) | 1986-02-06 |
DK49479A (en) | 1979-08-07 |
NL7900766A (en) | 1979-08-08 |
DK158138C (en) | 1990-08-27 |
SE7900798L (en) | 1979-08-07 |
HK30283A (en) | 1983-09-02 |
GB2013691A (en) | 1979-08-15 |
FR2416015B1 (en) | 1983-06-17 |
SE448344B (en) | 1987-02-16 |
JPS54113425A (en) | 1979-09-05 |
FR2416015A1 (en) | 1979-08-31 |
IT1116524B (en) | 1986-02-10 |
JPH0160455B2 (en) | 1989-12-22 |
CH651210A5 (en) | 1985-09-13 |
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