CN102552306A - Method for treating septicemia with human neutrophil peptide (HNP) blocking agents - Google Patents
Method for treating septicemia with human neutrophil peptide (HNP) blocking agents Download PDFInfo
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- CN102552306A CN102552306A CN2010105832701A CN201010583270A CN102552306A CN 102552306 A CN102552306 A CN 102552306A CN 2010105832701 A CN2010105832701 A CN 2010105832701A CN 201010583270 A CN201010583270 A CN 201010583270A CN 102552306 A CN102552306 A CN 102552306A
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Abstract
The invention discloses a method for treating septicemia with human neutrophil peptide (HNP) blocking agents. The method comprises the following steps of: preparing small interfering RNA (siRNA) and anti-HNP antibody blocking agents and the like, and blocking, neutralizing and reducing the yield, the function and the biological activity of HNP. The siRNA is prepared in vitro through a design and a chemical synthesis method. A HNP-1 polypeptide is produced through a design to be cross-linked with KLH (Keyhole Limpet Hemocyanin) and then to immunize an experimental rabbit, and a rabbit immune globulin is obtained. The same one HNP-1 polypeptide is used for immunizing a mouse, an anti-HNP antibody variable region is prepared, and then a humanized monoclonal anti-HNP-1 antibody is prepared. Both of the siRNA and the anti-HNP-1 antibody can effectively block, neutralize and reduce the yield, the function and the biological activity of HNP, so that the method can be used for treating septicemia and other related diseases caused by bacterial infections.
Description
Technical field
The present invention relates to field of biological pharmacy.Specifically; The present invention relates to a kind of method of neutrophilic granulocyte antibacterial peptide blocker treatment septicemia; Comprise blockeres such as preparation small molecules interference RNA (siRNA) and anti-people HNP antibody; Output, function and the biological activity of blocking-up, neutralization and minimizing neutrophilic granulocyte HNP, septicemia and other relevant diseases that the treatment bacterial infection causes.
Background technology
The known neutral granulocyte plays critical effect [consult document Brown, etc., Lancet 368,157-169 (2006)] in the incidence and development of septicemia and multiple organ dysfunction syndrome.Neutrophilic granulocyte contains materials such as a large amount of polypeptide, enzyme, micromolecule.They kill, cracking and elimination engulfed the antibacterial, virus and the fungus that get in the neutrophilic granulocyte and played an important role.Yet this effect only can be brought into play in neutrophilic granulocyte fully.In case neutrophilic granulocyte self cracking, these materials can damage peripheral cell, tissue and even organ.Therefore, protecting neutrophilic granulocyte complete is the important means of treatment septicemia.
Defense peptides (defensin) in the body natural immunity, play a significant role [consulting document Klotman etc., Nat Rev Immunol 6,447-56 (2006) and Selsted etc., Nat Immunol 6,551-7 (2005)].They kill and wound antibacterial, virus, fungus and other microorganisms directly or indirectly.Human leukocytes and epithelial cell produce and secrete multiple defense peptides.Human neutrophil is excretory to have neutrophilic granulocyte defense peptides (HNP), comprises HNP-1 ,-2 ,-3 and-4, is main α-defense peptides, and they play an important role in neutrophilic granulocyte defence and control infection.Intestinal Paneth cell is also secreted α-defense peptides.They are two kinds of HD-5 and HD-6, are the main doors of intestinal defence and control infection.Many epidermis cell are like excreting beta-defense peptides then such as multiple epithelial cell and Skin Cell, like hBD-1, hBD-2, hBD-3, hBD-4 or the like.
In the neutrophilic granulocyte nearly 40% protein ingredient be HNP [consulting document Ganz etc., Curr OpinImmunol 6,584-9 (1994) and Selsted etc., J Clin Invest 76,1436-1439 (1985)].These HNP under normal circumstances are encapsulated in the secretory granule of neutrophilic granulocyte.Therefore, under the normal condition in the human serum concentration of HNP very low, most detect less than, the highest in 0.2 mcg/ml.Yet under pathologic condition, particularly when bacterial infection, a large amount of neutrophilic granulocytes are activated and destroy, HNP content obviously raise [consult document Brown, etc., Lancet 368,157-169 (2006)] in the blood.Existing when reporting the bacterial infection septicemia in the blood HNP amount can reach 170 mcg/ml [consulting document Ihi etc., Clin Infect Dis 25,1134-1140 (1997) and Panyutich etc., J Lab Clin Med122,202-207 (1993)].Outside the microorganism that this prompting HNP invades, also has the pathologic pathogenic effects except directly killing.Document did not report as yet that HNP had the pathologic pathogenic effects in septicemia.Have only one piece of document to mention and cause the low and lung failure [consulting document Zhang etc., Am J Physiol Lung Cell Mol Physiol 280, L947-L954 (2001)] of its pulmonary function when heavy dose of HNP is used for normal rat pulmonary.This can only show indirectly that HNP possibly play an important role in the incidence and development of septicemia.
Up to the present, still do not have medical science and method of pharmacy block, reduce and in and output, function and the biological activity of neutrophilic granulocyte HNP, be used to treat the diseases such as septicemia that bacterial infection causes.
Summary of the invention
The object of the invention be exactly with medical science and method of pharmacy block, reduce and in and output, function and the biological activity of the outer HNP of neutrophilic granulocyte, septicemia and other relevant diseases that the treatment bacterial infection causes.Initiate the method for a kind of neutrophilic granulocyte antibacterial peptide blocker treatment septicemia and other relevant diseases; Comprise preparation small molecules interference RNA (siRNA) and the agent of anti-people HNP antibody blocking; Blocking-up, reduce and in and neutrophilic granulocyte HNP output, function and biological activity, septicemia and other relevant diseases that the treatment bacterial infection causes.
For realizing the present invention's purpose, neutrophilic granulocyte antibacterial peptide blocker of the present invention is realized through following technical scheme.
1, preparation siRNA.Double-stranded RNA through enzyme action can form a lot of small fragments, is called small fragment and suppresses RNA (siRNA).SiRNA combines with the homologous sequence of messenger RNA (mRNA) is complementary, makes mRNA be degraded into small fragment RNA, thereby causes mRNA to lose function, can not be translated into protein.Design siRNA, 5 '-AGGCACUGCUCUCCAAGAU-3 ', and the external preparation of applied chemistry synthetic method siRNA small fragment, be stored in the solution that contains the RNA stabilizing agent.In theory, the siRNA small fragment can be used to reduce the expression of all HNP hypotypes (HNP-1-4) of neutrophilic granulocyte.This micromolecule siRNA can reduce neutrophilic granulocyte effectively and produce the HNP (see figure 1).Thereby guarantee that single siRNA preparation can effectively reduce the complementary HNP albumen of homology.
2, the anti-people HNP-1 antibody of preparation.In order to produce special anti-people HNP-1 antibody, HNP-1 polypeptide, CACYCRIPACIAGERRYGTCIYQGRLWAFCC have been produced in design.Crosslinked this polypeptide and KLH, the immunity test rabbit is obtained lot of antibodies serum then.Through the method purified rabbit serum of immunology affinity chromatograph, obtain rabbit immunoglobulin (IgG) again.Show through animal and test cell line result, this anti-people HNP-1 antibody can be effectively in the outer HNP (seeing Fig. 2 and Fig. 3) of neutrophilic granulocyte.In order to reach this purpose of curing the disease, need to produce the special anti-people HNP of Humanized monoclonal antibody.Use above-mentioned identical HNP-1 polypeptide, CACYCRIPACIAGERRYGTCIYQGRLWAFCC, with KLH crosslinked after, immune Balb/c mice, ELISA method proof has produced high anti-people HNP-1 antibody of tiring.The variable region for preparing anti-HNP-1 antibody is processed the anti-people HNP-1 of Humanized monoclonal antibody then.Fig. 4 is the production routine of humanization monoclonal anti-human HNP antibody.
Septicemia and other kinds disease that HNP blocker treatment bacterial infection causes are cores of the present invention.SiRNA and anti-people HNP-1 antibody all can suppress and block HNP output, function and biological activity effectively.Anti-people HNP-1 antibody can suppress the cell injury that HNP causes, also can suppress the apoptosis that HNP causes.
SiRNA is two kinds of different preparations with anti-people HNP-1 antibody.SiRNA reduces HNP to express in neutrophilic granulocyte, however anti-people HNP-1 antibody be in the outer HNP-1 of neutrophilic granulocyte, have booster action so these two kinds of preparations are used simultaneously.
The present invention has minimizing, suppresses and eliminates the pathogenic effects of HNP in bacterial infection disease.With the antibiotic drug combination, can strengthen antibiotic therapeutic effect.
Description of drawings
Fig. 1: siRNA reduces the HNP expression.From people's bone marrow separation and Culture mononuclearcell, infect the medullary cell importing after siRNA48 hour with every milliliter of 1 * 16-8 slow virus pfu, get the total RNA reverse transcription of 1.5 micrograms and become cDNA, quantitative PCR detection HNP expression after 50 times of dilutions.
Fig. 2: activate Akt with the outer HNP of neutrophilic granulocyte in the anti-HNP-1 antibody.HNP complex that from people's sputum, extracts and anti-people HNP-1 antibody incubation act on lung cancer A549 cell 30 minutes after 30 minutes.Detect Akt activity in the cell with the immunoenzyme labelling method behind the cell lysis.*, #p＜0.001vs HNP group.
Fig. 3: cause apoptosis with the outer HNP of neutrophilic granulocyte in the anti-HNP-1 antibody.HNP complex that from people's sputum, extracts and anti-people HNP-1 antibody incubation after 30 minutes combined effect detect apoptosis in lung cancer A549 cell after 8 hours.*, #p＜0.001vs HNP group.
The production routine of the anti-people HNP of Fig. 4 Humanized monoclonal antibody
The specific embodiment
For further describing the present invention, the method for a kind of neutrophilic granulocyte antibacterial peptide of the present invention blocker treatment septicemia is done further to describe below in conjunction with embodiment.
For efficiently expressing siRNA, used slow virus carrier (Lentiviral vector) system, because slow virus carrier has wider host range than retroviral vector.Gene order AGGCACTGCTCTCCAAGAT is assembled in the slow virus carrier of development voluntarily.Slow virus carrier and other carrier components import in the people 293T cell jointly, express slow virus so that duplicate.After 48 hours, the slow virus titre reaches every milliliter 1 * 10
13Plaque forming unit (pfu).
Express in order to check above-mentioned siRNA can effectively suppress HNP, from rat marrow, prepare medullary cell.2 Wistar rats are put to death in the cervical vertebra dislocation.75% alcohol disinfecting whole body is got 4 femurs altogether.In gnotobasis, wash out whole medullary cells with RPMI1640 (pH7.2).With suction pipe piping and druming 5 times, through No. 4 syringe needles 5 times, process single cell suspension again.Descended centrifugal 10 minutes at 1000 rev/mins, abandon supernatant.Deposition transfers cell concentration to every milliliter 1 * 10 with RPMI1640 liquid
7Individual.Active with 2% trypan blue chromoscopy medullary cell, the cytoactive of each preparation is all more than 95%.In 6 orifice plates, add 1 milliliter 1 * 10
7Individual cell culture.Next day is with every milliliter 1 * 10
8Pfu slow virus infection medullary cell extracts total RNA after 48 hours, become cDNA with the total RNA reverse transcription of 1.5 micrograms, quantitative PCR detection HNP expression after 50 times of dilutions.As shown in Figure 1, at every milliliter 1 * 10
6The HNP expression of medullary cell promptly has obvious decline after the pfu slow virus infection.With every milliliter 1 * 10
8Reduce medullary cell after the pfu slow virus infection to a greater degree and expressed HNP.
Embodiment 2
For illustrate anti-people HNP-1 antibody can be effectively in the activity of the outer HNP of neutrophilic granulocyte, done two tests.First test; From 30 routine chronic bronchial pneumonia patients' mixing sputum, extracted compound HNP (70% for HNP-1, the 21%th, and HNP-2 and have only 5% to be HNP-3 does not have detectable HNP-4) [consult document Khine, etc.; Blood 107,2936-2942 (2006)].After hatching 30 minutes under 100 mcg/ml HNP complex and anti-people HNP-1 antibody (1, the 10 and 200 mcg/ml) room temperature; Get its mixture 10 mcg/ml and act on lung cancer A549 cell, cell lysis detects Akt enzymatic activity in the cell with the immunoenzyme labelling method after 30 minutes.The result shows that anti-people HNP-1 antibody can block HNP and activate Akt enzymatic activity [seeing Fig. 2] in the lung cancer A549 cell.Second test; After 100 mcg/ml HNP complex that extract in the personnel selection sputum and anti-people HNP-1 antibody (1,10 and 200 mcg/ml) are hatched 30 minutes; Combined effect detects apoptosis [see Fig. 3] with Apoptosis Detection Kit in lung cancer A549 cell after 8 hours.Clearly, single with behind the HNP complex (100 mcg/ml), 65% apoptosis.Anti-people HNP-1 antibody promptly obviously stops the cytotoxic effect of HNP in 1 mcg/ml level.After dosage strengthened, this BE of anti-people HNP-1 antibody strengthened.
At last, with anti-people HNP Antybody therapy septicemia animal model.The septicemia animal model is set up in Wi star rat.6 Wistar rats are used to test altogether, wherein inject anti-people HNP-1 antibody (50 microgram/kilogram) in 3 rat abdominal cavities, and injecting normal salines compare in 3 rat abdominal cavities.Normal saline injection rat is all successfully induced septicemia, and anti-none routine septicemia of people HNP-1 Antybody therapy person is induced successfully.
Claims (4)
1. the method for neutrophilic granulocyte antibacterial peptide blocker treatment septicemia; It is characterized in that: comprise blockeres such as preparation small molecules interference RNA (siRNA) and anti-people HNP antibody; Output, function and the biological activity of blocking-up, neutralization and minimizing neutrophilic granulocyte HNP, septicemia and other relevant diseases that the treatment bacterial infection causes.
2. the method for a kind of neutrophilic granulocyte antibacterial peptide blocker treatment septicemia according to claim 1; It is characterized in that: described small molecules interference RNA (siRNA) blocker prepares in order to following method; Double-stranded RNA through enzyme action can form small fragment inhibition (siRNA); SiRNA combines with the homologous sequence of messenger RNA (mRNA) is complementary, makes mRNA be degraded into small fragment, thereby causes mRNA to lose function; Design siRNA, AGGCACUGCUCUCCAAGAU, and the external preparation of applied chemistry synthetic method siRNA small fragment are stored in the solution that contains the RNA stabilizing agent.
3. the method for a kind of neutrophilic granulocyte antibacterial peptide blocker treatment septicemia according to claim 1; It is characterized in that: the agent of described anti-people HNP antibody blocking prepares in order to following method; The HNP-1 polypeptide is produced in design, and CACYCRIPACIAGERRYGTCIYQGRLWAFCC is crosslinked with KLH; The immunity test rabbit is obtained a large amount of antibody serums; Through the method purified rabbit serum of immunology affinity chromatograph, obtain rabbit immunoglobulin again; Same HNP-1 polypeptide, CACYCRIPACIAGERRYGTCIYQGRLWAFCC, with KLH crosslinked after, immune Balb/c mice is processed the anti-people HNP of Humanized monoclonal antibody.
4. the method for a kind of neutrophilic granulocyte antibacterial peptide blocker treatment septicemia according to claim 1; It is characterized in that: when the septicemia that the treatment bacterial infection causes and other relevant diseases, be output, function and the bioactive method that adopts blocking-up, neutralization and reduce neutrophilic granulocyte HNP.
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Cited By (4)
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| CN104535771A (en) * | 2014-12-19 | 2015-04-22 | 武汉市星熠艾克生物医药有限责任公司 | Human alpha-defensin peptide enzyme linked immunosorbent assay kit |
| CN108241054A (en) * | 2017-12-26 | 2018-07-03 | 天津市中西医结合医院（天津市南开医院） | G protein coupled receptor 18 is preparing septicemia monitoring and is judging to apply in reagent |
| CN108484765A (en) * | 2018-04-28 | 2018-09-04 | 浙江大学 | A kind of 1 monoclonal antibody of anti-Human α-Defensin-1 and its application |
| CN109694910A (en) * | 2018-04-24 | 2019-04-30 | 广州呼吸健康研究院 | Application of the alexin HNP gene in treating organs damage |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108241054A (en) * | 2017-12-26 | 2018-07-03 | 天津市中西医结合医院（天津市南开医院） | G protein coupled receptor 18 is preparing septicemia monitoring and is judging to apply in reagent |
| CN109694910A (en) * | 2018-04-24 | 2019-04-30 | 广州呼吸健康研究院 | Application of the alexin HNP gene in treating organs damage |
| CN108484765A (en) * | 2018-04-28 | 2018-09-04 | 浙江大学 | A kind of 1 monoclonal antibody of anti-Human α-Defensin-1 and its application |
| CN108484765B (en) * | 2018-04-28 | 2020-08-25 | 浙江大学 | Anti-human alpha-defensin-1 monoclonal antibody and application thereof |
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