CN107325160B - Non-human primate cynomolgus monkey hepatitis B virus effector T cell specific antigen polypeptide and vaccine - Google Patents
Non-human primate cynomolgus monkey hepatitis B virus effector T cell specific antigen polypeptide and vaccine Download PDFInfo
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Abstract
The invention belongs to the field of biological medicine, and discloses a non-human primate cynomolgus monkey hepatitis B virus effector T cell specific antigen polypeptide, and application and vaccine thereof in a diagnostic kit. The non-human primate hepatitis B virus effector T cell specific polypeptide is obtained by analyzing the topological conformation of the structure of the hepatitis B virus functional protein, and a brand new peptide segment which can be used for diagnosing the non-human primate hepatitis B disease is screened out by analyzing the structure of related polypeptide after combination and rearrangement. In ELISpot experiment, the obtained peptide segment is utilized to stimulate the effector T cells in non-human primate diseases infected by hepatitis B to secrete gamma-IFN, and the feasibility and the therapeutic value of the peptide segment in the diagnosis of the diseases are proved. The method has strong specificity, high sensitivity and simple and convenient operation, can be developed into a diagnostic kit for clinically detecting hepatitis B diagnosis and differential diagnosis of primates, and lays a foundation for screening and treating zoonosis.
Description
Technical field
The invention belongs to Medical Immunology diagnostic techniques fields, are related to a kind of non-human primates machin hepatitis type B virus
The special antigen polypeptide of effector T cell and its application and vaccine on diagnostic kit, and in particular to use ELISpot method
It is hepatitis b virus infected to non-human primates machin to diagnose.
Background technique
Hepatitis B is higher in developing country's disease incidence, and 6,000,000,000 population of the world, 2.5 hundred million people are hepatitis type B viruses
(HBV) carrier, and induce hepatocellular carcinoma (HCC) and a kind of serious zoonosis of infectiousness.Since HBV has found,
A variety of Hepadna Virus related to this are isolated in wild rodent, wild birds and non-human primates in succession, this is several
Kind animal virus and human hepatitis B virus form a unique Hepadnaviridae (Hepadnaviridae).At present
It has been found that HBV plants of non-human primate have, HBV plants of orangutan (Warren, 1999), HBV plants of gibbon (Norder,
1996), chimpanzee HBV plants (MacDonaid, 2000) etc..These Strain are different from other on DNA sequence dna and protein structure
Wild animal Hepadna Virus strain, their strain extremely similar, morphology of virus and hepatitis type B viruses to viruses of human hepatitis B
(HBV) similar.It is some studies have shown that non-human primates Hepadna Virus infection after, morphology of virus is similar to people HBV, through HBV table
As a result face antigen (HBsAg) test includes its viral archaeal dna polymerase in the serum of surface antigen positive, and active.This
Illustrate that hepatitis b virus s antigen is similar to the thermophilic liver antigenic surface structure of non-human primates, there are cross reactions.Therefore,
The research of non-human primates HBV is of great significance to the diagnosing and treating of human hepatitis B.
Non-human primate (chimpanzee, gibbon, machin, rhesus macaque etc.) can infect HBV, and the HBV infected
Genotype is essentially the same with the infection mankind's, and the serology and liver pathomorphology change after infecting HBV are closer to people.
HBV only has 3200bp, is a fairly small virus.There are four ORF altogether for its genome, encode following some albumen: Core egg
White and pre-core albumen, Pol albumen, X protein and S protein (L, M, S).Core is nucleocapsid protein；Pre-core is present
Do not know there is He Gongneng, it is not necessary the duplication of virus, but may be related with the immune response of host is inhibited；X egg
It is white that virus replication is important, it is also related with the generation of liver cancer；S protein is the envelope protein of virus, with cell entry cell
It is related.The antigen of HBV has 3 kinds: surface antigen (HBsAg), core antigen (HBcAg) and e antigen (HBeAg).Surface antigen is big
Amount is present in the infected's blood, is the outstanding feature of HBV infection and detection.Core antigen is by 183 or 185 amino acid
Composition, hyperphosphorylation has strongly immunogenic, can induce very strong humoral immunity and cellular immunity, stimulation body generates anti-
Body.
Enzyme linked immunospot (Enzyme-linked Immunospot, ELISpot) the technology tool that nineteen eighty-three establishes
Have the sensibility of height and the popularity of application, it has also become immune detection antigen specific immune reaction important detection means it
One.
The Analysis of Immunogenicity discovery of HBV albumen is successively carried out in the polypeptide superposition with 4 amino acid, HBV is different
Peptide fragment is different to the immunogenicity of T cell, wherein core protein (65-75 and 86-95) and polymerase functional areas albumen (385-
391 and 401-411) amino acid all has stronger T cell immunogenicity.The present invention is in conjunction with HBV antigenic structure feature, root
Antigenicity analysis and secondary structure prediction are carried out to the amino acid sequence that these are selected according to software, its cell immunogenicity is strong
Polypeptide is reassembled into two segment polypeptide sequences, constructs the special antigen polypeptide of non-human primates HBV viral effector T cell, benefit
Diagnosing and treating is carried out with non-human primates disease of the ELISpot method to HBV.
Summary of the invention
The object of the present invention is to provide a kind of antigens that non-human primates machin hepatitis type B virus effector T cell is special
Polypeptide improves inhuman spirit for detecting the T cell of the specific γ-IFN secreted after non-human primates HBV infection in peripheral blood
The sensitivity and specificity of long class HBV, assist the diagnosis and differential diagnosis of zoonosis.
The technical scheme is that
The special antigen polypeptide of non-human primates machin hepatitis type B virus effector T cell, including polypeptide 1 and polypeptide 2,
Polypeptide 1 has the amino acid sequence as shown in SEQ ID No:1, and polypeptide 2 has the amino acid sequence as shown in SEQ ID No:2
Column.
The present invention show that non-human primates are B-mode by the topological conformation analysis to hepatitis type B virus functional protein structure
The special polypeptide of hepatitis virus effector T cell, then to related polypeptide combination reset after structural analysis, filter out can be used for it is non-
The completely new peptide fragment of people's primate hepatitis B medical diagnosis on disease.
Preferably, the polypeptide 1 be to the amino acid sequence of non-human primates machin hepatitis B virus into
What row combination obtained after resetting.
Preferably, the polypeptide 2 be to the amino acid sequence of non-human primates machin hepatitis B envelope protein into
What row combination obtained after resetting.
The application and vaccine that the present invention also provides above-mentioned antigen polypeptides on diagnostic kit.
Application of the antigen polypeptide on non-human primates machin diagnosis of hepatitis b kit.Using polypeptide 1
It is used as stimulator antigen with polypeptide 2, non-human primates hepatitis B is diagnosed by detecting the T cell of the polypeptide.
Preferably, in the diagnostic kit containing ELISpot detection plate, γ-IFN capture antibody, polypeptide 1, polypeptide 2,
Interferon (γ-IFN) detection antibody, Avidin-HRP conjugate and the TMB developing solution of biotin labeling.
A kind of vaccine, including adjuvant, polypeptide 1 and polypeptide 2.
The preferred Fox Freund's complete adjuvant of adjuvant.
Application of the vaccine on the drug for the treatment of non-human primates machin hepatitis B.Using polypeptide 1 and more
Peptide 2 is used as polypeptide drugs, forms polypeptide therapeutic vaccine with adjuvant, can activate the intracorporal T of non-human primate thin after injection
Born of the same parents generate the interferon of specificity to kill hepatitis B.
Antigen polypeptide high specificity of the present invention, high sensitivity is easy to operate, and diagnostic kit of the invention can be used for clinic
Diagnosis of hepatitis b and the antidiastole of primate are detected, is laid a good foundation for the screening and treatment of zoonosis.
Detailed description of the invention
Fig. 1 is the test map exemplary diagram of embodiment.Wherein, A behavior negative control hole, 1 detection hole of B behavior polypeptide, C row
For 2 detection hole of polypeptide, 2 detection hole of D behavior polypeptide 1+ polypeptide, E behavior anti-cd 3 antibodies Positive control wells.
Fig. 2 is the statistical chart of embodiment testing result.
Fig. 3 is influence of the polypeptide vaccine to the various dose HBV machin body γ-IFN level being inoculated with.
Specific embodiment
Below in conjunction with Detailed description of the invention and embodiment, present invention is further described in detail.
Embodiment
The present invention is to 8 healthy machin control groups (Control group), 16 machin HBV inoculation groups (105VP and
107The HBV inoculation group without fertility of VP, every group 8) antidiastole is carried out, so that the tentatively judgement present invention is in machin
Specificity and sensibility in HBV infection diagnosis.
Specific step is as follows:
(1) it is coated with:
γ-IFN capture the antibody of addition working concentration (500 nanograms/milliliter) in ELISpot filter membrane plate, 100 microlitres/hole,
4 DEG C overnight after, with sterile phosphate buffer (PBS) board-washing 3 times, 3min/ times；
PBS, the 37 DEG C of incubation 2h for containing 5% bovine serum albumin(BSA) are added in every hole, after sealing, set 4 DEG C of preservations, use in 1 week.
(2) animal experiment:
This test is divided into three groups: physiological saline vehicle control group, and 105VP without fertility HBV inoculation group (1.0 ×
105VP/ is only) and 107The HBV inoculation group (1.0 × 10 without fertility of VP7VP/ is only)；Every group 8, half male and half female is subcutaneous to infuse
Penetrate inoculation.Weekly administration 1 time, continuous 3 times, last time takes out periphery heparin anti-coagulating 4-5ml after being administered, and is stored at room temperature, in 6h
Interior detection.
(3) ELISpot is detected:
A) .ELISpot plate prepares:
1) ELISpot plate prepares: after taking out pre-coated ELISpot plate, washed 4 times in superclean bench with sterile PBS,
200 holes μ L/；After discarding PBS liquid, with AIM-V serum free medium (200 hole μ L/) preincubate 30min, room temperature；
2) HBV polypeptide dilutes: being dissolved according to the respective quality inspection report of 2 polypeptides, is taken for every group respectively after dissolution
10mLAIM-V culture medium, according to 1 group of polypeptide of test setting, 2 groups of polypeptide and polypeptide 1+2 group, draw the 10 each polypeptide solutions of μ L into
Row mixing, the concentration of each polypeptide is 10 μ g/mL after mixing.Negative control group: 10mLAIM-V culture medium.Positive control:
- 1 antibody of AntiCD3 McAb (1:1000) of 10 μ L is added in the AIM-V culture medium of 10mL；
3) the AIM-V culture medium in preincubate culture plate is discarded, sets CD3 positive control, feminine gender respectively according to every animal
(PBS), 1 group of polypeptide, 2 groups of polypeptide and polypeptide 1+2 group are compareed, the AIM-V for being onboard separately added into these polypeptides and control group is mixed
Close liquid, 50 holes μ L/, if dual control.
Polypeptide fragment 1 has following amino acid sequence: Leu Met Asn Leu Ala Thr Trp Val Gly Ser
Asn Val Ser Tyr Val Asn Val Asn Met Gly, which is to non-human primates machin hepatitis B core
The amino acid sequence of heart protein is combined reset after obtain.
Polypeptide fragment 2 has following amino acid sequence: Glu Ser Arg Leu Val Val Asp Arg Val Ser
Trp Pro Lys Phe Arg Val Pro, which is the amino to non-human primates machin hepatitis B envelope protein
Acid sequence is combined reset after obtain.
B) lymphocyte is incubated for:
1) prepared by peripheral blood lymphocytes: each animal takes periphery heparin anti-coagulating 3mL, in 15mL centrifuge tube with equal bodies
Long-pending 1640 culture mediums mixing, is added 3mL lymphocyte separation medium, the mixing of peripheral blood in other 1 15mL centrifuge tube
Liquid is added slowly to the upper surface of lymphocyte separation medium, room temperature, and 400g is centrifuged 20min；
2) it after being centrifuged, is sucked out in buffy coat to another new centrifuge tube with aseptic straw, 1640 culture medium of 10mL is added
After mixing, 250g is centrifuged 10min washing；
3) after abandoning supernatant, after the mixing of 10mLAIM-V culture medium is added, after 250g is centrifuged 10min washing, 1mLAIM-V is added
After culture medium mixes, after the 0.4% platform phenol indigo plant mixing dyeing for drawing 10 μ L cell suspensions and 40 μ L, carried out with cell counting board
It counts.Every milliliter of cell quantity=cell count × 5 × 10 in mother liquor4；
4) cell is adjusted to 4 × 10 with AIM-V culture medium6After a cell/mL, in the plate of above-mentioned ready ELISpot
In every hole 50 μ L cell suspensions, i.e., every hole 2 × 10 is added5A cell, at 37 DEG C, 5%CO240h is incubated in incubator.
C) spot detection:
1) culture medium and cell in culture plate are removed, is washed 5 times with PBS, each 5min；
2) antibody-solutions are detected with the interferon (γ-IFN) of the PBS dilution biotin labeling containing 0.5%BSA, added
Enter in 96 hole ELISpot plates, every 100 μ L of hole, is incubated at room temperature 2h；
3) solution in culture plate is removed, is washed 5 times with PBS, each 5min；
4) 100 μ L Avidin-HRP conjugates are added in every hole, after being incubated at room temperature 1h, remove the solution in culture plate, use PBS
Washing 5 times, each 5min；
5) the TMB developing solution substrate of 100 μ L, color development at room temperature 30min is added in every hole；
6) it terminates: after colour developing, removing the solution in culture plate, after washing 2 times with distilled water, be placed in 37 DEG C of insulating boxs and dry in the air
After dry, counted.
D) interpretation of result: being captured a photograph with hiccough, and after reading the number of spots in each hole, takes duplicate hole
Average value × 5 acquire every 106The quantity of effector T cell in a cell.
According to Fig. 1 and Fig. 2 it is found that all testing results may determine that its negative or positive findings, in 16 different agent
In the machin for measuring HBV inoculation, using of the invention detection example 13, recall rate is 81.25% (wherein 107VP group recall rate
8/8,105VP group recall rate 5/8).Therefore polypeptide 1 and polypeptide 2 of the invention can be used for diagnosis and the mirror of machin HBV disease
It does not diagnose.
Show that the recall rate diagnosed with the present invention for machin HBV infection is 87% through test of many times, specificity is
95%, sensibility 85%.
(4), 1 week after third time is inoculated with, each dosage group animal is divided into control group and treatment group, is subcutaneously injected, 1
The level of γ-IFN in serum ELISA detection machin serum is taken after week.
Control group: 4, Fox Freund's complete adjuvant, subcutaneous injection are only injected；
Treatment group: 4, the milky white shape of white for being mixed into Water-In-Oil in equal volume with polypeptide solution with Fox Freund's complete adjuvant is suspended
Liquid (wherein, polypeptide 1 and 2 dosage of polypeptide are respectively 10 μ g/kg), subcutaneous injection.
The results show that treatment group can increase the level of γ-IFN in cynomolgus monkey relative to adjuvant control group, illustrate more
Peptide 1 and polypeptide 2 can stimulate the effector T cell in the non-human primates disease of hepatitis B infection to secrete γ-IFN, it was confirmed that
Feasibility and therapeutic value of the peptide fragment in such medical diagnosis on disease.
In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can be to this
Invention makes various changes or modifications, and such equivalent forms equally fall within the limited range of the application the appended claims.
<110>Jiangsu Ding Tai Remedy Research Limited
<120>the special antigen polypeptide of non-human primates machin hepatitis type B virus effector T cell and its application on kit
And vaccine
<160> 1
<210> 1
<211> 37
<212> AA
<213>people (Homo sapiens)
<400>1
Leu Met Asn Leu Ala Thr Trp Val Gly Ser Asn Val Ser Tyr Val Asn Val Asn Met Gly
<400>2
Glu Ser Arg Leu Val Val Asp Arg Val Ser Trp Pro Lys Phe Arg Val Pro
Claims (3)
1. the special antigen polypeptide of non-human primates machin hepatitis type B virus effector T cell, it is characterized in that: including polypeptide 1
With polypeptide 2, the amino acid sequence of polypeptide 1 is amino acid sequence shown in SEQ ID No:1, and the amino acid sequence of polypeptide 2 is SEQ
Amino acid sequence shown in ID No:2.
2. vaccine made from antigen polypeptide described in claim 1, it is characterized in that: including adjuvant, polypeptide 1 and polypeptide 2.
3. vaccine according to claim 2, it is characterized in that: the adjuvant is Fox Freund's complete adjuvant.
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| CN201710537720.5A CN107325160B (en) | 2017-07-04 | 2017-07-04 | Non-human primate cynomolgus monkey hepatitis B virus effector T cell specific antigen polypeptide and vaccine |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101036784A (en) * | 2007-03-09 | 2007-09-19 | 中国人民解放军第二军医大学 | Toxicity T cell position vaccine of the cell for treating Hepatitis B and the preparing method |
| WO2011048386A1 (en) * | 2009-10-23 | 2011-04-28 | Iqur Limited | Influenza vaccine |
| CN104341506A (en) * | 2013-07-30 | 2015-02-11 | 复旦大学 | Recombinant fusion protein and use thereof |
-
2017
- 2017-07-04 CN CN201710537720.5A patent/CN107325160B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101036784A (en) * | 2007-03-09 | 2007-09-19 | 中国人民解放军第二军医大学 | Toxicity T cell position vaccine of the cell for treating Hepatitis B and the preparing method |
| WO2011048386A1 (en) * | 2009-10-23 | 2011-04-28 | Iqur Limited | Influenza vaccine |
| CN104341506A (en) * | 2013-07-30 | 2015-02-11 | 复旦大学 | Recombinant fusion protein and use thereof |
Non-Patent Citations (4)
| Title |
|---|
| core protein [Hepatitis B virus];Tangkijvanich,P.等;《GenBank》;20121225;ORIGIN * |
| polymerase, partial [Hepatitis B virus];Huang,C.J.等;《GenBank》;20130820;ORIGIN * |
| 乙型肝炎病毒多聚酶末端蛋白的结构和功能研究;赵超 等;《生命科学》;20041031;第16卷(第5期);第267-270页 * |
| 乙型肝炎病毒核心蛋白作为表位疫苗载体的应用;殷瑛 等;《生物工程学报》;20100425;第26卷(第4期);第431-438页 * |
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Address after: Room 825-6, building a, phase I, Zhongdan Ecological Life Science Industrial Park, no.3-1, xinjinhu Road, Jiangbei new district, Nanjing City, Jiangsu Province, 211800 Patentee after: Jiangsu Dingtai pharmaceutical research (Group) Co.,Ltd. Address before: 210000 Jiangpu Road, Xingpu District, Nanjing, Jiangsu Province Patentee before: JIANGSU TRIPOD PRECLINICAL RESEARCH LABORATORIES Co.,Ltd. |