JPH0160455B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Background of the Invention In the past, rheumatoid arthritis was commonly thought to have an infectious etiology. Inflammatory features and constitutive manifestations of rheumatoid arthritis - synovitis and endoblastic lesions, fever, frequent sweating, leukocytosis, lymphadenopathy and occasional spelnomegaly, accelerated erythrocyte sedimentation rate and “sensitive phase reactants”
All other changes in the number of infections are compatible with an infectious process, but this view is not common today. Through extensive and repeated bacteriological studies, blood, synovial fluid,
No single infectious agent could be consistently isolated from the synovial tissue or subcutaneous nodules. Attempts to transfer the disease by injecting synovial fluid from patients with rheumatoid arthritis into the joints of other subjects have been unsuccessful. Subcutaneous nodules were unable to remain viable after homologous transplantation (Bauer, et al. 1951). Infectious processes appear to precipitate the attack of rheumatoid arthritis in a significant number of patients and can have a deleterious effect on the disease process if the disease is already established. There is statistical evidence to support this clinical result (Lewis-Faning, 1950). Many attempts have been made to induce diseases similar to rheumatoid arthritis in animals. Although various bacteria can cause arthritis in animals, they are responsible for the clinical and pathological features of rheumatoid arthritis,
In particular, it is unable to reproduce the self-perpetuating features of proliferative arthritis. Arthritis with some similarities to human disease has been caused in mice by pleuropneumoniae (Sabin, 1939) and in pigs by erysipelas (Sikes, et al., 1955). The concept was postulated that these bacteria could initiate hypersensitivity mechanisms (Sikes, et al., 1955). Still, rheumatoid arthritis researchers remain interested in certain recurring themes that suggest a link between infection and joint disease. For example, gonorrhea can not only cause typical gonorrhea arthritis, but can also lead to chronic arthritis that sometimes develops into typical rheumatoid arthritis. No statistics are available on the rate at which this occurs. Therefore, I don't know how much to emphasize that relationship. Tonsillitis or pharyngitis may also be accompanied by polyarthritis,
This first manifests as rheumatic fever and progresses to rheumatoid arthritis. Acute viral infections, especially rubella in young women, can be accompanied by persistent polyarthritis involving large as well as small joints, and these arthritis are generally the result of several months of persistent joint disease resembling rheumatoid arthritis. It goes through a process and then gradually subsides. Although chronic infection of unknown origin remains the common assumption for the pathogenesis of rheumatoid arthritis,
However, there is no published data to support this assumption. Some researchers believe that if infection is a factor, it is not infection with a particular type of microorganism, but rather a variety of infections with altered host responses that are responsible for the disease. I suspect that it may be an infection caused by a common microorganism. The present invention is based on this theory for the origin of rheumatoid arthritis. Although an infectious etiology has never been established, several recent developments appear to support this theory. Some of these are: 1. Patients with rheumatoid arthritis have lower than normal levels of IgA, a class of immunoglobulin found in secretions of the gastrointestinal tract. 2 Immunoglobulin A, produced in response to immunization via the salivary glands, is found in serum colostrum and milk as well as saliva. IgA is transported to these various fluids via the gastrointestinal tract and lymphatic system. (Michelok, et al., 1975). 3 After intestinal bypass surgery for morbid obesity, some patients exhibit symptoms that are virtually identical to rheumatoid arthritis. The onset of arthritis occurs in serum
IgG, IgM, IgA, supplementary components C ₃ , C ₄ , C ₅ and E. coli and B. fragilis
It is accompanied by the appearance of circulating cryo-rotein, which consists of IgG antibodies against Symptoms completely subside after intestinal bypass is removed (Woods,
et al., 1976). 4. One type of polyStreptococcus alactis belonging to Streptococcus group B has been implicated as an etiologic agent of rheumatoid arthritis (Svartz, 1972). This streptococcus is present in most commercially available pasteurized milk, but not in immune milk. 5 Predisposition to rheumatic diseases appears to be inherited via histocompatibility antigen (HL-A). These antigens likely determine the host response to infectious agents. Based on this evidence, rheumatoid arthritis has an infectious source; the infected side originates in the gastrointestinal tract; a number of different bacterial strains are involved in the infection; the infection probably occurs due to a defect in the host's immune defense mechanisms; and It is concluded that the most effective way to treat the above diseases is to re-establish immune protection against infectious agents in the gastrointestinal tract. Treatment of Infections There are basically two methods that can be used to treat infections. i.e. immunization methods involving active or passive immunization against infectious agents and antibiotics such as penicillin, tetracycline,
The use of ampicillin, etc. Antibiotics are non-specific in their activity and kill a wide range of harmful as well as beneficial bacteria. Immunization methods, on the other hand, are highly specific. Bactericidal antibodies raised against a particular strain of bacteria act only against that strain and have no harmful effect on other types of bacteria. Furthermore, unlike antibiotics, antibodies are natural body products and have no known side effects. Immunization is the method of choice since the aim of the invention is to control infections by a specific group of bacteria without harming the beneficial bacteria in the gastrointestinal tract. Active and Passive Immunization There are two different ways to achieve immune protection. Active immunization is a method of actively immunizing a host with a vaccine that stimulates the host's immune system to produce protective antibodies against the factors contained in the vaccine. Active immunity occurs under natural conditions when a host is exposed to an infectious agent. Passive immunization is a method in which antibodies obtained from one actively immunized individual are given to a second individual. According to this method,
Protective antibodies are transferred from the immune host to the recipient. Passive immune protection is temporary and lasts only as long as passively acquired antibodies persist in the recipient's system. For example, antibodies collected from horses immunized against tetanus toxin can be given to humans infected with tetanus to provide temporary immune protection against the toxin produced by the tetanus bacteria. The previous patent (U.S. Patent No. 3,626,057) includes
A method for producing tetanus antitoxin in milk is described. This patent states that cows can be actively immunized against tetanus toxin; that antibodies against the toxin produced by cows can be obtained from milk; and that these antibodies can be obtained from animals infected with tetanus bacteria. It is taught that antibodies can be used to treat toxins in a manner that neutralizes them. This patent teaches that passively administered antibodies neutralize life-threatening toxins produced by bacteria, thereby providing temporary immunity to the toxins. Passive immunization differs from active immunization in that immune protection is temporary and lasts only as long as protective antibodies are present. Active immunization is more permanent. This is because the host's immune system continues to produce protective antibodies in the presence of stimulating antigens. Recent studies in the field of gastrointestinal immunology have shown the existence of local immune mechanisms in the gastrointestinal tract. This immune system of the gastrointestinal tract produces special antibodies that serve to inhibit bacterial invasion in the lumen of the gastrointestinal tract. Antibodies, called secreted immunoglobulins or IgA, are produced in response to local active immunization of the gastrointestinal mucosa by antigens. The secretory immune system of the gastrointestinal tract serves to prevent the translocation and proliferation of harmful bacterial species in this environment. It is believed that a weakened local immune system in the gastrointestinal tract allows for the colonization of unknown harmful bacteria that cause rheumatoid arthritis. According to this theory, rheumatoid arthritis results from a lack of the local immune system in the gastrointestinal tract to produce and secrete protective antibodies against harmful bacteria. Therefore, the inability of the host to respond to active immunity precludes this method as a treatment for rheumatoid arthritis. The present invention describes methods for controlling the growth and proliferation of harmful bacterial pathogens, particularly in the environment of the human gastrointestinal tract. The above method is a method of passive immunization through oral ingestion of protective antibodies produced in cattle. The method provides temporary immune protection that is highly specific for the bacterial species used for antibody production and is not harmful to common beneficial bacteria living in the gastrointestinal tract. The antibodies used in the methods of the invention constitute a unique and useful product of the invention. Milk is a preferred source of the antibody products of the invention. It defines a unique population of antibodies (IgG type) in the milk that reacts with a known range of bacteria, and this reaction is highly specific in that it has beneficial effects in the treatment and prevention of rheumatoid arthritis. There is. The type of immunoglobulin is an important consideration regarding the patentability of this invention. If anything,
There are five known types of immunoglobulins, termed IgG, IgM, IgA, IgD and IgE (Nisonoff, et al., 1971). The various immunoglobulins have different structures (Waldman, et al.
1970) and have different biological functions in the body (Waldman, et al., 1971 and Franklin, 1964).
Additionally, there are surprising changes in the location of immunoglobulins in the body. For example, the distribution of the immunoglobulin types IgA and IgG is distinctly different. IgA
Its most surprising feature is that it is present in high concentrations in the external essential fluids of the body, including gastrointestinal fluids. The immune system that supplies IgA to gastrointestinal fluids is a different system than the system that produces IgG. In humans, IgG occurs primarily in the body's vasculature and intracellular spaces (Waldman, et al., 1970) and is rarely found in gastrointestinal fluids. Another important difference between types of immunoglobulins relates to metabolic rate. The degradation of each type of immunoglobulin appears to be under different control, regardless of its location in the body. Functional catabolic rates range from as low as 6.5% for IgG to 90% for IgE
and other immunoglobulin types fall in between (Waldman, et al., 1970). Furthermore, different immunoglobulin species differ in their binding properties to antigens and their ability to fix complement, which is one of the prerequisites for killing living bacterial cells (Heremans, 1960). It is important to emphasize these differences in antibody type since the immune effect can vary depending on the type of antibody involved. The most commonly held theory is that different types of immunoglobulins perform their functions in different environments within the body. For example, it is known that there is a unique immune system specialized for the production of antibodies that functions in the environment of the gastrointestinal tract. Furthermore, it is generally accepted that the immune function of the gastrointestinal tract is specifically controlled by IgA antibodies rather than IgG antibodies.
Therefore, under natural conditions, IgA is a type of immunoglobulin that regulates immune control against bacterial infections that occur in the human gastrointestinal cavity. IgG, IgM,
Since IgD and IgE are not normally found in intestinal secretions, it is illogical to expect either of these types of antibodies to be effective in treating infections in the gastrointestinal environment. The major immunoglobulin in milk is IgG, not IgA (Sullivan, et al., 1969). Therefore, it is clear that milk is not a source of antibodies for treating bacterial infections of the human gastrointestinal tract due to its high IgG and low IgA concentrations. Immunization method is another important parameter when considering different types of immunoglobulins. It is well known to those skilled in the art that different immunization methods selectively produce different types of antibodies. For example, local immunization of secretory tissue, achieved by exposing the tissue to an antigen, stimulates the selective production and secretion of immunoglobulins of the IgA type. The intramammary perfusion technique, as described in US Pat. No. 3,376,198, is an example of a local immunization method. This method stimulates the production and secretion of IgA antibodies and is not an effective method for producing IgG. According to the invention, the products of the invention are produced using intramuscular injection. After all, it's not IgA.
IgG is the major immunoglobulin in milk, and in cows, systemic immunization is the preferred method to generate IgG-type antibodies in milk. This difference between IgG and IgA type immunoglobulins is important. This is because it teaches that systemic rather than local immunization is the preferred method for obtaining high titers of milk antibodies. Furthermore, this difference teaches that the immune product produced by mammary perfusion of a vaccine is distinctly different from the immune product produced by intramuscular injection of the same vaccine. The products of the invention (IgG antibodies) are therefore distinctly different from the products obtained by the method described in US Pat. No. 3,376,198. The immunization product of the present invention has an IgG type antibody concentration.
This is an improvement over the product of the patent as it is significantly greater than the IgA type antibody concentration. There is no evidence in the above literature to support the claim that IgG antibodies can be produced by intramammary perfusion of antigen. Furthermore, since the levels of IgA immunoglobulin are absent or significantly low in milk, it is unreasonable to think that the teachings of the above US patents have any bearing on the claims of the present invention. On the contrary, the teaching of the above-mentioned US patent does not lead us away from the findings of the present invention since it implies that IgA is a biologically active factor in milk with potential therapeutic applications. be. SUMMARY OF THE INVENTION According to the present invention, a unique combination of bacterial species is formulated into a vaccine that is administered to healthy dairy cows. Obtained from the milk of immunized cows
IgG antibodies constitute the products of the invention. The method of the invention involves passive immunization of a patient by oral infusion of IgG immunoglobulin, thereby passively immunizing the patient against a mixed range of infectious bacteria residing in the gastrointestinal tract. This treatment eliminates the conditions in the gastrointestinal tract that cause rheumatoid arthritis. DETAILED DESCRIPTION The product of the invention is a low-fat milk powder containing a population of natural IgG-type antibodies acting against the bacterial species shown in Table 1. [Table] [Table] * American type culture
Lexion Antibacterial Milk contains all the substances normally found in low fat powdered milk. Table 2 shows the main components that make up antibacterial milk. Table 2 Quantitative and Qualitative Analysis of Antibacterial Milk Protein 35.6% Fat 1.0% Carbohydrate 52% Minerals 7.8% Moisture 3.5% Each 3-4 oz reliquefied quart of non-fat dry milk contains approximately: 1200 mg Calcium 157% 935 mg Phosphorus 125% 0.3 mg Thiamine 32% 1.78 mg Riboflavin 140% 1.04 mg Niacin 10% 324 Calories Antibacterial milk and regular milk contain the same approximate weight percent concentrations of ingredients. Furthermore, the IgG type immunoglobulin concentrations in antibacterial milk and normal milk are the same. Therefore, the only thing that distinguishes antibacterial milk from normal milk is the specificity of the antibodies that make up antibacterial milk. The specificity of an immunoglobulin refers to the range of bacterial species against which the antibody acts. Antibacterial milk does not contain pharmaceutical additives or other ingredients that are not natural bovine food products. The immune milk of the present invention is also effective in controlling autoimmune diseases such as lupus erythematosus, which are caused or exacerbated by bacterial infections in the gastrointestinal tract. Multivalent antigens used to induce antibacterial milk are prepared as follows. Vaccine Preparation The bacterial strains listed in Table 1 were obtained from The American Type Culture Collection, which guarantees the authenticity of the bacterial strains and the highest standards of purity available. Upon receipt, each bacterial strain was grown on blood agar plates to test the viability of the culture and determine whether the growth pattern was typical or atypical for the bacteria in question. A single colony from each of the test media was taken for histological examination to further confirm culture authenticity and purity. A single colony of each medium was used to inoculate 500 ml of standard culture broth. The·
Each of the specific bacteria listed in Table 1 was grown using standard broth recommended by the American Type Culture Collection. All bacteria were inoculated as static media except 12, 13, 14 and 60 which were inoculated on a shaker to provide agitation. Bacterial strains and American
Type Culture Collection Catalog
Table 1 shows the identity of the numbers. 37℃ for each medium
The cells were cultured for 48 hours. After inoculation, the medium was killed by heating at 60°C for 2 hours. A sample of the killed bacteria was used to inoculate fresh meat broth and then incubated at 37°C for 24 hours to determine whether the sterilization method was complete. Only media that were found to be sterilized by this technique were used for further processing. The sterile medium was then washed five times with distilled water, and the cells were collected by centrifugation. Bacterial cells were frozen by immersing them in liquid nitrogen and lyophilized using a freeze-drying method. The lyophilized cells were stored in sterile vials until used for the production of multivalent vaccines. Multivalent vaccines were prepared by weighing out 1 g of each bacterial strain. The dried cells were mixed together and the mixture was suspended in sterile saline (20 g bacteria per 500 ml saline). Samples of the concentrated solution were serially diluted with saline.
The dilution was determined to give a concentration of ×10 ⁸ ml/cc. The original concentrated multivalent vaccine was distributed into multiple containers, frozen and stored. Each container contained enough concentrated antigen to immunize 50 cows. The final dilution of the concentrate was performed immediately before immunization. The preferred approach is to remove a sufficient number of vials to immunize the number of cows being processed. For example, the vials are removed 24 hours prior to the scheduled time of the immunization, and the concentrated sample is then diluted in a sterile container to a final concentration of 4 x 10 ⁸ cells/ml. Maximal responses are obtained in cattle by injecting 5 c.c. of a sterile preparation with 20 x 10 ⁸ bacterial cells or 4 x 10 ⁸ cells/ml using the immunization method described below. Preferred Immunization Method for Cattle The antibody products of the invention are produced by immunizing cattle with multivalent antigens prepared as described above. Cows are injected with 5 c.c. of multivalent antigen containing 20 x 10 ⁸ bacterial cells. The injection is given in the gluteus maximus muscle of the hind leg. This method can be repeated at weekly intervals for four consecutive weeks starting 2-3 weeks before the expected delivery date. After the first immunization, booster injections are given every 14 days using the same concentration of antigen. This immunization method gives maximum antibody titers. Milk Collection, Handling and Processing Dairy cows are collected from immunized cows in modern milking sheds. A fully automated milking system collects and stores milk under perfect sanitary conditions. The milking system consists of an automatic machine connected directly to a frozen storage tank by a closed system of pipes. Clean and sterilize the entire system after each milking to ensure maximum hygiene. It is important to take care to prevent bacterial growth on the immune milk during processing. This is because such bacteria can reduce the titer of antibodies in milk. Milk is transported daily from refrigerated storage tanks to the dairy plant by milk transport trucks. Dairy plants use high temperature short time systems to sterilize antibacterial milk. A special dairy machine flash-heats a continuous stream of milk to 155°C for less than 15 seconds. Temperature and time are critical. This is because antibodies are sensitive to thermal degradation. Milk antibody is 165
Decomposes if kept at temperatures above 1 minute or more.
After sterilization, the whole milk is immediately cooled, the fat is removed by centrifugation, and the defatted antibacterial whole milk is powdered by a spray method. The spray method consists of a large drying chamber into which hot air (350ⓓ) is blown at high velocity. Skimmed milk is atomized into the chamber where the fine milk particles dry immediately as they fall to the bottom of the tank. The dry milk is automatically removed by a mechanical device and the milk powder is packaged under hygienic conditions. Before atomization, skim milk is boiled in a vacuum chamber (100-110〓)
Concentrate by At each stage it is critical to prevent bacteria from contaminating the milk.
This is because this contamination reduces antibody titers. Test method: Immunized milk was prepared from Holstein cows bred inbred. Cattle were immunized by intramuscular injection with the mixture of bacterial antigens shown in the table. The vaccine was prepared by the method described above. The immunological response of the cows was enhanced by two weekly injections of the vaccine. The milk from these cows was pooled, the fat was removed, and the non-fat milk was pasteurized by exposing it to 160° for 16 seconds and then subjected to a spray drying process in which the milk temperature did not exceed 85°. The milk was packaged in 1 quart polyethylene containers. The control milk (placebo) was non-fat powdered milk purchased from a local manufacturer. Erythrocyte sedimentation rates were determined on freshly collected blood by the Westergren method and corrected for hematocrit by the Wintroph and Landsburg method (1935). Rheumatoid factor titers were determined by the Singer-Plotz (1966) macroscopic tube test. The patient was accepted for study based on high erythrocyte sedimentation rate and positive rheumatoid factor titer. Nine patients were studied for 12 months and 11 patients were studied for 18 months.
I researched it for months. The patient group was 32 to 69 years old with an average age of 50.4 years.
13 Caucasian women aged 43 to 58.1 years and an average age of 58.1 years
It consisted of seven white men, all 70 years old. The average duration of arthritis is 10.8 years for women and 11.0 years for men.
It was a year ago. Patients were randomly placed on immunized milk or non-immunized milk (a commercial product purchased in the Dayton area that served as a placebo). Both milk products were packaged in the same container, and each was identified as immune milk or placebo by a blue or red pressure-sensitive label attached to each container at the time of filling. This label was removed immediately before dispensing the milk to the patient. Therefore, there was no time to know whether a patient received immunized milk or placebo. Patients were randomly selected (determined by flip of a coin) to receive immunized milk or placebo during the first 6 months. After this period, patients who received immunized milk were placed on placebo and those who received placebo were placed on immunized milk for a second 6-month period. After the second 6 months, 11 patients volunteered to remain in the study for an additional 6 months. At this point, the type of milk (immune or placebo) was changed again and observation continued. Therefore, the research focuses on three six points.
Eleven patients participated in three periods and nine patients participated in two periods. Patients were observed at monthly intervals, at which point they were given a month's milk supply, completed an evaluation questionnaire, and blood samples were collected for rheumatoid factor titers, erythrocyte sedimentation rate, and hematocrit measurements. . Patients were instructed to consume an amount of nonfat milk solids equivalent to 1 quart of milk twice a day after meals. Milk solids were freshly dissolved in 1 pint of cold tap water just before consumption in the morning upon awakening and just before going to bed at night. They were told to see their doctor as usual and follow the treatment prescribed by the doctor. Medication was administered ad libitum or as prescribed by the attending physician. The inventor is
They were only required to report the amount of drugs they took. Survey samples (Figure 1, 1A) are given to each patient every month.
Figure) was written. It was divided into six parts: 1. Morning stiffness time 2. Severity of pain experienced in each of the 8 joints 3. Type and amount of short-acting medication taken 4. Length of time taken Type and amount of medicinal product with a duration of action; 5. Ability of the patient to perform normal activities; 6. Severity of symptoms of rheumatoid arthritis. The number shown in the blank space following each answer indicates the score assigned to that answer during the questionnaire evaluation process. When evaluating the score of the area treated with medication,
Efforts were made to reflect the relevant anti-inflammatory and analgesic activities of the various drugs used. A value of 1 was given to a 5 grain aspirin tablet. All other medications (gold, plaquenil and cortisone shots considered separately)
) were given arbitrary values for aspirin. Therefore, all salicylates, Tylenol, Darbon, Motrin, etc. were considered equivalent to a 5 grain aspirin tablet and were also given a value of 1. The number of mg of prednisone is 4 times the value, and the number of indocine capsules taken is
It was 2.5 times more expensive. The number of grains of codeine was 2 times the value and the number of butazolazine tablets taken was 7 times the value. Average scores for each category were calculated for each 6-month period. The difference in mean values was then calculated by subtracting the mean value recorded during administration of immunized milk from the mean value recorded during administration of placebo. If the results are calculated in this way, the improvement in the patient's condition during the period when the patient took the immunized milk is
was noted by negative values for and positive values for all other questions. Mean corrected erythrocyte sedimentation rate (ESR) and rheumatoid factor titer (RF) were each shown similarly. These were calculated such that positive values reflected lower erythrocyte sedimentation rates or rheumatoid factor titers during administration of immunized milk. Data are from Goodnight et al. Statistical Analysis
Statistical evaluation was performed using the SAS Institute (SAS Institute, Raling, NC). Calculations are done using IBM model 370/
155 computer was used. Results Immune milk was well tolerated by all patients except one with pernicious anemia. The patient complained of diarrhea and was discontinued from the study. One patient reported weight gain during the course of the study. This is likely due to increased caloric intake from milk;
Or perhaps it reflects an overall improvement in physical condition. Table: As shown in Table 3, patients were observed for a total of 27 control periods (6-month periods receiving placebo) and 24 study periods (6-month periods receiving immunized milk). One patient had 1 of the ankle and foot.
suffered physical damage. Pain in these joints was not assessed. This explains the existence of a smaller number of evaluation periods for those joints. The erythrocyte sedimentation rates for one patient were highly abnormal (more than 2 standard deviations from the average value for other patients) and therefore their rates were not included. This omission explains the lower number of observations reported for that variable. The mean value and coefficient of variation (CV) are shown in the table for each variable. The difference between the means was calculated by subtracting the mean value obtained during the period when patients received the immunized milk from the mean value obtained during the period when they received the placebo. A favorable response to immunized milk is indicated by negative values for AM stiffness (Problem 1) and monthly changes (Problems 6a, b and c) and positive values for all other variables. A valid response to the immunized milk was obtained for all data obtained from the questionnaire. Probability (P) points out a high degree of statistical meaning in all cases. The small mean differences obtained for erythrocyte sedimentation rate and rheumatoid factor titer were not significant. However, when considering the erythrocyte sedimentation rate on an individual basis, the 20
Four of the patients had statistically significant reductions while receiving immunized milk. Although immunized milk had no significant effect on average rheumatoid factor titers, an interesting response was revealed when examining individual patients. Seven of the 20 patients studied had negative rheumatoid factor titers on at least one occasion while receiving immunized milk. Four of them became negative during the period receiving immunized milk, and their titers did not become positive during the subsequent 6 months receiving control (placeb) milk, as shown in Figure 2. Ta. Continuing the study after this reporting period, 13 of the 25 patients lost rheumatoid factor from their blood. Discussion The scientist in charge of the study met personally with each patient at monthly intervals and recorded their answers to the questions. Nothing was done to influence the patient's answers. Patients were initially informed and frequently reminded that they would receive a placebo during certain periods of the study. This knowledge was expected to act as an incentive for patients to answer questions objectively and without prejudice. Patients were not informed at any time whether they were receiving immunized milk or placebo. The questions regarding medications given “yesterday” (Question #3) and the questions regarding Goldshot, Prequenil and Cortisone shots (Question #4) are objective and should be considered when considering the answers given to the other questions. The first important thing. These questions are important for two reasons: 1. If immunized milk is effective in reducing symptoms of disease, patients would be expected to take less of the ad libitum drug. On average, patients reported taking four fewer aspirins or equivalents per day while receiving immunized milk. They also reported that they took fewer Goldshot, Prequenil, and Cortisone shots during these periods; and 2. Patients took lower doses of painkillers and other pharmaceutical agents effective in treating rheumatoid arthritis. When taking immunized milk, they are expected to report increased discomfort unless the immunized milk favorably affects the disease. As shown in Table 2, significantly fewer joint complications were reported during the period when patients were receiving immune milk even if they were taking less than their arthritis medication. Patients were enrolled in the study at monthly intervals over a year, and the type of milk product they initially received (immune milk or placebo) was randomized. The observation that positive responses or improvements were obtained for all parameters of the questionnaire and that these average responses were statistically significant strongly points out that immunized milk has a beneficial effect on patients. It is something. This conclusion is statistically significant for erythrocyte sedimentation rate (p
<0.05) reinforced by the observation of experiencing a decrease. It is difficult to assess the results of rheumatoid factor titers. This is based, at least in part, on the fact that the origin and role of rheumatoid factors in the pathogenesis and prognosis of rheumatoid arthritis is not understood. Rose et al. (1948) showed that sheep red blood cells sensitized with rabbit antibodies undergo agglutination in the presence of serum from patients with rheumatoid arthritis. The test relies on a specific reaction between common immunoglobulins (rabbit or human IgG) and rheumatoid factors. The specificity exhibited by rheumatoid factor is the same as that expected for antibodies to IgG (Epstein et al. 1956). The presence of rheumatoid factor has been correlated with the disease severity of rheumatoid arthritis and can be identified in proteins precipitated in the tissues of patients with rheumatoid arthritis. Although a small percentage of patients with rheumatoid arthritis do not have positive rheumatoid factor titers, it is generally accepted by most rheumatologists that positive agglutination responses do not revert to negative even when the disease is in remission. It is being However, De Forest et al. (1958) described a small number of patients with positive rheumatoid factor titers that returned to negative after sedation. When a relapse of the disease occurred, the test became positive again. However, Aho, et al. (1959) noted that most patients whose disease became inactive remained serologically positive. The fact that negative titers were observed in 60% of our patients and that in half of the patients the titers remained negative for 6 months suggests that immunized milk may be a primary cause of rheumatoid arthritis. It has been shown to influence etiological factors. The effect of immunized milk on reducing symptoms of rheumatoid arthritis is due to the recently described histocompatibility antigen (HL-A).
This is particularly relevant when considered on the basis of the relationship between rheumatoid arthritis and susceptibility to rheumatism (Brewerton, 1976). Histocompatibility antigens are genetically determined antigens found in all human cells. The genes that control heredity are called histocompatibility genes. More than 40 of these genetically determined antigens are now known. They are responsible for the rejection of tissue transplants made in individuals other than identical twins. Superficially, the HL-A antigen is similar to the ABO blood group in that it is inherited throughout the lifespan. Their function is still unknown except in highly artificial situations created by transplantation. However, the histocompatibility gene
It is known that it is closely linked to the immune response genes on the th chromosome. In this connection, they can determine an individual's immune response to foreign invaders such as bacteria. People with HLA-B27 appear to be particularly susceptible to various rheumatic diseases. This histocompatibility antigen is hypothesized to direct the immune response that leads to rheumatoid arthritis in the presence of other predisposing factors. After intestinal infection with Yersinia enterocolitica , some patients develop acute peripheral arthritis (Ahvon, et al. 1969). Similarly, after Salmonella infection,
Approximately 2% of patients develop acute peripheral arthritis (Warren, 1970). HLA-B27 was found in 43 of 49 patients with Yersinia arthritis and in 15 of 16 patients with Salmonella arthritis (Aho, 1974). It is an attractive possibility that infectious agents can spread in the intestinal tract without causing local symptoms. In patients with HLA-B27, a host response is established that results in arthritis. Therefore, there is no need for the infectious agent to enter the joint. Immune milk is advantageous for patients with rheumatoid arthritis as it contains antibodies that effectively inactivate or neutralize pathogenic bacteria and/or their metabolic products.

[Brief explanation of drawings]

Figure 1 is a sample of the questionnaire described in the text, Figure 1A is a continuation of the questionnaire in Figure 1, and Figure 2 shows RF titers versus time over 12 months, 6 months for immunized milk, and 6 months for placebo. This is a graph plotting the test results.

Claims (1)

Claims: 1. A vaccine is first prepared from killed bacteria from two or more of the American Type Culture Collection Bacterial Antigens, including: Staphylococcus aureus 11631 Staphylococcus cutaneous Staphylococcus pyogenes 155 Streptococcus pyogenes A Type 1 8671 〃 Type 3 10389 〃 Type 5 12347 〃 Type 8 12349 〃 Type 12 11434 〃 Type 14 12972 〃 Type 18 12357 〃 Type 22 10403 Aerogenic bacteria 88 4 Escherichia coli 26 Salmonella Enteritidis 13076 Pyogenes 7700 Streptococcus pneumoniae 9590 Salmonella typhimurium 13311 Haemophilus influenzae 9333 Streptococcus greenus 6249 M. vulgaris 13315 Shigella vulgaris 11835 Streptococcus, group B Streptococcus pneumoniae mutans P. acnes, types 1 and 2 Above The vaccine was injected intramuscularly into healthy cows once a week for four consecutive weeks and then twice a month, each with 20 x 10 ⁸ bacterial cells, and starting from the fourth week milk was collected from the immunized cows and the bacteria A mixed bacterial infection of the gastrointestinal tract produced by performing a titer test to ensure that the minimum titer for each of the Antibodies to suppress. 2. The antibody according to claim 1, wherein the antibody product type 1gG is a pure immunoglobulin obtained from cow's milk.