CN102670652B - Application of macrophaphage in terms of preparation of medicines for treating diseases caused by infection of type-71 human enteroviruses - Google Patents
Application of macrophaphage in terms of preparation of medicines for treating diseases caused by infection of type-71 human enteroviruses Download PDFInfo
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Abstract
The invention relates to the field of medicines, in particular to application of macrophaphage in terms of preparation of medicines for treating diseases caused by infection of type-71 human enteroviruses. Effects of using the macrophaphage in an adotive treatment method for suppressing replication of the type-71 human enteroviruses and treating the diseases caused by infection of the type-71 human enteroviruses are researched on the basis of an EV71 infected mouse model in a laboratory, and the macrophaphage is proved to have a good treatment effect.
Description
Technical field
The present invention relates to field of medicaments, the application that particularly macrophage catches in medicine at preparation treatment human enterovirus 71.
Background technology
Enterovirns type 71 is (English by name: Human enterovirus71), being called for short EV71, is to cause Children (hand-foot and mouth disease; HFMD) one of main pathogens.Mankind's enteric virus71 type is separated in the infant faeces specimen of suffering from first central nervous system disease for 1969 from California, and these viruses can be cultured in Rhesus Macacus kidney cell (rhesus monkey kidney cell; RhMK) and in people's embryo diploid cell (human fetal diploid cell).If a corpse or other object for laboratory examination and chemical testing is taken from Feces of Patients and is organized with human embryo kidney (HEK) diploid cell (diploid strain of human fetal kidney cell; HFDK) cultivate; If a brush,throat corpse or other object for laboratory examination and chemical testing selects human embryonic lung diploid fibroblast cell (diploid strain of human fetal lung cell) to cultivate.Via pure strain virus analysis after these cell culture, find there will be typical case by (the cytopathetic effect of the cytopathy due to enterovirus; CPE) phenomenon, all similar with other known at that time enteroviruses by its form of observed under electron microscope (morphology) and physical chemistry (physicochemical) characteristic, but carry out after neutralizing antibody test (neutralization test) or immunodiffusion (immunodiffusion test), but find that it does not have interactive phenomenon to each other, therefore infer that the virus found is at that time a kind of novel enterovirus, therefore by this Strain called after enteric virus71 type.
6 years old Infants Below of human enterovirus 71 (EV71) main infection, can cause hand-foot-mouth disease and herpangina etc., and serious symptom comprises brain stem encephalitis, aseptic meningitis, slowness paralysis etc.Heating is the common symptoms that infant EV71 infects, and the patient overwhelming majority is less than 6 months babies.Acute respiratory disease is the another common symptoms that EV71 infects, and has in the groove report at the EV71 in Australia, Canada and Taiwan Province of China in 1998.It comprises some common respiratory symptoms, and as pharyngitis, asthma, bronchiolitis and pneumonia, age of onset is generally 1～3 years old, needs hospitalization.Acute pharyngolaryngitis is also a clinical symptoms of EV71, in Hong Kong, the EV71 of tw Taiwan and Japan Area once had report in the groove.Wherein the EV71 of Taiwan Province of China epidemic period acute pharyngolaryngitis Proportion of patients in 1998 is larger, reaches more than 10%.Initial infection patient shows as low grade fever, watery nasal discharge, appetite decline, stomatalgia, vomiting, diarrhoea etc.There is exanthema vesiculosum in oral mucosa, is often distributed in tongue, cheek mucosa, hard palate, also can appear at tonsil, gingiva and pharyngeal etc., after herpes ulceration, forms ulcer.Can there is maculopapule in skin in pathological change of oral cavity, taking brothers as common, erythra is mainly distributed in the back of the hand, refer between, locate occasionally in trunk, thigh, buttocks, upper arm etc., be centrifugal property and distribute, maculopapule transfers exanthema vesiculosum very soon to, diameter 3～7mm, quality is slightly hard, from several to dozens of not etc., within 2nd～3, absorb voluntarily, do not stay crust.Great majority are optimum process, many spontaneous recovery, but can recur, aseptic meningitis, myocarditis etc. sometimes occur together.
It is aseptic meningitis, encephalitis and paralysis property disease that EV71 involves nervous system main manifestations, is multiplely born in 5 years old following child, and within 1 years old, following baby's sickness rate is the highest.Clinical manifestation changes various, and state of an illness weight differs, and generally shows as clonic spasm, vomiting, ataxia, intentional tremor, nystagmus and apathy etc.Head MRI and EEG (electrocardiogram) examination contribute to the seriousness of clear and definite disease.
Postmortems and histopathological study show in a large number, and the pulmonary edema that EV71 causes is neurogenic.First EV71 destroys the structure of the specific tool regulatory function of brain stem tissue, causes the disorder of autonomic nervous function, finally causes pulmonary edema.
Neurogenic pulmonary edema, pneumorrhagia and heart failure are the main causes that causes Infant and child deaths.At present, there is no clinically the treatment measure of specially good effect, comprise public health prevention and control and the symptomatic treatment to infected patient etc. for the major control mode of epidemic situation, infect still not generally acknowledged specific medicament or vaccine for EV71.
Utilizing adoptive immunity cell to carry out antiviral therapy, is one of method of the treatment disease of viral infection that adopted clinically, at present the main T lymphocyte that uses virus-specific.In host's natural immune system that macrophage infects at preventing microorganism, play a significant role, it can be by engulfing or regulation of secretion inflammatory factor is brought into play anti-infectious function.Macrophage is adopted and is treated the research or the application that have been applied to treating cancer, reperfusion injury and pneumonia etc.But the antiviral activity that utilizes macrophage is treated the research of EV71 infectious disease and is but had no report.
Summary of the invention
In view of this, the invention provides the application that macrophage catches in medicine at preparation treatment human enterovirus 71.The EV71 infecting mouse model that the present invention utilizes laboratory to set up, suppresses human enterovirus 71 and copies and treat human enterovirus 71 and infect diseases induced effect and be studied the macrophage therapy of adopting, and confirms that it has good therapeutic effect.
In order to realize foregoing invention object, the invention provides following technical scheme:
The invention provides the application that macrophage catches in medicine at preparation treatment human enterovirus 71.
As preferably, the model of action of medicine is adoptive immunity.
As preferably, the mononuclear cell that medicine is donor, the macrophage of donor activation or the blood constituent that donor contains mononuclear cell or macrophage.
The EV71 infecting mouse model that the present invention utilizes laboratory to set up, suppresses human enterovirus 71 and copies and treat human enterovirus 71 and infect diseases induced effect and be studied the macrophage therapy of adopting, and confirms that it has good therapeutic effect.
Brief description of the drawings
Fig. 1 is shown as the macrophage (Macrophage) separating in year Mice Body and has in vitro the activity of engulfing and killing EV71 virus, by the TCID of EV71 in RD cell titration macrophage
50; Line I is shown RD cell, and line II is shown macrophage;
Fig. 2 is shown as the macrophage (Macrophage) separating in year Mice Body and has in vitro the activity of engulfing and killing EV71 virus, measures the copy number of virus in culture medium by qRT-PCR method; Line I is shown RD cell, and line II is shown macrophage;
Fig. 3 shows that liquid paraffin stimulates the macrophage activity of mice can improve the survival rate of mice while infected by EV71; Line II is shown placebo group, and line I is shown liquid paraffin group;
Fig. 4 shows that the treatment of adopting of the macrophage of adult mice can reduce the mortality rate of EV71 infecting mouse; Line I is shown the macrophage group of adopting, and line II is shown placebo group;
Fig. 5 shows the macrophage of the adult mice treatment clinical symptoms order of severity of adopting; Line I is shown placebo group, and line II is shown the macrophage group of adopting;
Fig. 6 show the macrophage of adult mice adopt treatment after skeletal muscle inner virus facsimile log; Line I is shown placebo group, and line II is shown the macrophage group of adopting.
Detailed description of the invention
The invention discloses the application that macrophage catches in medicine at preparation treatment human enterovirus 71, those skilled in the art can use for reference content herein, suitably improve technological parameter and realize.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the artly, they are all deemed to be included in the present invention.Method of the present invention and application are described by preferred embodiment, related personnel obviously can change methods and applications as herein described in content of the present invention, spirit and scope or suitably change and combination not departing from, and realizes and apply the technology of the present invention.
In the application that macrophage of the present invention catches in medicine at preparation treatment human enterovirus 71, macrophage used can stimulate adult mice by paraffin, collect and separate the macrophage gained in abdominal cavity, also can stimulate differentiation to obtain by separating the mononuclear cell of adult mice.In actual applications, can be by the mononuclear cell of separation and purification mice, and stimulate in vitro it be divided into macrophage and obtain.
Below in conjunction with embodiment, further set forth the present invention:
Embodiment 1 macrophages in vitro antivirus action
In the ICR mouse peritoneal of growing up, inject 1 milliliter of aseptic liquid paraffin, activating macrophage.After 4 days, by mouse anesthesia, inject the DMEM culture medium of 10 milliliters of aseptic ice pre-coolings and clean mouse peritoneal, obtain macrophage suspension.By PBS washing 3 times for macrophage, be inoculated in containing in the DMEM culture medium of 10% hyclone subsequently, cultivate 1 hour for 37 DEG C.Not adherent cell rinses out with PBS, and macrophage continues to spend the night with the DMEM culture medium culturing containing 10% hyclone.
The macrophage of purification is inoculated in 6 porocyte culture plates (2 × 10
5cells/well), subsequently, every porocyte inoculation 1 × 10
5tCID
50eV71 virus (FY0805, GenBank storage number:
hQ882182).
Metainfective cell continues, with the DMEM culture medium culturing containing containing 2% hyclone, to get cells and supernatant and cell measure respectively the copy number of EV71 viral RNA and viral TCID every 1 hour
50, with the people's rhabdomyoma cell (RD) that can support virus replication in contrast.EV71 infects after macrophage, removes culture medium supernatant every 1 hour, PBS washing 3 times for macrophage.Subsequently, macrophage is resuspended in 1 milliliter of PBS, freeze thawing tertiary crushing cell, and the centrifugal cell debris of removing, utilizes the TCID50 of EV71 in RD cell titration macrophage; V71 infects after macrophage, gets 200 microlitre culture medium supernatants every 1 hour, and qRT-PCR method is measured the copy number of virus in culture medium, and experimental result repeats 3 times.
The results are shown in Figure 1, Fig. 2.Result shows: EV71 infects after the macrophage of adult mice, can in macrophage, detect that EV71 virus exists, but the virulence of virus is along with the prolongation of time reduces gradually.Viral copy number in the culture medium of extracellular, along with there is downward trend gradually the time, shows and can support that the RD cell that EV71 copies is contrary simultaneously, and EV71 can be engulfed and kill lentamente to macrophage in vitro.
Before embodiment 2 infects virus, activating macrophage can reduce the mortality rate of mice
In the ICR mouse peritoneal of 6 ages in days, inject the aseptic liquid paraffin of 200 microlitres, to activate the macrophage of young Mus, the mice of injecting with equal-volume PBS in contrast.After 4 days, every ICR children Mus infects 1 × 10 through lumbar injection
7tCID
50eV71 mice adapted strain MP10 (GenBank storage number:
hQ712020), 20 mices of every group of experiment, this experiment repeats twice.
The mortality rate that records mice, the results are shown in Figure 3.Found that, the mice stimulating without liquid paraffin is being stood after EV71 viral infection, all dead in 10 days.And before infection virus, give the activity of liquid paraffin stimulating expression of macrophage, and can improve the survival rate (reach 20% left and right) of mice while facing virus attack, show that activating macrophage activity can reduce the mortality rate of mice in the time facing EV71 viral infection.
Embodiment 3 macrophages can reduce the mortality rate of EV71 infecting mouse
Peritoneal macrophage according to the adult ICR mice of the method separation and purification of embodiment 1 is stand-by.The ICR children Mus of every 10 ages in days infects 1 × 10 through lumbar injection
7tCID
50eV71 mice adapted strain MP10.Infect after 1 day, every mice gives 1 × 10 through lumbar injection
7individual separation is from the macrophage of the mouse peritoneal of growing up.
Subsequently, record survival rate (testing with 30 mices for every group), the clinical symptoms (testing with 30 mices for every group) of mice, and with the virus load (6 mices of each time point) in qRT-PCR mensuration mice skeletal, test and repeat 3 times, the results are shown in Figure 4,5,6.Found that: all dead in 10 days after EV71 viral infection without the adopt mice for the treatment of of macrophage, and adopt the peritoneal macrophage of adult mice to adopt mice that treatment EV71 infects, can improve the survival rate to 35% of mice, and the symptom of mice obviously alleviates, paralysis duration of symptoms shortens, the order of severity reduces, the remarkable reduction from the 5th day of the virus load in skeletal muscle.This shows that the treatment of adopting of the macrophage of adult mice can reduce EV71 and infect the mortality rate of young Mus.
Embodiment 4 macrophages can reduce the mortality rate of EV71 infecting mouse
The grow up mononuclear cell of ICR mice of separation and purification, stimulate in vitro differentiation its to be divided into macrophage stand-by.The ICR children Mus of every 10 ages in days infects 1 × 10 through lumbar injection
7tCID
50eV71 mice adapted strain MP10.Infect after 1 day, every mice gives 1 × 10 through lumbar injection
7the macrophage of individual separation after the mouse monokaryon cell activation of growing up.
Subsequently, record survival rate (testing with 30 mices for every group), the clinical symptoms (testing with 30 mices for every group) of mice, and with the virus load (6 mices of each time point) in qRT-PCR mensuration mice skeletal, test and repeat 3 times.Found that: all dead in 10 days after EV71 viral infection without the adopt mice for the treatment of of macrophage, inject and adopt adult mice monocytes in vitro to stimulate the rear macrophage obtaining to adopt the mice that EV71 infects, can improve the survival rate to 35% of mice, and the symptom of mice obviously alleviates, paralysis duration of symptoms shortens, the order of severity reduces, the remarkable reduction from the 5th day of the virus load in skeletal muscle.This shows that the treatment of adopting of the macrophage of adult mice can reduce EV71 and infect the mortality rate of young Mus.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (1)
1. the application that macrophage catches in medicine at preparation treatment human enterovirus 71;
Described medicine is the macrophage of activation;
The model of action of described medicine is adoptive immunity.
Priority Applications (1)
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Non-Patent Citations (6)
| Title |
|---|
| "Status of Cellular Rather Than Humoral Immunity is Correlated with Clinical Outcome of Enterovirus 71";LUAN-YIN CHANG, et al.;《PEDIATRIC RESEARCH》;20060828;第60卷(第4期);摘要，第469页右列最后1段，第470页左列第2段第6-9行；表1、2 * |
| "康复新液联合莲花清瘟胶囊治疗手足口病临床观察";张谨等;《中国中医药信息杂志》;20110115;第18卷(第1期);第70页右列第1段第2行，第2段倒数第1-5行 * |
| "清开灵治疗手足口病临床观察";江雪娟等;《临床和实验医学杂志》;20061030;第5卷(第10期);第1610页右列第1段 * |
| LUAN-YIN CHANG, et al.."Status of Cellular Rather Than Humoral Immunity is Correlated with Clinical Outcome of Enterovirus 71".《PEDIATRIC RESEARCH》.2006,第60卷(第4期),第466-471页. |
| 张谨等."康复新液联合莲花清瘟胶囊治疗手足口病临床观察".《中国中医药信息杂志》.2011,第18卷(第1期), |
| 江雪娟等."清开灵治疗手足口病临床观察".《临床和实验医学杂志》.2006,第5卷(第10期),第1610页. |
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