Tool with immunostimulating action

 

(57) Abstract:

Usage: in immunology to restore immune homeostasis, including in the treatment of immunodeficiency and acute infectious diseases. The inventive application of zeolite tuff Chivyrkuyskogo field - RIVERTWIN - as a means to an immunostimulating action. table 4. 15 Il.

The invention relates to medicine, in particular immunology, and can be used to restore immune homeostasis, including the treatment of immunodeficiency and acute infectious conditions.

Known for a large group of drugs that increase the overall resistance of the organism or its nonspecific immunity (stimulants - caffeine, amphetamine, Siberian ginseng, and other vitamins retinol, ascorbic acid, B vitamins and others), as well as influence the specific immune response, such as a series of extracts of the thymus gland (thymalin, T-activin, timoptic, vilonen) [1]

Among the drugs that can stimulate the immune processes and specifically activate immunocompetent cells (T - and B-lymphocytes), as well as additional immunity factors (m and others) [1]

The prototype of the claimed invention can be considered prodigiozan - bacterial polysaccharide, representing an amorphous powder, grayish-yellow color [1]

However, it is usually applied daily dosage prodigiozana often causes the patient's side effects: fever, headache, aching joints, leukopenia, diarrhea.

The task of the invention is the finding immunostimulatory means of natural origin, is effective in small doses, excluding side effects and providing a wider compared with the known Immunostimulants and beneficial effect on all systems of the body, i.e. the body as a whole.

Known natural zeolite-containing tuffs different zoning, among which the dominant importance clinoptilolite breed. The high content of clinoptilolite (from 30% to 90%) in domestic zeolite tuffs determines the similarity of geochemical, adsorption, ion exchange, and catalytic screening properties of different varieties of zeolite tuff, a typical representative of which is RIVERTWIN-clinoptilolite tuff Chivyrkuyskogo field (H Is 1 (animal Feeding and zeolites: guidelines for the study of natural zeolites in the feeding of farm animals. Kemerovo. 1990. C. 5-6).

Standards for levels of toxic trace elements in zeolite tuffs are in accordance with specifications on zeolites [1] From table.1 shows that the content of toxic trace elements in sivertone does not exceed the rate determined by the technical conditions on the zeolite raw material.

Fineness of grind used zeolite tuff was less than 1 mm, which also corresponds to the technical conditions, which shows that the most effective fineness of grind these tuffs up to 1 mm

A unique combination of zeolite raw material sorption, catalytic, ion exchange, screening and other properties provides a wide range of industrial and agricultural applications.

However, modern technology is not found data on the use of zeolite tuff as Immunostimulants in immunodeficiency States and acute infectious diseases.

The invention consists in the application of zeolite tuff Chivyrkuyskogo field as a means to an immunostimulating action. Schemas influence RIVERTWIN shown in Fig. 1-15: Fig. 1 influence RIVERTWIN on the weight of the thymus in irradiated mice; the Weena on the weight of the spleen in irradiated mice; Fig. 4 impact RIVERTWIN on the number of nucleated cells in the spleen of irradiated mice; Fig. 5 - influence RIVERTWIN on the number of leukocytes in the peripheral blood of irradiated mice; Fig. 6 impact RIVERTWIN on the number of nucleated cells in the spleen of irradiated mice at 4 days after immunization DL; Fig. 7 impact RIVERTWIN on the magnitude of the humoral immune response to EB in irradiated mice; Fig. 8-influence RIVERTWIN on the value of the integral index of infection in irradiated mice; Fig. 9-influence RIVERTWIN on the weight of the thymus after injection of hydrocortisone; Fig. 10 impact RIVERTWIN on the number of nucleated cells in the thymus of mice after injection of hydrocortisone; Fig. 11 impact RIVERTWIN on the weight of the spleen of mice after injection of hydrocortisone; Fig. 12 - influence RIVERTWIN on the number of nucleated cells in the spleen of mice after injection of hydrocortisone; Fig. 13 impact RIVERTWIN on the number of leucocytes in peripheral blood of mice after injection of hydrocortisone; Fig. 14-influence RIVERTWIN on the number of nucleated cells in the spleen of mice treated with hydrocortisone, on the 4th day after immunization DL; Fig. 15 impact RIVERTWIN on the magnitude of the humoral immune response to DL the Ufa Chivyrkuyskogo field (RIVERTWIN) studies have been conducted on laboratory animals (white rats and mice).

Example 1. Immunostimulatory effects RIVERTWIN by immunization of animals with sheep erythrocytes.

In the first series of experiments evaluated the magnitude of the humoral immune response using the method of immunization of white Wistar rats with sheep erythrocytes. The immune response was determined on day 5 after immunization of animals (PL. 2). Introduction RIVERTWIN in the diet of rats lasted 3 months.

Analysis of the results showed that feeding animals RIVERTWIN in subsequent immunization with sheep red blood cells increases the immune response.

On the weight of the spleen in rats consumption RIVERTWIN had no effect. In the group treated with RIVERTWIN marked relative increase in the number of rosette cells (ROCK) compared with the control. When evaluating the results of the determination of IgM-producing cells has the same regularity that the definition of ROCK. The immune response on this indicator in rats consumed RIVERTWIN was almost 2 times higher than in the control.

Thus, the three-month introduction RIVERTWIN in the diet to rats produces an immunostimulating effect on the animal organism, causing more pronounced than in the control group, the immune otoofi white pulp in animals treated with food RIVERTWIN.

In the lymphoid apparatus draws the attention of macrophage activation elements not only in its germinative centers, but also in the marginal parts of the follicles (table. 3).

Similar morphological response observed in the follicles of lymph nodes (pratimoksa and root of the mesentery). In lymph nodes, in addition, there are morphological signs of activity on both T-dependent and B-dependent structures. In B-dependent areas of lymph nodes increased in size and number of lymphoid follicles, in its germinative centers are marked accumulation bestransformatornym cells. Nakatnye the fibres are in a state of hypertrophy by increasing the number of cells plasmacytoma series. In T-dependent areas of lymph nodes and spleen are morphological signs of increasing functions mates in the immune response: an increase in the absolute volume of the nuclei of reticular cells and macrophages, the prevalence among lymphoid cells, lymphocytes differentiate into plasmacytoma direction, as well as the increase in the number of macrophage-sockets.

In cerebral sinuses of lymph nodes is observed dense lymphocytosis, cscom study of the intestine of rats, receiving RIVERTWIN found to increase the specific volume of lymphoid tissue in a proper plate of the intestine. In all departments of the intestine significantly increased number of lymphoid follicles. The main part of the follicles has clearly differentiated its germinative center. In the last marked activation of macrophages, which form together with the adjacent lymphoid cells typical macrophage-sockets. The mantle zone of the follicle consists of densely aggregated small and medium lymphocytes.

Thus, RIVERTWIN was found positive effects: stimulation of the immune system, which can be of great value in the treatment of many diseases.

Example 2. Impact RIVERTWIN on morphological and functional parameters of the immune status of animals in terms of experimentally created models of immunodeficiency in vivo.

In experiments to study the immunostimulating action RIVERTWIN used mouse-hybrids F1 (CBA x C57B1), females aged 2-4 months. The animals were kept in standard vivarium conditions, RIVERTWIN added them to feed, replacing 5% of the weight of the feed.

To create experimental immunodeficiency mice used two way is Zetta dose of 1 mg/mouse.

To assess the effect RIVERTWIN parameters immunodeficiency States all animals were divided into 5 experimental groups):

intact mouse;

control mice irradiated at a dose of 200 rads;

control mice received an injection of hydrocortisone;

"experimental mice irradiated at a dose of 200 rads and receiving food additive RIVERTWIN;

"experienced" mouse received an injection of hydrocortisone and receiving food additive RIVERTWIN.

Animals "experienced" groups (group 4 and 5) within three weeks I received the food RIVERTWIN then them and control animals were either irradiated (groups 2 and 4), or were introduced them hydrocortisone (groups 3 and 5). After irradiation or administration of hydrocortisone animals "experienced" groups continued to receive food RIVERTWIN before the end of the experience. Intact mice (group 1) were not subjected to any stress.

Day of exposure (or the introduction of hydrocortisone) was designated as day 0. On the 3rd, 10th and 17th day after the beginning of the creation of immunodeficiency in the intact control and experimental mice (the same day the animals of all groups) evaluated the analyzed parameters of the immune status. For this part of the mice from each group were scored by defining them koliganek, and some mice were immunized with sheep red blood cells, determining on the 4th day after immunization, the number of antibody productive cells in the spleen.

Obtained in the control and experimental groups the results were expressed in percent of the initial level, taking account of the value of the parameters studied in the intact animals (group 1) for 100%

Animals were scored by stealing blood and highlighting the thymus and spleen. Lymphoid organs were weighed, after which they were made up of cell suspension and counted the number of leukocytes in the peripheral blood and the number of nucleated cells in the thymus and spleen in a standard way in the camera Goryaeva.

The magnitude of the humoral immune response was evaluated according to the method of Cunningham (Cunningham A. J. A. Szenberg // Immunology 1968. V. 14, No. 3. P. 599-600), determining the amount of antibody productive cells (AFC) in the spleen of mice 4 days after intravenous immunization of their EB dose of 200 million cells. For this spleen cells suspended in 5 ml of medium 199 and the camera Goryaeva counted the number of nucleated cells in the spleen. The cell suspension was diluted 10 times and mixed in different objects (0.5 ml solution of complement serum of the Guinea pig (dilution 1:5) and is in thermostat at 37oC for 45 minutes and then under a binocular magnifier was calculated in each cell the number of zones of lysis of red blood cells, corresponding to the spleen cells that produce antibodies to EB. The results were expressed in number of AFC in the spleen.

For statistical evaluation compare different samples used nonparametric test of Wilcoxon-Mann-Whitney.

In table. 4 and in figures (Fig. 1-15) presents simple averages (M) and error medium (m). The level of significance of the difference was accepted at P < 0,05.

Statistical processing of data was performed on a personal computer PC/XT program "StatGraphics" (USA).

To create a radiation model of immunodeficiency in mice was used single irradiation of animals in a relatively small dose (200 rads), which practically does not increase the mortality of mice, but at the same time causes a significant damage of the immune system, resulting in mass death radiosensitive immune cells (mainly lymphocytes of the thymus) and in the suppression of their functional activity. The effect of the selected dose of radiation in the investigated indicators of immune status at different times after irradiation of p is x the investigated indicators of immune status as morphological (the weight of the thymus and spleen and the number of leukocytes in peripheral blood are reduced by 50 to 70% as compared with intact animals, and the number of nucleated cells in the thymus almost 90% ), and characterizing the functional activity of the immune system (non-specific proliferative response of spleen cells for immunization is reduced by half and the number of cells synthesizing specific immunoglobulin M to sheep erythrocytes, it drops to 15% of control). But due to the fact that there was a small dose that does not cause complete devastation of bone marrow and sharp oppression of the process of hematopoiesis, at a later date (after 10 and 17 days after exposure), there was a noticeable increase in the weight and cellularity of lymphoid organs and restore the intensity of the immune response on the DL, although some indicators of immune status remained significantly decreased until the end of the experience.

It was assumed that this model of the "small" immunodeficiency, caused by the action of radiation, will reveal the influence of the studied zeolite tuff RIVERTWIN on the recovery process of the immune system radiation injury. The experimental results shown in Fig. 1-8.

The data obtained suggest that the introduction of zeolites in experimental animals feed (before and after irradiation) OK the em radiation.

For example, an additive in animal feed RIVERTWIN significantly increases the number of nucleated cells in the spleen of irradiated mice (Fig. 4), the number of leukocytes in the blood of animals on the 17th day after irradiation (Fig. 5). Similarly reception RIVERTWIN effect on the magnitude of the humoral immune response to sheep red blood cells in irradiated mice (Fig. 7).

Considering the obtained data, one can notice that the effect of RIVERTWIN on indicators of immune status in the radiation model immunodeficiency characterized by the upward trend of the studied parameters in comparison with the irradiated animals. To illustrate this, due to Sibirtelekom effect in Fig. 8 presents the values of the integral index that characterizes the degree of immunodeficiency in irradiated mice treated and not treated RIVERTWIN with food, at different times after the start of the experiment (integral index of immunodeficiency is calculated simply by summing and averaging all of the defined parameters, expressed in relative units, 1 was accepted value of the corresponding parameter in the intact animals). It is clear that the 17-th day after irradiation, the value of the index in the group of animals, sex is advised to check as far as the effect RIVERTWIN depends on the specific conditions created by the radiation model of immunodeficiency, experimentally investigated the effects of RIVERTWIN on parameters of immune status in other standard models of immunodeficiency caused by the introduction of animal hydrocortisone. With the overall scheme of experiments (analyzed parameters, terms, their definitions, and so on) was exactly the same in the study of both models of immunodeficiency.

From the data given in table. 4, it is seen that intraperitoneal administration to mice of hydrocortisone is accompanied by a reduction of the main measurable indicators of immune status, and vyrazhennosti immunodeficiency on the 3rd day after exposure similar to that observed after irradiation at a dose of 200 rads. As in the radiation model, at a later date, these indices returned to normal, and on the 10th and 17th days of the magnitude of some parameters significantly differ from their values in the intact animals. The only (but important) difference between these models of immunodeficiency is that the introduction of hydrocortisone is not only caused a decrease in the intensity of the humoral immune response to sheep erythrocytes, but, on the contrary, led to doscover is cunosti immune response in the presence of undoubted animals (tested on other parameters) syndrome can be explained by the fact a well known fact, the greatest (compared to other lymphoid populations) sensitivity to the inhibitory action of hydrocortisone have T-suppressors, specifically suppressing the development of immune responses (Behrens T. W. Goodwin J. S. // The pharmacology of lymphocytes. B. H. N. Y. 1988. P. 425-439). Therefore, in certain experimental conditions, the effect of hydrocortisone, which inhibits suppressor activity to a greater extent than the functions of other cell populations, manifested in the visible intensity of immune responses (ibid; Piccolella e et. al. // J. Immunol. 1985. V. 134, No. 2. -P 1166-1171). With high probability we can assume that a similar stimulating effect used in the experiment is relatively small doses of hydrocortisone on the specific immune response was observed in the above experiments. This explanation of the obtained results is confirmed by the fact that those same animals hydrocortisone suppressed non-specific proliferative response of splenocytes to antigenic stimulation, significantly reducing the number of nucleated cells in the spleen after immunization.

The results of research of influence RIVERTWIN on parameters of immune status in mice after injection of hydrocortisone presents increased cellularity of the spleen on the 17th day after injection of hydrocortisone (Fig. 11);

under the action of RIVERTWIN on the 17th day of experience increases the number of leukocytes in peripheral blood compared to animals not receiving RIVERTWIN;

RIVERTWIN on the 10-th day after injection of hydrocortisone increases the number of cells in the spleen after immunization with sheep erythrocytes (Fig. 14).

In General, the obtained data indicate that, as in the radiation model of immunodeficiency, oral administration to animals RIVERTWIN has a stimulating effect on the parameters of the immune status of mice at various times after injection of hydrocortisone.

It can be assumed that the most probable and reasonable from the point of view of current knowledge of the mechanism of action RIVERTWIN when immunodeficiency is binding on its surface and excretion of intestinal bacterial toxins that play an important role in conditions of artificial models of immunodeficiency.

The use of natural zeolite tuff Chivyrkuyskogo field RIVERTWIN as a means to an immunostimulating action.

 

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