CN106890187A - Triptolide and its trim are suppressing the application during B cell produces antibody - Google Patents
Triptolide and its trim are suppressing the application during B cell produces antibody Download PDFInfo
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- CN106890187A CN106890187A CN201710095165.5A CN201710095165A CN106890187A CN 106890187 A CN106890187 A CN 106890187A CN 201710095165 A CN201710095165 A CN 201710095165A CN 106890187 A CN106890187 A CN 106890187A
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- triptolide
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
- A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
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Abstract
Suppressing the application during B cell produces antibody the invention discloses triptolide and its trim, present inventor processes the mouse of different lines dermatoplasty sensitization using triptolide, it was found that it can suppress the generation of circulating antibody DSA, and further using experiment in vitro confirm that triptolide can suppress B cell and produce antibody.Present invention is disclosed a kind of new application of triptolide, it was confirmed that triptolide and its trim can suppress B cell and produce antibody, the medicine that B cell generation antibody can be suppressed to prepare provides foundation.
Description
Technical field
The present invention relates to the purposes of triptolide and its trim in immunosuppressive action, more particularly to thunder godvine first
Element and its trim are suppressing the application during B cell produces antibody, belong to medical domain.
Background technology
Post-transplantation rejection is the main cause for influenceing graft survival time, and rejection is divided into cell-mediated row
Reprimand reaction and antibody-mediated rejection (AMR), compared with the cellularity rejection of T cell mediation, the transplanting that B cell is participated in
Postoperative acute or chronic AMR therapeutic effects are poor, patient's prognosis is not good, belongs to refractory rejection, therefore, how to suppress B thin
Born of the same parents produce antibody, are always the problem of trnasplantion immunity field urgent need to resolve.Organ transplant (kidney transplant, dermatoplasty, lung transplantation
Deng) the acute AMR that occurs afterwards is main caused by circulating antibody (DSA), therapeutic effect is poor, and prognosis is not good, belongs to intractable acute
Rejection.
Triptolide is the monomer extracted from Chinese herb triperygium wilfordii, has now been found that it has four big functions：It is antitumor, anti-
Reproduction, anti-inflammatory and immunosupress, its immunosuppressive action early has been reported that, has been applied to the Chinese patent drug of clinic：Rheumatism can be treated, closed
Section inflammation, skin disease, immune-related ephritis etc., but influence of the triptolide in terms of antibody is produced to B cell does not appear in the newspapers
Road.
The content of the invention
There is provided it is an object of the invention to the weak point for overcoming above-mentioned prior art to exist a kind of triptolide and
Its trim is suppressing the application during B cell produces antibody, and it is anti-that the triptolide and its trim can suppress B cell generation
Body, the medicine that B cell generation antibody is suppressed to prepare provides foundation.
To achieve the above object, the technical scheme taken of the present invention is：Triptolide and its trim are suppressing B cell
Produce the application in antibody.
Used as the further improvement to above-mentioned technical proposal, the antibody is the antibody that B cell is produced.
Used as the further improvement to above-mentioned technical proposal, the triptolide trim is citric acid dimethylamine acetyl
Triptolide ester.Citric acid dimethylamine acetyl triptolide ester is metabolizable in Mice Body to be made for triptolide is played
With.
Used as the further improvement to above-mentioned technical proposal, the citric acid dimethylamine acetyl triptolide ester suppresses B
It is hypodermic injection that cell produces the application method of antibody.
Dosage is used to enter to acceptor Balb/c mouse for the citric acid dimethylamine acetyl triptolide ester of 1mg/kg body weight
Row hypodermic injection, it is found that the circulating antibody level in the mouse of injection citric acid dimethylamine acetyl triptolide ester is significantly lower than
Circulating antibody level in the mouse of injecting normal saline, shows that citric acid dimethylamine acetyl triptolide ester can suppress B thin
Born of the same parents produce antibody.
Used as the further improvement to above-mentioned technical proposal, the triptolide suppresses the use that B cell produces antibody
Concentration is 0.04ng/ml-4 μ g/ml.The concentration of triptolide does not influence B cell activity in 0.04ng/ml-4 μ g/ml,
Can be used to explore influence of the triptolide to B cell apoptosis.
Used as the further improvement to above-mentioned technical proposal, the triptolide suppresses the use that B cell produces antibody
Concentration is 4ng/ml.When concentration is 4ng/ml, the apoptosis on B cell does not influence triptolide, and can be further used for
Triptolide is inquired into B cell differentiation and the research of function.
On the other hand, the present invention discloses a kind of triptolide and its trim anti-for preparing suppression B cell generation
Application in the medicine of body.
On the other hand, the present invention discloses a kind of medicine for suppressing B cell generation antibody, and the medicine includes thunder godvine
A prime or its trim.The medicine can suppress B cell and produce antibody, can be used for clinically antibody-mediated acute and chronic and repel anti-
The treatment answered and the treatment of the related autoimmune disease of antibody.
Used as the further improvement to above-mentioned technical proposal, the medicine also includes pharmaceutically acceptable carrier.
Relative to prior art, beneficial effects of the present invention are：
Experimental result of the present invention confirms that in the mouse of different lines dermatoplasty sensitization triptolide can suppress first
The generation of circulating antibody DSA, and further experiment in vitro confirms that triptolide can suppress B cell and produce antibody.As can be seen here,
Triptolide and its trim can suppress B cell and produce antibody, and the medicine that B cell generation antibody can be suppressed to prepare is provided
Foundation.
Brief description of the drawings
Fig. 1 be inject citric acid dimethylamine acetyl triptolide ester and physiological saline mouse it is different after dermatoplasty
The titre change curve of bad DSA is followed in time, wherein average fluorescent strength situation of change of the figure (A) for IgG, figure (B) is IgM
Average fluorescent strength situation of change；
Fig. 2 is sub- using the triptolide (TPL) and control treatment group dimethyl of Flow cytometry various concentrations
The Apoptosis figure of the peripheral blood CD19+ cells of sulfone (DMSO) treatment purifying；
Fig. 3 is using the triptolide (TPL) and control group dimethyl sulfoxide (DMSO) of Flow cytometry 4ng/ml concentration
(DMSO) the ration statisticses figure of peripheral blood CD19+ cells CD138+CD27++ thick liquid cells after 8 days for the treatment of purifying；
Fig. 4 is to be counted using the cylindricality of the production of enzyme-linked immunosorbent assay (ELISA) detection immunoglobulin
Figure；
Fig. 5 is detection triptolide (TPL) on the cylindricality statistics of the immunoglobulin hypervariable region multifarious influences of VH3
Figure；
Fig. 6 is the histogram of the expression quantity using RT-PCR experiment detection variety classes immunoglobulins.
Specific embodiment
For the object, technical solutions and advantages of the present invention are better described, below in conjunction with specific embodiment and accompanying drawing pair
The present invention is described further.
The experiment in vivo of embodiment 1
Experimental technique：Experiment is divided into 2 groups, experimental group and control group, all row C3h → Balb/c dermatoplastys (H2k →
H2d), every group 6.Experimental group can injection citric acid dimethylamine acetyl triptolide using the triptolide after modification
Ester (article No. MC002), its in Mice Body intracellular metabolite for triptolide plays a role, to acceptor Balb/c mouse subcutaneous injections,
Dosage is 1mg/Kg, and the frequency is for once every other day；Control group is injection normal saline, the identical frequency.Two groups of mouse are in skin
Leave and take within 2,4,6,8,12,16,24,28 days after transplanting blood specimen, DSA intensity and compare between carrying out group in detection sample, as a result such as
Shown in Fig. 1.
Wherein DSA detection methods are：The complete spleen of donor is taken, spleen cell is obtained after grinding filtering, it is resuspended in HBSS
It is 10 to cell concentration6, 30min is incubated altogether in ice face with the standby serum of 100ul acceptors, carry out fluorescence mark after washing re-suspended cell
Note dyeing；Flow cytometer analysis of fluorescence intensity after cell, it is determined that circulation DSA titre changes.
Experimental result：As shown in Figure 1, experimental group DSA levels are significantly lower than control group, and specific significant difference is provable
Triptolide can suppress the generation of DSA after mouse skin transplanting sensitization, caused by AMR is mainly due to DSA, so Thunder God
Rattan A prime is possible to have preventive and therapeutic effect to AMR.
The experiment in vitro of embodiment 2
Present invention applicant considers the effect of current triptolide to B cell, there is no the external experimental study can at present
For reference, therefore in pre-experiment stage concentration exploration has been carried out, with reference to the concentration that triptolide is used in other cells, and
Under not influenceing premised on B cell activity, the triptolide of 0.04ng/ml-4 μ g/ml intervals concentration is explored to B cell apoptosis
Influence, using the triptolide (TPL) and control treatment group dimethyl sulfoxide (DMSO) of various concentrations (0.04ng/ml-4 μ g/ml)
(DMSO) the peripheral blood CD19 for the treatment of purifying+Cell, i.e. B cell 8 days, and using Flow cytometry PI+(propidium iodide)
Concentration, for detecting Apoptosis number.Result as shown in Fig. 2 when triptolide concentration be 4ng/ml when, to B cell
Apoptosis does not influence, and can be further used for inquiring into triptolide to B cell differentiation and the research of function, i.e. triptolide
(TPL) the most suitable concentration of extracorporeal treatment B cell is 4ng/ml.
Using the triptolide (TPL) and control group dimethyl sulfoxide (DMSO) (DMSO) of Flow cytometry 4ng/ml concentration
Process the peripheral blood CD19 of purifying+After cell 8 days, CD27 is obtained++CD138+The ratio of thick liquid cell.Result is as shown in figure 3, Thunder God
Rattan A prime treatment group CD27++CD138+The ratio of thick liquid cell is substantially less than control group, and difference is statistically significant, points out thunder godvine
A prime can substantially suppress B cell and be converted into CD27++CD138+Thick liquid cell.
Using the periphery of triptolide (TPL) and control group dimethyl sulfoxide (DMSO) (DMSO) the treatment purifying of 4ng/ml concentration
Blood CD19+Cell 8 days, the production of immunoglobulin is detected using enzyme-linked immunosorbent assay (ELISA), to observe thunder
The influence that public rattan A prime (TPL) produces to B cell antibody.Result is as shown in figure 4, triptolide treatment group antibody titer water
It is flat, control group is substantially less than including IgM, IgA and IgG etc., difference has statistical significance, points out triptolide substantially to press down
B cell processed produces antibody.
Using the periphery of triptolide (TPL) and control group dimethyl sulfoxide (DMSO) (DMSO) the treatment purifying of 4ng/ml concentration
Blood CD19+Cell 8 days, in the culture dish containing 100 μ l culture mediums, collection culture density is 2x105The supernatant of B cell is used
In detection triptolide (TPL) on the multifarious influences of VH3 of immunoglobulin hypervariable region.Result is as shown in figure 5, thunder godvine first
Plain treatment group immunoglobulin hypervariable region VH3 diversity indices is substantially less than control group, and difference is statistically significant, points out Thunder God
Rattan A prime can substantially suppress immunoglobulin hypervariable region VH3 diversity.
Using the periphery of triptolide (TPL) and control group dimethyl sulfoxide (DMSO) (DMSO) the treatment purifying of 4ng/ml concentration
Blood CD19+Cell 8 days, in the culture dish containing 100 μ l culture mediums, collection culture density is 2x105The supernatant of B cell, profit
The expression quantity of detection variety classes immunoglobulin is tested with RT-PCR.Result is as shown in fig. 6, triptolide treatment group is compared
In control group, the antibody level of different subtype, including IgM, IgA1, IgA2, IgG1, IgG2, IgG4 and IgG4 can be significantly reduced
Deng, difference is statistically significant, point out triptolide can significantly inhibit B cell produce antibody.
The above results are confirmed：Triptolide can substantially suppress B cell and produce antibody in vitro.
It is last to should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention rather than the present invention is protected
The limitation of scope is protected, although being explained in detail to the present invention with reference to preferred embodiment, one of ordinary skill in the art should
Understand, technical scheme can be modified or equivalent, without deviating from the essence of technical solution of the present invention
And scope.
Claims (9)
1. triptolide and its trim are suppressing the application during B cell produces antibody.
2. application according to claim 1, it is characterised in that：The antibody is the antibody that B cell is produced.
3. application according to claim 1, it is characterised in that：The triptolide trim is citric acid decil
Acyl triptolide ester.
4. application according to claim 3, it is characterised in that：The citric acid dimethylamine acetyl triptolide ester suppresses
It is hypodermic injection that B cell produces the application method of antibody.
5. application according to claim 1, it is characterised in that：The concentration of the triptolide is 0.04ng/ml-
4μg/ml。
6. apply according to claim 1 or 5, it is characterised in that：The concentration of the triptolide is 4ng/ml.
7. triptolide and its trim are for preparing the application suppressed during B cell produces the medicine of antibody.
8. it is a kind of for suppress B cell produce antibody medicine, it is characterised in that：Including triptolide or its trim.
9. medicine according to claim 8, it is characterised in that：The medicine also includes pharmaceutically acceptable carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710095165.5A CN106890187A (en) | 2017-02-22 | 2017-02-22 | Triptolide and its trim are suppressing the application during B cell produces antibody |
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|---|---|---|---|
| CN201710095165.5A CN106890187A (en) | 2017-02-22 | 2017-02-22 | Triptolide and its trim are suppressing the application during B cell produces antibody |
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| CN106890187A true CN106890187A (en) | 2017-06-27 |
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| CN201710095165.5A Pending CN106890187A (en) | 2017-02-22 | 2017-02-22 | Triptolide and its trim are suppressing the application during B cell produces antibody |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117159740A (en) * | 2023-08-28 | 2023-12-05 | 中国医学科学院皮肤病医院(中国医学科学院皮肤病研究所) | Tripterine antibody drug conjugate and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1179306A (en) * | 1996-10-15 | 1998-04-22 | 中国人民解放军南京军区南京总医院 | Medicine containing tripdiolide for preventing and treating graft acute rejection |
| CN1246121A (en) * | 1996-03-01 | 2000-03-01 | 法玛吉尼西斯公司 | Immunosuppressive compounds and methods |
-
2017
- 2017-02-22 CN CN201710095165.5A patent/CN106890187A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1246121A (en) * | 1996-03-01 | 2000-03-01 | 法玛吉尼西斯公司 | Immunosuppressive compounds and methods |
| CN1179306A (en) * | 1996-10-15 | 1998-04-22 | 中国人民解放军南京军区南京总医院 | Medicine containing tripdiolide for preventing and treating graft acute rejection |
Non-Patent Citations (2)
| Title |
|---|
| 孟楣，姜辉主编: ""雷公藤"", 《风湿病中药研究开发》 * |
| 孟楣，姜辉主编: "《风湿病中药研究开发》", 31 March 2014, 安徽科学技术出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117159740A (en) * | 2023-08-28 | 2023-12-05 | 中国医学科学院皮肤病医院(中国医学科学院皮肤病研究所) | Tripterine antibody drug conjugate and preparation method and application thereof |
| CN117159740B (en) * | 2023-08-28 | 2024-02-23 | 中国医学科学院皮肤病医院(中国医学科学院皮肤病研究所) | Tripterine antibody drug conjugate and preparation method and application thereof |
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| Date | Code | Title | Description |
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| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20170627 |
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| RJ01 | Rejection of invention patent application after publication |