CN107325160A - Non-human primate cynomolgus monkey hepatitis B virus effector T cell specific antigen polypeptide, application thereof in kit and vaccine - Google Patents
Non-human primate cynomolgus monkey hepatitis B virus effector T cell specific antigen polypeptide, application thereof in kit 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 field, it is related to a kind of non-human primates machin hepatitis type B virus
The special antigen polypeptide of effector T cell and its application on diagnostic kit and vaccine, and in particular to use ELISpot methods
It is hepatitis b virus infected to non-human primates machin to diagnose.
Background technology
Hepatitis B is higher in developing country's incidence of disease, the population of the world 6,000,000,000, and it is hepatitis type B virus to have 2.5 hundred million people
(HBV) carrier, and hepatocellular carcinoma (HCC) is induced, it is also 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
Plant animal virus and constitute a unique Hepadnaviridae (Hepadnaviridae) with human hepatitis B virus.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, they and viruses of human hepatitis B strain extremely similar, morphology of virus and hepatitis type B virus
(HBV) it is similar.Some researchs show that after the infection of non-human primates Hepadna Virus, its morphology of virus is similar to people HBV, through HBV tables
Face antigen (HBsAg) is tested, and as a result includes its viral archaeal dna polymerase in the serum of surface antigen positive, and active.This
A little explanation hepatitis b virus s antigens are similar to the thermophilic liver antigenic surface structure of non-human primates, there is cross reaction.Therefore,
Diagnosis and treatment of the non-human primates HBV research to human hepatitis B are significant.
Non-human primate (chimpanzee, gibbon, machin, rhesus macaque etc.) can infect HBV, and the HBV of infection
Genotype is essentially the same with the infection mankind's, and it infects the serology after HBV and liver pathomorphology change is closer to people.
HBV only has 3200bp, is a fairly small virus.Its genome has four ORF, encodes following some albumen：Core eggs
White and pre-core albumen, Pol albumen, X protein, and S protein (L, M, S).Core is nucleocapsid protein；Pre-core is present
What function does not know has, and it is replicated not necessarily to virus, but immune response that may be with suppressing host is relevant；X eggs
It is white be to virus replication it is important, it is relevant also with the generation of liver cancer；S protein is the envelope protein of virus, with cell entry cell
It is relevant.HBV antigen has 3 kinds：Surface antigen (HBsAg), cAg (HBcAg) and e antigens (HBeAg).Surface antigen is big
Amount is present in the infected's blood, is HBV infection and the outstanding feature of detection.CAg is by 183 or 185 amino acid
Composition, hyperphosphorylation, with strongly immunogenic, can induce very strong humoral immunity and cellular immunity, stimulate body to produce anti-
Body.
Enzyme linked immunospot (Enzyme-linked Immunospot, ELISpot) technology tool that nineteen eighty-three sets up
Have the sensitiveness 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 for carrying out HBV albumen successively in the polypeptide superposition with 4 amino acid finds that 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 is respectively provided with stronger T cell immunogenicity.The present invention is with reference to HBV antigenic structure features, 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 sections of peptide sequences, constructs the special antigen polypeptide of non-human primates HBV viral effector T cells, profit
HBV non-human primates disease is diagnosed and treated with ELISpot methods.
The content of the invention
It is an object of the invention to provide a kind of special antigen of non-human primates machin hepatitis type B virus effector T cell
Polypeptide, the specific γ-IFN secreted for detecting after non-human primates HBV infection in peripheral blood T cell improves inhuman spirit
Long class HBV sensitivity and specificity, aid in 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 such as SEQ ID No：Amino acid sequence shown in 1, polypeptide 2 has such as SEQ ID No：Amino acid sequence shown in 2
Row.
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 viruse effector T cell, then to related polypeptide combine reset after structural analysis, filter out can be used for it is non-
The brand-new peptide fragment of people's primate hepatitis B medical diagnosis on disease.
Preferably, the polypeptide 1 is that the amino acid sequence of non-human primates machin hepatitis B virus is entered
What row combination was obtained after resetting.
Preferably, the polypeptide 2 is that the amino acid sequence of non-human primates machin hepatitis B envelope protein is entered
What row combination was obtained after resetting.
Present invention also offers application of the above-mentioned antigen polypeptide on diagnostic kit and vaccine.
Application of the described antigen polypeptide on non-human primates machin diagnosis of hepatitis b kit.Using polypeptide 1
With polypeptide 2 as stimulator antigen, non-human primates hepatitis B is diagnosed by detecting the T cell of the polypeptide.
Preferably, in the diagnostic kit containing ELISpot detection plates, γ-IFN capture antibody, polypeptide 1, polypeptide 2,
Interferon (γ-IFN) detection antibody, Avidin-HRP conjugates and the TMB nitrite ions 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 described vaccine on the medicine for the treatment of non-human primates machin hepatitis B.Using polypeptide 1 and many
Peptide 2 is as polypeptide drugs, and with adjuvant formation polypeptide therapeutic vaccine, the T that can be activated in non-human primate body after injection is thin
Born of the same parents produce specific interferon to kill hepatitis B.
Antigen polypeptide high specificity of the present invention, sensitivity is high, 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 that the examination and treatment of zoonosis are laid a good foundation.
Brief description of the drawings
Fig. 1 is the detection collection of illustrative plates exemplary plot of embodiment.Wherein, A behaviors negative control hole, the detection hole of B behaviors polypeptide 1, C rows
For the detection hole of polypeptide 2, the detection hole of D behavior polypeptide 1+ polypeptides 2, E behavior anti-cd 3 antibodies Positive control wells.
Fig. 2 is the statistical chart of embodiment testing result.
Fig. 3 is the influence for the machin body γ-IFN levels that polypeptide vaccine is inoculated with to various dose HBV.
Embodiment
The present invention is described in further detail below in conjunction with brief description of the drawings and embodiment.
Embodiment
The present invention is to 8 healthy machin control groups (Control groups), 16 machin HBV inoculation groups (105VP and
107The VP HBV inoculation groups without fertility, every group 8) antidiastole is carried out, so as to tentatively judge the present invention in machin
Specificity and sensitiveness in HBV infection diagnosis.
Comprise the following steps that：
(1) it is coated with：
γ-IFN capture the antibody of addition working concentration (500 nanograms/milliliter) in ELISpot filter membrane plates, 100 microlitres/hole,
4 DEG C overnight after, with sterile phosphate buffer (PBS) board-washing 3 times, 3min/ times；
The PBS containing 5% bovine serum albumin(BSA), 37 DEG C of incubation 2h are added per hole, after sealing, puts in 4 DEG C of preservations, 1 week and uses.
(2) animal experiment：
This experiment is divided into three groups：Physiological saline vehicle control group, 105VP without fertility HBV inoculation groups (1.0 ×
105VP/ is only) and 107The VP HBV inoculation groups (1.0 × 10 without fertility7VP/ is only)；Every group 8, male and female half and half, subcutaneous note
Penetrate inoculation.Weekly administration 1 time, continuous 3 times, last time takes out periphery heparin anti-coagulating 4-5ml after being administered, normal temperature is preserved, in 6h
Interior detection.
(3) ELISpot is detected：
A) .ELISpot plates prepare：
1) ELISpot plates prepare：Take out after pre-coated ELISpot plates, washed in superclean bench with sterile PBS 4 times,
200 μ L/ holes；Discard after PBS liquid, with AIM-V serum free mediums (200 μ L/ holes) preincubate 30min, room temperature；
2) HBV polypeptides dilute：Dissolved respectively according to the respective quality inspection report of 2 polypeptides, every group takes after dissolving
10mLAIM-V culture mediums, 1 group of polypeptide, 2 groups of polypeptide and polypeptide 1+2 groups are set according to experiment, are drawn the 10 each polypeptide solutions of μ L and are entered
Row mixing, the concentration of each polypeptide is 10 μ g/mL after mixing.Negative control group：10mLAIM-V culture mediums.Positive control：
The 10 μ L antibody of AntiCD3 McAb -1 (1 is added in 10mL AIM-V culture mediums:1000)；
3) the AIM-V culture mediums in preincubate culture plate are discarded, CD3 positive controls, feminine gender are set respectively according to every animal
(PBS), 1 group of polypeptide, 2 groups of polypeptide and polypeptide 1+2 groups are compareed, the AIM-V for being onboard separately added into these polypeptides and control group is mixed
Close liquid, 50 μ L/ holes, 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, the sequence is to non-human primates machin hepatitis B core
The amino acid sequence of heart protein is combined what is obtained after rearrangement.
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, the sequence is the amino to non-human primates machin hepatitis B envelope protein
Acid sequence is combined what is obtained after rearrangement.
B) lymphocytes are incubated：
1) prepared by PBLC：Each animal takes periphery heparin anti-coagulating 3mL, with waiting body in 15mL centrifuge tubes
Long-pending 1640 culture mediums mixing, adds 3mL lymphocyte separation mediums, the mixing of peripheral blood in other 1 15mL centrifuge tube
Liquid is added slowly to above lymphocyte separation medium, room temperature, 400g centrifugations 20min；
2) after centrifuging, suctioned out with aseptic straw in buffy coat to another new centrifuge tube, add the culture mediums of 10mL 1640
After mixing, 250g centrifugation 10min washings；
3) abandon after supernatant, add after the mixing of 10mLAIM-V culture mediums, after 250g centrifugation 10min washings, add 1mLAIM-V
After culture medium is mixed, the 0.4% platform phenol indigo plant for drawing 10 μ L cell suspensions and 40 μ L is mixed after dyeing, is carried out with cell counting count board
Count.Every milliliter of cell quantity=cell count × 5 × 10 in mother liquor4；
4) cell is adjusted to 4 × 10 with AIM-V culture mediums6After individual cell/mL, in above-mentioned ready ELISpot plate
In per hole add 50 μ L cell suspensions, i.e., often hole 2 × 105Individual cell, in 37 DEG C, 5%CO240h is incubated in incubator.
C) spot detections：
1) culture medium and cell fallen in culture plate, is washed 5 times, each 5min with PBS；
2) antibody-solutions are detected with the interferons (γ-IFN) for diluting biotin labeling of the PBS containing 0.5%BSA, plus
Enter in 96 hole ELISpot plates, per the μ L of hole 100, be incubated at room temperature 2h；
3) solution fallen in culture plate, is washed 5 times, each 5min with PBS；
4) added per hole after 100 μ L Avidin-HRP conjugates, incubation at room temperature 1h, the solution gone in culture plate uses PBS
Washing 5 times, each 5min；
5) 100 μ L TMB nitrite ion substrates, color development at room temperature 30min are added per hole；
6) terminate：After colour developing, the solution gone in culture plate is washed after 2 times with distilled water, is placed in 37 DEG C of insulating boxs and is dried in the air
After dry, counted.
D) interpretations of result：Captured a photograph, and read after the number of spots in each hole with hiccough, take duplicate hole
Average value × 5, try to achieve every 106The quantity of effector T cell in individual cell.
It can be seen from Fig. 1 and Fig. 2, all testing results may determine that its negative or positive findings, in 16 different agent
In the machin for measuring HBV inoculations, using the detection example 13 of the present invention, recall rate is 81.25% (wherein 107VP group recall rates
8/8,105VP groups recall rate 5/8).Therefore the polypeptide 1 and polypeptide 2 of the present invention can be used for diagnosis and the mirror of machin HBV diseases
Do not diagnose.
Show through test of many times, the recall rate diagnosed with the present invention for machin HBV infection is 87%, and specificity is
95%, sensitiveness is 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
Serum ELISA is taken to detect the level of γ-IFN in machin serum after week.
Control group：4, FOX Freund's complete adjuvant is only injected, is subcutaneously injected；
Treatment group：4, the white milky white shape 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 the dosage of polypeptide 2 are respectively 10 μ g/kg), is subcutaneously injected.
As a result show, relative to vehicle control group, treatment group can increase the level of γ-IFN in cynomolgus monkey, illustrate many
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 is to be understood that after the above-mentioned instruction content of the present invention has been read, those skilled in the art can be to this
Invention makes various changes or modifications, and these equivalent form of values equally fall within the application appended claims and limit scope.
<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 on kit
Using 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 (8)
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, polypeptide 1 has such as SEQ ID No：Amino acid sequence shown in 1, polypeptide 2 has such as SEQ ID No：Ammonia shown in 2
Base acid sequence.
2. the special antigen polypeptide of non-human primates machin hepatitis type B virus effector T cell according to claim 1,
It is characterized in that：The polypeptide 1 is that weight is combined to the amino acid sequence of non-human primates machin hepatitis B virus
Obtained after row.
3. the special antigen polypeptide of non-human primates machin hepatitis type B virus effector T cell according to claim 1,
It is characterized in that：The polypeptide 2 is that weight is combined to the amino acid sequence of non-human primates machin hepatitis B envelope protein
Obtained after row.
4. application of the antigen polypeptide on non-human primates machin diagnosis of hepatitis b kit described in claim 1.
5. antigen polypeptide according to claim 4 answering on non-human primates machin diagnosis of hepatitis b kit
With, it is characterized in that：Contain ELISpot detection plates, γ-IFN captures antibody, polypeptide 1, polypeptide 2, biology in the diagnostic kit
γ-IFN detections antibody, Avidin-HRP conjugates and the TMB nitrite ions of element mark.
6. vaccine made from the antigen polypeptide described in claim 1, it is characterized in that：Including adjuvant, polypeptide 1 and polypeptide 2.
7. vaccine according to claim 6, it is characterized in that：The adjuvant is FOX Freund's complete adjuvant.
8. application of the vaccine on the medicine for the treatment of non-human primates machin hepatitis B described in claim 6.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114317410A (en) * | 2021-12-31 | 2022-04-12 | 江苏鼎泰药物研究(集团)股份有限公司 | Establishment and application of simian ips cell line DT-M001 |
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| 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 |
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2017
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|---|---|---|---|---|
| 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 |
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| HUANG,C.J.等: "polymerase, partial [Hepatitis B virus]", 《GENBANK》 * |
| TANGKIJVANICH,P.等: "core protein [Hepatitis B virus]", 《GENBANK》 * |
| 殷瑛 等: "乙型肝炎病毒核心蛋白作为表位疫苗载体的应用", 《生物工程学报》 * |
| 赵超 等: "乙型肝炎病毒多聚酶末端蛋白的结构和功能研究", 《生命科学》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114317410A (en) * | 2021-12-31 | 2022-04-12 | 江苏鼎泰药物研究(集团)股份有限公司 | Establishment and application of simian ips cell line DT-M001 |
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