CN104090115B - Secondary T cells relies on antibody response and detects exogenous compounds IM - Google Patents
Secondary T cells relies on antibody response and detects exogenous compounds IM Download PDFInfo
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- CN104090115B CN104090115B CN201410328523.9A CN201410328523A CN104090115B CN 104090115 B CN104090115 B CN 104090115B CN 201410328523 A CN201410328523 A CN 201410328523A CN 104090115 B CN104090115 B CN 104090115B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 32
- 210000001744 T-lymphocyte Anatomy 0.000 title claims abstract description 30
- 230000005875 antibody response Effects 0.000 title claims abstract description 8
- 239000000427 antigen Substances 0.000 claims abstract description 29
- 102000036639 antigens Human genes 0.000 claims abstract description 29
- 108091007433 antigens Proteins 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 22
- 238000002347 injection Methods 0.000 claims abstract description 18
- 239000007924 injection Substances 0.000 claims abstract description 18
- 210000005259 peripheral blood Anatomy 0.000 claims abstract description 10
- 239000011886 peripheral blood Substances 0.000 claims abstract description 10
- 241001465754 Metazoa Species 0.000 claims abstract description 9
- 210000002966 serum Anatomy 0.000 claims abstract description 9
- 238000000926 separation method Methods 0.000 claims abstract description 7
- 229960003444 immunosuppressant agent Drugs 0.000 claims abstract description 6
- 230000001861 immunosuppressant effect Effects 0.000 claims abstract description 6
- 239000003018 immunosuppressive agent Substances 0.000 claims abstract description 6
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims description 19
- 108010036949 Cyclosporine Proteins 0.000 claims description 17
- 229960001265 ciclosporin Drugs 0.000 claims description 17
- 229930182912 cyclosporin Natural products 0.000 claims description 17
- 108010045069 keyhole-limpet hemocyanin Proteins 0.000 claims description 17
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 13
- 238000010253 intravenous injection Methods 0.000 claims description 4
- 241000237988 Patellidae Species 0.000 claims description 2
- 108060003552 hemocyanin Proteins 0.000 claims description 2
- 230000028993 immune response Effects 0.000 abstract description 8
- 238000007877 drug screening Methods 0.000 abstract description 5
- 230000004044 response Effects 0.000 abstract description 3
- 238000001514 detection method Methods 0.000 abstract description 2
- 241000700159 Rattus Species 0.000 description 12
- 230000009273 T-cell dependend antibody response Effects 0.000 description 12
- 210000000265 leukocyte Anatomy 0.000 description 10
- 238000010241 blood sampling Methods 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 210000001541 thymus gland Anatomy 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- 210000001835 viscera Anatomy 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 3
- 210000000987 immune system Anatomy 0.000 description 3
- 230000036039 immunity Effects 0.000 description 3
- 230000006054 immunological memory Effects 0.000 description 3
- 230000001506 immunosuppresive effect Effects 0.000 description 3
- 230000007688 immunotoxicity Effects 0.000 description 3
- 231100000386 immunotoxicity Toxicity 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 241000700605 Viruses Species 0.000 description 2
- 238000004820 blood count Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000003118 histopathologic effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2500/00—Screening for compounds of potential therapeutic value
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Abstract
The invention discloses a kind of secondary T cells and rely on the immunosuppressant method of antibody response detection exogenous compounds, comprise the following steps: animal is injected T cell dependence antigen by (1); (2) within 15th ~ 25 days after the injection described in step (1), again injecting identical T cell dependence antigen excites secondary immune to reply, and starts continuous 2 ~ 5 days per os simultaneously and gives exogenous compounds; (3), after step (2) completes 6 ~ 10 days, peripheral blood is gathered, separation of serum, the specific antibody of the antigen described in detecting step (1).The method immune response time is shorter, and response degree is stronger, and required exogenous compounds consumption is less, and can be applied to early stage drug screening.
Description
Technical field
The present invention relates to biological technical field, be specifically related to a kind of secondary T cells and rely on the immunosuppressant method of antibody response detection exogenous compounds.
Background technology
Immunotoxicity is that allogenic material makes immune system structure or function occur the toxic reaction of any lasting or modulation.Immunotoxicity effect is mainly divided into 5 kinds: immunosupress, Immune-enhancing effect, hypersensitivity, autoimmunity, immunogenicity.Wherein immunosupress is the most common, studies more in immunotoxicity.
T cell dependence antibody response (Tcell-dependentantibodyresponse, TDAR) is at present for detecting the immunosuppressant goldstandard of exogenous compounds.TDAR is that animal is when giving exogenous compounds, adopt T cell dependence antigen to attack simultaneously, after continuing to give exogenous compounds certain hour, gather the specific antibody content of Virus monitory for this antigen, thus judge whether the immune system of animal is suppressed.Along with the popularization of TDAR application, the defect of TDAR also comes out gradually, and as Some Animals is insensitive to specific T cells dependence antigen, individual difference is comparatively large, and experimental period is longer, tested exogenous compounds large usage quantity and be difficult to use in early stage drug screening.
Summary of the invention
What the present invention will solve is that to overcome existing TDAR technology insensitive to specific T cells dependence antigen with technical matters, experimental period is longer, tested exogenous compounds large usage quantity and be difficult to use in the defect of early stage drug screening, provides a kind of secondary T cells to rely on antibody response and detects the immunosuppressant method of exogenous compounds.Method of the present invention, immune response time is shorter, intensity is larger, and required exogenous compounds consumption is less, more rapidly, sensitive, can investigate the impact on immunological memory system simultaneously, and can be applied to early stage drug screening.
The present invention solves above-mentioned technical matters by the following technical solutions:
Technical scheme of the present invention is:
A kind of secondary T cells relies on antibody response and detects the immunosuppressant method of exogenous compounds, comprises the following steps:
(1) animal is injected T cell dependence antigen;
(2) within 15th ~ 25 days after the injection described in step (1), again injecting identical T cell dependence antigen excites secondary immune to reply, and starts continuous 2 ~ 5 days to exogenous compounds simultaneously;
(3) step (2) complete after 6th ~ 10 days, gather peripheral blood, separation of serum, the specific antibody of the T cell dependence antigen described in detecting step (1).
In step of the present invention (2), preferably, the described time of again injecting identical T cell dependence antigen is after the injection described in step (1) the 20th day.
In step of the present invention (2), preferably, the time that described continuous per os gives exogenous compounds is 3 days.
In step of the present invention (3), preferably, time of described collection peripheral blood is after step (2) completes the 8th day.
In step of the present invention (1), described T cell dependence antigen is that this area is conventional, preferably keyhole limpet hemocyanin (KLH); In step of the present invention (3), described specific antibody is that this area is conventional, preferably anti-keyhole limpet hemocyanin IgG antibody (anti-KLHIgG antibody).Preferably, the consumption of the T cell dependence antigen described in step of the present invention (1) is equal with the consumption of the T cell dependence antigen described in step (2).
The consumption of the T cell dependence antigen described in step of the present invention (1) is that this area is conventional, preferably 200 ~ 400 μ g/kg, more preferably 300 μ g/kg.
Exogenous compounds of the present invention is that this area is conventional, preferably cyclosporine or endoxan.Preferably, the exogenous compounds described in step of the present invention (2) is cyclosporine, and the consumption of described exogenous compounds is 7.5 ~ 30mg/Kg.
Preferably, the exogenous compounds described in step of the present invention (2) is endoxan, and described exogenous compounds concentration is 5 ~ 20mg/Kg.
Animal of the present invention is that this area is conventional, preferably rat.
Injection of the present invention is that this area is conventional, preferably intravenous injection.
The method of the specific antibody of the antigen described in detecting step (1) described in step of the present invention (3) is that this area is conventional, preferably gathers peripheral blood, separation of serum, detects the specific antibody for this antigen; More preferably gather peripheral blood, separation of serum, detect and conciliate and take internal organs for the specific antibody of this antigen, counting peripheral blood leucocyte and do histopathological examination.
Collection peripheral blood of the present invention detects the specific antibody for this antigen, and concrete operation steps is: tail vein blood, centrifuging serum, 96 orifice plates wraps by KLH, and ELISA method detects titre or the concentration of anti-KLHIgG antibody in serum.
On the basis meeting this area general knowledge, above-mentioned each optimum condition, can combination in any, obtains the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material are all commercially.
Positive progressive effect of the present invention is: the present invention is after giving T cell dependence antigen, through certain hour, give exogenous compounds and T cell dependence antigen again, secondary immune is caused to reply, gather the specific antibody content of Virus monitory for this antigen, to evaluate the suppression situation of animal immune system.Method of the present invention is secondary TDAR, and immune response time is shorter, and response degree is stronger, and required exogenous compounds consumption is less, and interindividual variation is less, has investigated the impact on immunological memory system simultaneously.And early stage drug screening can be applied to.
Accompanying drawing explanation
Fig. 1 is that secondary TDAR detects the cyclosporine of variable concentrations to SD rat immunity inhibitory effect.
Fig. 2 is that secondary TDAR detects the endoxan of variable concentrations to SD rat immunity inhibitory effect.
Fig. 3 is that elementary TDAR detects the cyclosporine of variable concentrations to SD rat immunity inhibitory effect.
Fig. 4 is the histopathologic examination figure of normal SD female rats thymus gland.
Fig. 5 is the histopathologic examination figure of the SD female rats thymus gland of primary immune response 30mg/kg cyclosporine.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or selects according to catalogue.
Embodiment 1
Experimental technique: choose growing state good, SD female rats of the same size 20, the KLH of tail vein injection 300 μ g/kg; At first time injection KLH after the 21st day, the KLH of intravenous injection 300 μ g/kg carries out exciting secondary immune to reply again, is equally divided into 4 groups by by the rat of testing:
While second time injection KLH, respectively per os give deionized water, 7.5,15, the cyclosporine of 30mg/kg 1 time; Gather peripheral blood, separation of serum, adopt ELISA method to detect anti-KLHIgG, leukocyte counts, within after last per os gives the cyclosporine of deionized water and variable concentrations the 10th day, dissect taking internal organ and do histopathological examination.
Experimental result: leukocyte counts display secondary immune 15,30mg/kg cyclosporine group occur that immunological function repression is as shown in table 1;
The cyclosporine of different amounts to the secondary TDAR immunosuppressive effects of anti-KLH as shown in Figure 1, wherein: horizontal ordinate is blood sampling time, ordinate is each time point anti-KLHIgG titre relative to the logarithm of D21 (second time injection KLH and per os give the previous day of cyclosporine, based on level) changing value.
Embodiment 2
Experimental technique: choose growing state good, SD female rats of the same size 15, the KLH of tail vein injection 300 μ g/kg; At first time injection KLH after the 21st day, the KLH of intravenous injection 300 μ g/kg carries out exciting secondary immune to reply again, is equally divided into 3 groups by by the rat of testing:
While second time injection KLH, respectively per os give deionized water, 5, the endoxan of 20mg/kg 1 time; Gather peripheral blood, separation of serum, adopt ELISA method to detect anti-KLHIgG, leukocyte counts, within after last per os gives the endoxan of deionized water and variable concentrations the 10th day, dissect taking internal organ and do histopathological examination.
Experimental result: leukocyte counts display secondary immune 20mg/kg endoxan epidemic disease function inhibitio is as shown in table 1; Can find out, administration after 3 days only 20mg/kg endoxan group leucocyte obviously reduce, all the other respectively group all change and tissue pathologies change without white blood cell count(WBC).
The endoxan of different amounts to the secondary TDAR immunosuppressive effects of anti-KLH as shown in Figure 2, wherein: horizontal ordinate is blood sampling time, ordinate is each time point anti-KLHIgG titre relative to the logarithm of D21 (second time injection KLH and per os give the previous day of endoxan, based on level) changing value.
Table 1 secondary immune response white blood cell count(WBC)
**P＜0.01
Comparative example 1
Experimental technique: choose growing state good, SD female rats of the same size 20 (be divided into four groups, respectively continuous 28 days per os deionized waters, 7.5,15, the cyclosporine of 30mg/kg; The KLH of the 14th day tail vein injection 300 μ g/kg; Blood sampling in 29th day detects anti-KLHIgG, leukocyte counts, dissects taking internal organ and does histopathological examination.
Experimental result: the cyclosporine of different amounts to the elementary TDAR immunosuppressive effects of anti-KLH as shown in Figure 3, wherein: horizontal ordinate is blood sampling time, ordinate is each time point anti-KLHIgG titre relative to the logarithm of D21 (second time injection KLH and give the previous day of cyclosporine, based on level) changing value.
Histopathological examination shows, and per os gives cyclosporine group and occurs organic Pathologic changes after 28 days.As shown in Figure 4, Figure 5, at 50 times of Microscopic observations, compared with normal female sd inbred rats thymus gland, there is the thymus gland of immune response in per os, medullary substance reduces, cortical thickening after giving 30mg/Kg cyclosporine.
Compared with comparative example, embodiment 1-2, immune response time is shorter, time shorten: within 5 days, there is immune response upon administration, and reach peak value at the 8th day; Response degree is stronger: measured secondary immune reply that the 8th day specific antibody amount is about D21 (second time injection KLH and per os give the previous day of cyclosporine or endoxan, based on level) 1 × 10
3.5doubly; Required exogenous compounds consumption is less: cyclosporine conventional method administration 28 days, administration of the present invention 3 days, endoxan conventional method administration 28 days, administration of the present invention 3 days; And the impact investigated immunological memory system.
Claims (11)
1. secondary T cells relies on antibody response and detects the immunosuppressant method of exogenous compounds, comprises the following steps:
(1) animal is injected T cell dependence antigen;
(2) within 15th ~ 25 days after the injection described in step (1), again injecting identical T cell dependence antigen excites secondary immune to reply, and starts continuous 2 ~ 5 days per os simultaneously and gives exogenous compounds;
(3) step (2) complete after 6th ~ 10 days, gather peripheral blood, separation of serum, the specific antibody of the T cell dependence antigen described in detecting step (1).
2. the method for claim 1, is characterized in that, the time of again injecting identical T cell dependence antigen described in step (2) is after the injection described in step (1) the 20th day.
3. the method for claim 1, is characterized in that, the time that the continuous per os described in step (2) gives exogenous compounds is 3 days.
4. the method for claim 1, is characterized in that, time of the collection peripheral blood described in step (3) is after step (2) completes the 8th day.
5. the method for claim 1, is characterized in that, the T cell dependence antigen described in step (1) is keyhole limpet hemocyanin; Specific antibody described in step (3) is anti-keyhole limpet hemocyanin IgG antibody.
6. the method for claim 1, is characterized in that, the consumption of the T cell dependence antigen described in step (1) is 200 ~ 400 μ g/kg.
7. the method for claim 1, is characterized in that, the consumption of the T cell dependence antigen described in step (1) is 300 μ g/kg.
8. the method for claim 1, is characterized in that, the exogenous compounds described in step (2) is cyclosporine or endoxan.
9. method as claimed in claim 8, it is characterized in that, described exogenous compounds is cyclosporine, and the consumption of described exogenous compounds is 7.5 ~ 30mg/Kg.
10. method as claimed in claim 8, it is characterized in that, described exogenous compounds is endoxan, and the consumption of described exogenous compounds is 5 ~ 20mg/Kg.
11. the method for claim 1, is characterized in that, described animal is rat; Described injection is intravenous injection.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1747729A (en) * | 2002-12-09 | 2006-03-15 | 得克萨斯系统大学董事会 | Methods for Selective Inhibition of Janus Tyrosine Kinase 3 (JAK3) |
| WO2011034953A2 (en) * | 2009-09-16 | 2011-03-24 | The Administrators Of The Tulane Educational Fund | Lassa virus-like particles and methods of production thereof |
| WO2013056068A1 (en) * | 2011-10-13 | 2013-04-18 | Bristol-Myers Squibb Company | Antibody polypeptides that antagonize cd40l |
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2014
- 2014-07-10 CN CN201410328523.9A patent/CN104090115B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1747729A (en) * | 2002-12-09 | 2006-03-15 | 得克萨斯系统大学董事会 | Methods for Selective Inhibition of Janus Tyrosine Kinase 3 (JAK3) |
| WO2011034953A2 (en) * | 2009-09-16 | 2011-03-24 | The Administrators Of The Tulane Educational Fund | Lassa virus-like particles and methods of production thereof |
| WO2013056068A1 (en) * | 2011-10-13 | 2013-04-18 | Bristol-Myers Squibb Company | Antibody polypeptides that antagonize cd40l |
Non-Patent Citations (3)
| Title |
|---|
| Development and Validation of a Canine T-Cell-Dependent Antibody Response Model for Immunotoxicity Evaluation;Deborah Finco-Kent等;《Journal of Immunotoxicology》;20051231;197-201 * |
| Development of a Testing Battery to Assess Chemical-Induced Immunotoxicity: National Toxicology Program"s Guidelines for Immunotoxicity Evaluation in Mice;MICHAEL I. LUSTER等;《FUNDAMENTAL AND APPLIED TOXICOLOGY》;19881231;2-19 * |
| Evaluation of primary and secondary responses to a T-cell-dependent antigen, keyhole limpet hemocyanin, in rats;Ryota Kawai;《Journal of Immunotoxicology》;20131231;第10卷(第1期);40-48 * |
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