Stimulant antigennegative differentiation of b-lymphocytes

 

(57) Abstract:

The invention relates to medicine and medical industries and is the use of a peptide of the formula Tyr-Clu-Gly (L-tyrosyl-L-glutamyl-L-glycine) as a means of stimulating antigennegative the differentiation of b-lymphocytes. The invention consists in that as a means of stimulating antigennegative the differentiation of b-lymphocytes, using a synthetic peptide of structural formula: L-tyrosyl-L-glutamyl-L-glycine (Tyr-Glu-Gly). The invention is aimed at expanding Arsenal and increase biological activity funds, stimulating antigennegative the differentiation of b-lymphocytes. 3 table.

The invention relates to medicine and medical industries and is the use of a peptide of the formula Tyr-Glu-Gly (L-tyrosyl-L-glutamyl-L-glycine) as a means of stimulating antigennegative differentiation of B-lymphocytes.

Antigennegative differentiation of B-lymphocytes is a process of formation of functionally complete B-cells from precursor cells, which takes place on the territory of the Central organs of the immune system. Antigennegative differentiation end in the market, antigens CD21, CD22, and others), missing at early stages of development [1, 2]. One of the mechanisms of development of immunodeficiency in the B-system of immunity is oppression antigennegative differentiation of B-lymphocytes. Application in such cases, stimulants antigennegative differentiation may lead to normalization of immune status.

The number of known substances that have the ability to stimulate antigennegative differentiation of B-lymphocytes. For the first time this property was described in extracts of the Central organs of the immune system - Bursa fabritsiusa birds and bone marrow of mammals. Famous works that describe how to extract from a fabric bag fabritsiusa birds, capable of stimulating antigennegative differentiation of B-lymphocytes, and represents a crude extract of animal raw materials, which was not isolated and identified the active principle [3, 4].

Method acetic acid extraction from tissue bags fabritsiusa birds selected a substance that stimulates the maturation of B-lymphocytes [5], which is a complex of alkaline polypeptides with a molecular mass of from 2 to 12 KD belonging to the class of citomedines" and later called "burcelin". This GRE cells only at a concentration of 100 μg/ml [5, 6].

Stimulants antigennegative differentiation of B-cells are hemolymphoreticular growth factors, obtained from the supernatant of the culture of bone marrow cells and being a protein with 110-140 MM KD, which gives additional substance allergogennym properties. In addition, this substance stimulates antigennegative differentiation of B-lymphocytes only at a concentration of from 5 to 10 mg/ml [7].

The above substances are composed of a complex of peptides that can stimulate antigennegative differentiation of B-lymphocytes. Use them as drugs is difficult due to the complexity of the methods of preparation, low output active substances, considerable variability in their physical and chemical properties, and also because of the possibility of patients adverse reactions due to the presence of these drugs from the bag fabritsiusa and bone marrow ballast of high molecular weight components. It is preferable to use low molecular weight synthetic compounds. They are effective in extremely small doses, do not have allergogennym and toxic effects on the body.

Known synthetic peptide, emerenciano B-lymphocytes [8] , manufactured under the brand name "bursin" (Sigma, Sweden). This means the technical essence and the achieved effect is closest to the proposed solution and its prototype.

According to the prototype, a synthetic Tripeptide Lys-His-Gly-NH2dose-dependently and selectively stimulates the differentiation of precursor B cells into Mature B-cells, in other words stimulates antigennegative differentiation of B-lymphocytes, but does not affect T-cell differentiation. However, this peptide has low biological activity. Thus, the maximum activity of the substances is manifested in a concentration of 1 μg/ml in vitro and 1 mg/kg body weight at parenteral administration in vivo.

The present invention is directed to expanding Arsenal and increase biological activity funds, stimulating antigennegative differentiation of B-lymphocytes.

The solution of this problem is achieved by the fact that as a means of stimulating antigennegative differentiation of B-lymphocytes, are available to use synthetic peptide of structural formula L-tyrosyl-L-glutamyl-L-glycine (Tyr-Glu-Gly).

The Tripeptide of the formula Tyr-Glu-Gly was found by us in tissue sumc Aravali solid-phase method, by building up the peptide chain to the N-end.

In experimental study of the biological activity of the claimed substances identified its ability to stimulate antigennegative differentiation of B-lymphocytes.

The specific activity of the proposed tool was assessed by the ability of the latter to cause the expression of differencirovannyh antigens are markers of Mature B-lymphocyte. The level of expression of differencirovannyh antigens was assessed by indirect membrane immunofluorescence using monoclonal antibodies (MCAT) LT21, LT22, and CH2 ("Sorbent", Moscow) to differentsirovannym antigens CD21, CD22 and IgM, which is a marker of Mature B-cell - final stage antigennegative differentiation of B-lymphocytes. The study was performed on lymphocytes of patients with burns, because you know that if you burn the sickness disturbed antigennegative differentiation of B-lymphocytes in peripheral blood is sharply reduced the number of Mature forms of B-cells [9, 10]. The peripheral blood lymphocytes of patients with burns IIIB - IV 15 - 30% of body surface were incubated for 2 hours at a temperature of 37oC in complete nutrient medium with the test tool in the concentration of the volume of saline. The obtained data are presented in tables 1 and 2.

Found that patients with burns reduced the number of lymphocytes bearing surface IgM. The proposed peptide Tyr-Glu-Gly dose-dependently stimulates the expression of immunoglobulin receptors. Thus, the inventive agent is effective in concentrations of from 0.05 to 1 μg/ml, and the maximum activity was observed at concentrations of peptide concentration of 0.1 microgram/ml At the same time, a well-known tool bursin shows similar activity only at concentrations of 0.5-1 µg/ml Thus, the proposed tool is a synthetic peptide Tyr-Glu-Gly - increases the number of Mature B-lymphocytes bearing IgM receptors at doses 10 times smaller than the bursin.

Found that patients with burns reduced the number of lymphocytes bearing markers of Mature B-lymphocyte CD21 and CD22. Incubation of lymphocytes burn patients with peptide Tyr-Glu-Gly leads to a significant increase in the number of CD21+and CD22+cells at a concentration of from 0.05 to 1 μg/ml, bringing these figures to normal, and the maximum activity of the peptide Tyr-Glu-Gly was observed in the concentration of 0.1 μg/ml At the same time, a well-known tool bursin manifests its activity only at concentrations of 0.5-1 µg/ml Thus, the peptide TyrP CLASS="ptx2">

The specific biological activity of the inventive tool also studied in experiments in vivo in models of embryonic bursectomy. It is known that in the bag fabritsiusa is antigenetically differentiation of B-lymphocytes and its removal is accompanied by disruption of this process [6, 11]. However, there are marked inhibition of humoral immunity, which is associated with the lack bursectomised birds Mature B-lymphocytes that are able to be involved in the immune response. Bursectomised chickens significantly stunted and almost completely killed after 7-8 weeks of life.

The embryonic bursectomy performed surgery on the 19th day of embryonic development, the control group of embryos at the same time subjected to a false operation playback of all stages of surgical intervention except for the removal of Bursa fabritsiusa.

Since months of age during the week bursectomised Chicks intramuscularly received the peptide Tyr-Glu-Gly and bursin in doses of 0.01, 0.05, 0.1 and 1 mg/kg of body weight. The control were bursectomised chickens that received saline in the same volume.

The number of Mature B-lymphocytes that have poverhnost chicken IgG-chain) and light chain immunoglobulins chicken ("Sigma", Sweden). It is known that Ig-receptors are differentsirovannym marker of B-cells and are determined by B-lymphocytes in the final stages antigennegative differentiation, but not in pre-B cells [12] . The results are shown in table 3.

It is established that at the embryonic bursectomy Chicks sharply reduced the number of B-lymphocytes bearing surface Ig receptors , in particular membrane IgG. Introduction Tripeptide Tyr-Glu-Gly in doses from 0.01 to 1 mg/kg of body weight bursectomised birds leads to an increase in the number of Mature B-lymphocytes with Ig receptors on their surface, and the maximum activity of the peptide Tyr-Glu-Gly registered at a concentration of 0.1 mg/kg of body weight. A similar effect is achieved by the introduction Burkina in doses from 0.1 to 1 mg/kg, and the maximum activity Burkina is manifested in a concentration of 1 mg/kg of body weight of the chicken. Thus, the peptide Tyr-Glu-Gly stimulates antigennegative differentiation of B-lymphocytes at concentrations 10 times lower than the known peptide Lis-His-Gly-NH2.

Bursectomised chickens due to impaired differentiation of B-lymphocytes significantly suppressed the humoral immune response develops l is antaviliai differentiation of B-cells, the increase in the number of functionally complete B-lymphocytes, resulting in normalization of the immune response, increasing the number of peripheral blood leukocytes, body weight, spleen and thymus.

The results of experimental study of the proposed drug evidence of its high specific activity. The proposed synthetic peptide Tyr-Glu-Gly has a marked stimulating effect on the differentiation of B-lymphocytes. This is demonstrated in the following examples.

Example 1. Synthetic peptide Tyr-Glu-Gly stimulates antigennegative differentiation of B-lymphocytes in vitro model of lymphocytes of patients with burns.

The blood of patients with burns IIIB-IV degree 15-30% of the body surface stabilized with heparin (25 U/ml). Peripheral blood lymphocytes were isolated by density gradient ficoll-urografin (density of 1.077 g/ml). The number of cells in suspension when calculating the camera Goryaeva amounted to 2106/ml, cell viability staining Trifanova blue 98%.

Lymphocytes were incubated in medium RPMI-1640 (Flow) supplemented with 5% fetal calf serum (Flow), 2 mm L-glutamine (Flow), 40 µg/ml gentamicin ("Pharmachem") and 5 mm HEPES-buffer for 2 hours at Ntrolle used saline solution in an appropriate amount.

The level of expression of differencirovannyh antigens was evaluated in the reaction of indirect immunofluorescence using monoclonal antibodies anti-D21, anti-D22 and anti-IgM. As secondary antibodies used antibody labeled with FITZ ("Sorbent", ,Moscow).

Registration green fluorescence FITZ was performed using microscope EU Lumam-RPO 11" (eyepiece X3, lens h) when counting at least 200 cells in the preparation.

In patients with burns compared with healthy donors significantly reduced the number of cells that carry on their surface differencirovanie antigens CD21 (from 8.9 0.8 to 5,9 0,9%), CD22 (from 9.9 0.9 to 5,6 1,1%) and IgM (from 7.9 0.5 to 4,7 0,6 %). During the incubation of lymphocytes burn patients with peptide Tyr-Glu-Gly was significantly increased number Mature B-lymphocytes expressing differencirovanie antigens CD21, CD22 and IgM, respectively 8,6 0,6% (p<0,01), 9,0 0,8% (p<0.01) and 7,2 0,6% (p<0,01).

On day 19 of incubation, the embryos broiler chickens breed "Livorno" were subjected to surgical bursectomy in aseptic conditions. At the same time control groupenum removal of the Bursa fabritsiusa.

Starting from 4 weeks of age during the week bursectomised chickens 1 time per day intramuscularly injected with a peptide Tyr-Glu-Gly dose of 0.1 mg/kg of body weight. The control were bursectomised chickens that received saline in the same volume.

Evaluation of the effectiveness antigennegative differentiation of b-lymphocytes in experimental animals produced in the reaction by indirect membrane immunofluorescence assay using antibody to chicken IgG and light chains of chicken immunoglobulins (Sigma, Sweden). To do this, the birds at the end of treatment were taken blood stabilized with heparin (25 U/ml). Forth from heparinised peripheral blood lymphocytes were isolated by centrifugation on a density gradient ficoll-urografin. The obtained cells are washed three times with medium 199 without calcium ions at 37oC. cell Viability test with absorption Trypanosoma blue was 96-98%. Then cells were incubated with monoclonal antibodies against IgG and light chains of immunoglobulins chickens at a temperature of 37oC for 30 minutes. After that, cells are washed three times by PBS, incubated with FITZ-labeled antibodies (Sigma, Sweden) for 30 minutes at 4oC, osmyslennym microscope "EU Lumam-RPO 11". Each drug was calculated from 200 to 500 cells.

If bursectomy observed a significant decrease in the number of total sIg+cells and sIgG+cells. So lonaprisan and embryonic bursectomised birds the number of cells bearing surface IgG, was 9.6 0.9 and 3,4 0,5% (p<0.01), and total Ig of 19.1 and 1,1 8,7 0,5% (p<0,01), respectively. It is established that the introduction of the peptide Tyr-Glu-Gly bursectomised chickens increases the number of Mature B-lymphocytes with immunoglobulin receptors. The number sIgG+cells were increased from 3.4 to 0.5 in the control to 7.8 0.6% in experience (p<0.01) and the number of sIg+cells from 8.7 0.5 to 14,6 0,7% (p<0,01), approaching normal levels, although not reaching them.

In comparison with the known means Lis-His-Gly-NH2(prototype) of the claimed peptide Tyr-Glu-Gly able to stimulate antigennegative differentiation of B-lymphocytes at doses 10 times smaller, which indicates its higher specific activity. Reducing the dosage of the peptide to achieve the same effect makes it possible to reduce the risk of side effects.

Thus, in experimental study of the specific activity of the claimed substance found that Tr is>Sources of information

1. Samoilova, R. S. the Ontogeny of normal B-lymphocytes person // Hematol. and transfusion. - 1993. - #4. - S. 18-22.

2. Burrows, P. D., Cooper M. D. B cell development and differentiation // Curr. Opin. Immunol. - 1997. - Vol. 9 - N 2 - pp. 239-244.

3. Brand , A., Gilmour D. G., Goldstein G. Lymphocyte-differentiating hormone of bursa of Fabricius // Science. - 1976. - Vol. 193. - P. point of 319-321.

4. Goldstein G. , Scheid, M., Boyse, E. A. et al. Thymopoietin and bursopoietin: induction signals regulating early lymphocyte differentiation // Cold Spring Harb. Symp. Quant. Biol., - 1977. - N 41. - P. 5-8.

5. USSR author's certificate N 1438044, MKI5A 61 K 39/00, 1985.

6. Stepanov A. C. Polypeptide factors of handbags fabritsiusa and their impact on immunogenesis and hemostasis: author. dis. Kida. the honey. Sciences. - Chita, 1988. - 22 S.

7. U.S. patent N 5264418, MKI5C 07 K 3/20, 1993.

8. U.S. patent N 4584284, MKI4A 61 K 37/24; C 07 K 5/08; C 08 F 283/00, 1986.

9. Kolker, I. I., S. Vishnevskaya, M., Panov, Y. M. and other T - and B-lymphocytes in patients with thermal burns // Clinically. medicine. - 1985. - N 7. - S. 87-93.

10. Belotsky S. M., Borisova, So, Shastina T. I. and other Characteristics of phagocytes, T - and B-lymphocytes in annealed // Immunology. - 1983. - N-6. - S. 51-54.

11. Jalkanen, S., Granfors K., Jalkanen M. et al. Immune capacity of the chicken bursectomized at 60 hr of incubation: surface immunoglobulin and B-L (Ia-like antigen-bearing cells // J. Immunol. - 1983. - Vol. 130. - N of the peptide of the formula Tyr-Glu-Gly (L-tyrosyl-L-glutamyl-L-glycine) as a means of stimulating antigennegative differentiation of B-lymphocytes.

 

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