Cyclophilin a as granulocytopoiesis stimulant, radioprotector and immune stimulant

FIELD: medicine.

SUBSTANCE: invention concerns medicine, particularly granulocytopoiesis stimulants, radioprotectors and immune stimulants. Under cytostatics effect Cyclophilin A amplifies granulocyte precursor removal from marrowbone and stimulates granulocytopoiesis.

EFFECT: in case of sublethal radiation, cyclophilin A stimulates migration of marrowbone stem elements and participates in recovery of blood cells and immune system, and shows redioprotection properties.

4 dwg, 2 tbl

 

The invention relates to medicine, namely to funds with granulocytopoiesis, radioprotective and immunostimulatory properties.

It is known that in Oncology uses a number of medicines, promoting the recovery of hematopoiesis after application of radio - and chemotherapy, such as macrophage colony-stimulating factor (M-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (g-CSF) (Richards D. Prevention of oral mucositis in cancer patients treated with chemotherapy or radiotherapy. Evid Based Dent. 2006; 7 (4): 106; Peoples GE, Holmes JP, Hueman MT, Mittendorf EA, Amin A, Khoo S, Dehqanzada ZA, Gurney JM, Woll MM, Ryan GB, Storrer CE, Craig D, Ioannides CG, Ponniah S. Combined clinical trial results of a HER2/neu (E75) vaccine for the prevention of recurrence in high-risk breast cancer patients: the U.S. Military Cancer Institute Clinical Trials Group Study I-01 and I-02. Clin Cancer Res. 2008 Feb 1; 14 (3): 797-803).

The closest in purpose to the claimed tool (prototype) is a granulocyte colony-stimulating factor (g-CSF) (Xiao BG, Lu CZ, Link H. Cell biology and clinical promise of G-CSF: immunomodulation and neuroprotection. J Cell Mol Med. 2007; 11 (6): 1272-90). It is known that g-CSF induces the differentiation of stem elements of bone marrow neutrophils (granulocytes), mobilizes their release into the peripheral blood, increasing their production. G-CSF polarizes T-cell differentiation from T-helper 1 type to the helpers of the 2nd type (Pan L, Delmonte JJ, Jalonen CK, Ferrara JL. Prereatment of donor mice with granulocyte colony-stimulating factor polarizes donor T lymphocytes toward type-2 cytokine production and reduces severity of experimental graft-versus-host disease. Blood 1995; 86: 4422-9). The use of g-CSF promotes the generation of suppressor T cells (CD4+25+) and suppressor of cytokine (IL-10, TGF-β) (Morris ES, MacDonald KP, Rowe V, Johnson DH, Banovic T, Clouston AD, Hill GR. Donor treatment with pegylated G-CSF augments the generation of IL-10-producing regulatory T cells and promotes transplantation tolerance. Blood 2004; 103 3573-81). In addition, g-CSF is a radioprotector (Bertho JM, Frick J, Prat M, Demarquay C, Dudoignon N, Trompier F, Gorin NC, Thierry D, Gourmelon P. Comparison of autologous cell therapy and granulocyte-colony stimulating factor (G-CSF) injection vs. G-CSF injection alone for the treatment of acute radiation syndrome in a non-human primate model. Int J Radiat Oncol Biol Phys. 2005 Mar 1; 63 (3): 911-20., Streeter PR, Dudley LZ, Fleming WH. Activation of the G-CSF and Flt-3 receptors protects hematopoietic stem cells from lethal irradiation. Exp. Hematol. 2003 Nov; 31 (11): 1119-25).

Object of the invention is the expansion of the range of funds

with stimulating granoulozitopoez, radioprotective and immunostimuliruyushhim action.

Cyclophilin A - protein with a molecular mass of 18 KD with catransition activity (G. Fischer, H. Bang, C. Mech S. Determination of enzymatic catalysis for the cis-trans-isomerization of peptide binding in proline-containing peptides. Biomed. Biochim. Acta. 43. 1984. P.1101-11). Cyclophilin a is a ligand for binding of cyclosporine A, and this is due to the immunosuppressive effect of the latter (D.A.Fruman, S.J.Burakoff, B.E.Bierer. Immunophilins in protein folding and immunosuppression. FASEB J. 8. 1994. 391-400). Cyclophilin And is actively involved in autoimmune diseases, causing inflammation in the periphery (P.Zhu, J.Ding, J.Zhou et.al., Expresion of CD147 on monocytes/macrophages in rheumatoid arthritis: its potential role in monocyte accumulation and matrix metalloproteinase production. Arthritis Research & Therapy. 7. 2005. P.1023-33, A.Billich, G.Winkler, H.Aschauer, A.Rot, P.Peichl. J Exp Med. 185. 1997. P.975-80). Activated macrophages can secrete cyclophilin And the external environment (B.Sherry, N.Yarlett, A.Strupp. Identification of cyclophilin A as A proinflammatory secretory product of lipopolysaccharide-activated macrophages. Proc.Natl. Acad. Aci. 89 (1992) 3511-15). Cyclophilin a has a chemotactic effect, regulating the migration of Mature monocytes, neutrophils, eosinophils and T-lymphocytes, thus forming a zone of inflammation (Q.Xu, M.C.Leiva, SA.Fischkoff, R.E.Handschumacher, C.R.Lyttle. Leukocyte chemotactic activity of cyclophilin. J Biol.Chem. 267.1992. P.1168-71). Cyclophilin And is not used as a drug. The main efforts of the researchers focused on the search for substances antagonists (various forms of cyclosporine A), the neutralizing effect of cyclophilin And in inflammatory and other processes (Shuai Chen, Xuemei Zhao, Jinzhi Tan, et.al. Structure-based identification of small molecule compounds targeting cell cyclophilin A with anti-HIV-1 activity. European Journal of Pharmacology, 565. 2007. P.54-59).

To accomplish the task assessed the impact of cyclophilin And migration of stem cells from bone marrow in vivo in sublethal irradiated mice according to the method Till J.E., McCullough E.A (J.E.Till, ..McCullough. A direct measurment of the radiation sensitivity of normal mouse bone marrow cells. Rad Res. 14 (1961) 213-22). Native cyclophilin And were obtained from the culture fluid of cells murine thymoma EL-4 by biochemical purification to final protein purity not less than 95%. For irradiation use the built 35-50 adult mice females (C57BL/6x CBA) F1 at the age of 12-14 weeks weighing 20-22 g, which were divided into five groups of 7-10 animals in each group. Mice were irradiated With60gamma - ray therapeutic apparatus "Agat-R (Russia) with an initial capacity of 1.9×1014Bq dose of 4.5 Gy. The experiment was repeated three times.

Cyclophilin And were injected to the mice tail vein at a dose of 30 μg/mouse 24 hours after irradiation. As a control were injected buffer used when cleaning cyclophilin A. within seven days after irradiation, the mice were scored by the method of cervical dislocation. The spleen was removed and placed in fixative liquid, consisting of glacial acetic acid and absolute alcohol in a ratio of 1:3. Visual counting of endogenous colonies in each spleen was performed after 4 hours.

It was revealed that the number of colonies of stem cells produced in the spleen studied mice was increased 2-3 times compared to control animals.

Next was an in-depth analysis of the target cells of cyclophilin And in the bone marrow. Bone marrow cells were obtained by washing the culture medium RPMI 1640 femur and tibia bones of the mouse. Cell suspension was obtained by skipping through a needle of the syringe, and precipitated in a centrifuge. Erythrocytes were removed 0,85% solution of NH4Cl, then washed with a solution of Earl. Then the cells were diluted with RPMI medium 1640 and used at a concentration of ×10 6%.

When evaluating surface markers migrated bone marrow cells used transwell with the size of the pores are 5 micron (Costar). The buffer containing cyclophilin A, was placed on the bottom of 24-hole tablet in the amount of 600 ál. The bone marrow cells of mice (5×106/ml) were placed over the membrane in a volume of 100 μl and were cultured for 90 minutes at 37°C and 5% CO2. In the control buffer (the eluate from the column) and a buffer containing cyclophilin A, and bone marrow cells were added to bovine serum albumin to a final concentration of 0.5%. After a time the cultivation of the membrane were removed and the number of migrated cells in the bottom wells were counted under a microscope.

To determine the cellular phenotype was used the method of flow cytofluorometry (FaxCalibur, Beckon Dickenson Cell Quest program). Identification of cellular markers was performed using fluorescencebased monoclonal antibodies (Pharmingene), using antibodies to molecules: CD31 (PE), Gr-l(CD97) (FITC), SCA-1 (FITC),CD3 (FITC), B220 (PE), CD19 (FITC),.CDllb(PE), CDllc (FITC). Dead cells was determined by adding propecia iodide and were excluded from the study.

For detection of targets that are sensitive to the presence of cyclophilin And analyzed the phenotype of bone marrow cells that migrated in vitro under his influence.

SCA-1 marker characterizes the population of immature GE is poeticheskih stem cells in the bone marrow. The influence of cyclophilin And migration of stem SCA+cells presented on Figa, thus there is a slight increase in the number of cells carrying the marker. The influence of cyclophilin And susceptible cells later differentiation, lost a molecule of SCA-1 on its surface.

GR molecule-1 (CD97) is a marker of granulocytes different levels of differentiation and Mature neutrophils. The adhesion molecule CD31 is present on immature granulocytes (GR-1+cells) and its amount is reduced in the process of cell maturation (A.Solowiej, P.Biswas, D.Graesser, J.A.Madri. Lack of platelet endothelial cell adhesion molecule-1 attenuates foreign body inflammation because of decreased angiogenesis. American J. of Pathology. V.162. 2003. P.953-62). Immature precursors of granulocytes GR-1+CD31+carrying both of the analyzed molecules on their surface, show a pronounced ability to migrate under the influence of cyclophilin A. Influence of cyclophilin And migration of the precursors of granulocytes shown in Figv. Also, there was an increase of migration of immature CD31+not related to the granulocyte precursors.

CD3+- marker T-cell population. In the bone marrow are the T-cells of various degrees of differentiation. The influence of cyclophilin And migration of T-cells in the bone marrow presented on Figs. The analysis showed that T-cells are highly sensitive to resultview of cyclophilin A. The number of cells migrated in the presence of cyclophilin And increased more than 10-fold compared to control.

In the analysis of B220+CD19+markers shown that precursor cells are also susceptible chemoattractive action cyclophilin And that reflected on Fig.1D. Cyclophilin And influence the migration of precursor cells of different degrees of differentiation (less Mature - B220+and more Mature B220+CD19+).

Cyclophilin And also stimulates the migration of precursors of dendritic cells with the phenotype of CDllb+CDllc+and CDllc+presented at Five. At the same time, the precursors of macrophages with phenotype CDllb+CDllc-not sensitive to the presence of cyclophilin And that distinguishes them from Mature monocytes.

Evaluation of biological activities of recombinant cyclophilin And man. Because of the almost complete gomologichnosti (a difference of one amino acid) cyclophilin And mouse and human species shows nonspecific activity. The effect of recombinant human cyclophilin And those obtained from the transfected gene cyclophilin And human cells E-coli, education splenic colonies of stem cells in sublethal irradiated mice are presented in table 1 and in figure 2 (a, B). On Figa presents the spleen of a mouse treated with buffer, figure 2 is - the spleen of a mouse treated with 50 μg of cyclophilin A. As can be seen, cyclophilin And significantly increases the migration of stem cells that form colonies in the spleen.

To assess the ability of cyclophilin And to restore hematopoiesis conducted a comparative analysis of its activity with g-CSF on the model for determining the activity of g-CSF (Morrison SJ, Wright DE, Weissman IL. Cyclophosphamide/granulocyte colony-stimulating factor dosage of hematopoietic stem cells to proliferate prior to mobilization. Proc. Natl. Acad. Sci. USA Vol.94, pp.1908-1913, 1997). Mice CBA (H-2to) was treated with cyclophosphamide, which was administered intraperitoneally at a dose of 150 mg/kg of body weight. A day later the mice were injected subcutaneously cyclophilin A (25, 50 and 100 µg/mouse) or g-CSF (2 μg/mouse). As a control were injected buffer used when cleaning cyclophilin A. the Injection was carried out during four days, after which the blood of animals examined on the contents of the number of leukocytes, lymphocytes, granulocytes and monocytes.

Blood sampling was carried out from a cut tail vein in a volume of 5 microliters and bred her in 95 Microlitre 3% acetic acid. Blood smears were prepared on glass, dried, and treated with 96% ethanol for 1-2 s, re-dried and treated with paint Azur-eosin according to Romanovsky within 30-45 minutes, the slides were washed in water, dried and perform microscopic examination.

The obtained results revealed comparable in Sodeistvie of cyclophilin and g-CSF on the recovery of the number of leucocytes in peripheral blood of mice treated with cyclophosphamide (103on microliter of blood) (Figure 3 and Table 1). Cyclophilin as well as g-CSF is a means of promoting the differentiation of stem cells of bone marrow, granulocytes, and mobilizes them into the bloodstream (Figure 4, Table 2).

The technical result of the invention:

- Cyclophilin And enhances the migration of stem elements from the bone marrow to the periphery of sublethal irradiated animals.

- Stimulates the formation of precursors of granulocytes and their exit from the bone marrow into the bloodstream when applied chemotherapy.

- Stimulates migration of dendritic cells and precursors of T - and b-lymphocytes.

Cyclophilin And can be used as a stimulator granulocytopoiesis, radioprotector and immunostimulant.

Table 1
Dose cyclophilin And in µg/mouse01102550
The number of colonies in the spleen7,48,26,815,720,0

Table 2
Morphological groupControlcyclophilin AndG-CSF
Granulocytes7+-0,571,0+is 12.571,3+-5,8
Monocytes4+-0,82,0+-03,1+-1,0
Lymphocytes89+-027,0+is 12.525,6+-4,9

Cyclophilin A - stimulator granulocytopoiesis, radioprotector and immunostimulant.



 

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