CN113633642A - Application of ABT-263 in preparation of medicine for inhibiting corneal transplantation immune rejection - Google Patents
Application of ABT-263 in preparation of medicine for inhibiting corneal transplantation immune rejection Download PDFInfo
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- CN113633642A CN113633642A CN202110988440.2A CN202110988440A CN113633642A CN 113633642 A CN113633642 A CN 113633642A CN 202110988440 A CN202110988440 A CN 202110988440A CN 113633642 A CN113633642 A CN 113633642A
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Abstract
The invention provides an application of ABT-263 in preparing a medicine for inhibiting corneal transplantation immune rejection, belonging to the technical field of chemical medicines. The invention provides application of a small molecule Bcl-2 inhibitor Navitoclax (ABT-263) capable of inducing apoptosis in preparation of a product for inhibiting immunological rejection after corneal transplantation. The research shows that the Bcl-2 inhibitor ABT-263 can prolong the survival time of the corneal graft after the corneal transplantation, reduce the immune inflammatory reaction in the corneal graft, maintain the transparency of the corneal graft and reduce the immune rejection reaction, and can be used for preventing and treating the diseases such as the immune rejection reaction after the corneal transplantation, the corneal endothelial cell decompensation and the like.
Description
Technical Field
The invention belongs to the technical field of chemical drugs, and particularly relates to an application of ABT-263 in preparation of a drug for inhibiting corneal transplantation immune rejection.
Background
Keratopathy is one of the eye diseases with extremely high blindness rate, and Penetrating Keratoplasty (PK) is an important means for the patients with corneal blindness to become clear and is the last choice for preserving the vision of the patients. Although the success rate of corneal transplantation has been greatly improved with the improvement of microsurgery, immunological rejection after PK (especially high-risk corneal transplantation) is still the leading cause of corneal transplantation failure. Therefore, the method has important clinical significance and value in preventing and treating the immunological rejection reaction after PK operation and maintaining the transparency of the corneal graft. Normal corneal tissue is in a relatively "immune privileged state" due to the lack of blood and lymphatic vessels, and thus has a low incidence of immune rejection following non-high-risk corneal transplants. However, in many patients, the endothelial cells and stromal cells of corneal implants are also gradually changed in pathological ways such as edema, turbidity and loss of function without significant immunological rejection reactions characterized by corneal neovascularization and lymphatic vessels after PK operation. At present, the function of the corneal graft after corneal transplantation is lost, and one of important reasons for immunological rejection reaction is caused.
Cellular senescence is characterized by irreversible decline in cellular function and structure. In the corneal transplantation operation, the corneal parenchymal cells (especially corneal endothelial cells) show aging cell characteristics after being stimulated by inflammatory cells, corneal sutures, surgical wounds and the like. Research shows that the premature senility and ageing of key cells in tissue and organ are closely related to the function decline of the tissue and organ, and the cell ageing plays an important role in the pathophysiological processes of immunological rejection, chronic dysfunction and the like of parenchymal organ transplant. Once rejection occurs, the immune privileged state of the cornea is deviated and, stimulated by both internal and external factors, the corneal endothelial cells undergo a rapid loss of hyper-physiology, producing some degenerative changes prematurely and excessively. When the number of corneal endothelial cells is below a certain critical value, the residual cells cannot fully compensate for normal tissue function, which may lead to corneal edema and bullous keratopathy.
After the corneal transplantation, whether the corneal endothelial cells can be effectively prevented from being decompensated in time by inhibiting the aging and the function decline of the corneal parenchymal cells (especially the corneal endothelial cells) is the key for preventing the corneal immune rejection and maintaining good vision. At present, no medicine report about effectively inhibiting the aging and hypofunction of the corneal parenchymal cells and effectively preventing the decompensation of the corneal endothelial cells in time exists.
Disclosure of Invention
In view of the above, the present invention aims to provide an application of ABT-263 in preparing a medicament for suppressing immune rejection reaction of corneal transplantation.
The invention provides an application of ABT-263 in preparing a medicine for inhibiting corneal transplantation immune rejection.
Preferably, the structural formula of ABT-263 is shown in formula I:
preferably, the corneal transplant comprises an allogeneic corneal transplant.
Preferably, the inhibition of corneal graft immune rejection comprises prolonging the survival time of a donor corneal graft and reducing inflammatory response in the corneal graft.
Preferably, the prolonging of the survival time of the donor corneal graft is to eliminate senescent cells through ABT-263, delay immune rejection reaction of corneal transplantation and maintain the transparency of the corneal graft.
Preferably, the reduction of the inflammatory response in the corneal graft is a reduction in the expression level of an inflammation-associated cytokine in the corneal graft.
Preferably, the inflammation-associated cytokines include IL-1 β, IL-17A, TNF- α, and IFN- γ.
Preferably, the medicament comprises an injection.
Preferably, the concentration of ABT-263 in the injection is 1-10 mg/ml.
Preferably, the concentration of the ABT-263 is 1-5 mg/ml.
The invention provides an application of ABT-263 in preparing a medicine for inhibiting corneal transplantation immune rejection. Experiments prove that after the allogeneic mouse corneal transplantation, the corneal stroma and the endothelium have obvious aging phenotype: the number of SA-beta-Gal staining positive cells is obviously increased; the expression level of senescence-associated genes (p16, p21, etc.) is obviously increased; the age-related gene p16 deletion can effectively prolong the survival time of corneal transplants and delay the immunological rejection reaction of corneal transplantation by constructing an allogeneic mouse corneal transplantation model by using an age gene p16 deletion mouse as a corneal donor. The invention can obviously inhibit the immune rejection reaction of corneal transplantation, prolong the survival time of donor corneal graft, reduce the inflammatory reaction in the corneal graft and maintain the transparency of the corneal graft by injecting the anti-aging drug ABT-263 (such as 1.25mg/ml) into the abdominal cavity. Therefore, ABT-263 can be used for preventing and treating immune rejection after corneal transplantation operation.
Drawings
FIG. 1 is a phenotypic analysis of corneal senescence after normal mice (Nor), syngeneic corneal transplantation (Syn) and allogeneic corneal transplantation (Allo), wherein (A) analysis of SA- β -Gal staining of corneal slices of different groups of mice; (B) analyzing SA-beta-Gal staining in the corneal implant using frozen sections; (C) western Blot analysis of the expression of senescence-associated genes (p16 and p21) in corneal transplants.
FIG. 2 is a graph showing the effect of aging gene p16 knock-out mice as corneal donors on immunological rejection after PK operation, wherein (A) observation of corneal transparency of mice after corneal transplantation; (B) analyzing the survival curves of the corneal transplants of different groups of mice; (C) immunofluorescence analysis of CD45 in corneal grafts of mice of different groups+Infiltration of cells.
FIG. 3 is a graph of the effect of anti-aging drug ABT-263 on PK postoperative corneal graft immune rejection, wherein (A) the corneal transparency of mice was analyzed after intervention with anti-aging drug ABT-263; (B) analyzing the survival curve of the mouse cornea implant after the intervention of ABT-263; (C) analyzing the effect of ABT-263 on eliminating senescent cells by SA-beta-Gal staining; (D) real-time PCR analysis of the influence of ABT-263 intervention on the expression of senescence-associated genes in corneal transplants; (E) real-time PCR analysis the effect of ABT-263 intervention on the expression of major inflammatory factors in corneal transplants.
Detailed Description
The invention provides an application of ABT-263 in preparing a medicine for inhibiting corneal transplantation immune rejection.
In the present invention, the structural formula of ABT-263 is preferably as shown in formula I:
the molecular formula of the ABT-263 is C47H55ClF3N5O6S3, the molecular weight is 974.6127096, and the CAS number is 923564-51-6. The source of ABT-263 is not particularly limited in the present invention, and any ABT-263 known in the art may be used. In the present example, the ABT-263 is available from Selleck corporation.
In the present invention, the corneal transplantation preferably comprises an allogeneic corneal transplantation. After the allogeneic mouse corneal transplantation, the obvious senescence phenotype appears in the corneal stroma and the endothelium, wherein the number of SA-beta-Gal staining positive cells is obviously increased; the expression level of senescence-associated genes (p16, p21, etc.) is significantly increased. When ABT-263 is injected, compared with a model control group, the immune rejection reaction of corneal transplantation is obviously inhibited, and the transparency of the corneal graft is maintained. Preferably, the inhibition of immune rejection in corneal transplantation comprises prolonging the survival time of a donor corneal graft and reducing inflammatory response in the corneal graft. The prolonging of the survival time of the donor cornea implant is preferably to eliminate the senescent cells in the allogeneic cornea through ABT-263, delay the immune rejection reaction of the cornea transplantation and maintain the transparency of the cornea implant. The allogeneic cornea preferably includes corneal stroma and endothelial cells. The reduction of the inflammatory response in the corneal graft is preferably a reduction in the expression level of an inflammation-associated cytokine in the corneal graft. The inflammation-associated cytokines preferably include IL-1 β, IL-17A, TNF- α, and IFN- γ.
In the present invention, the medicament preferably comprises an injection. The injection preferably comprises ABT-263 and auxiliary materials acceptable in the medical field. The dressing comprises 2-hydroxypropyl-beta-cyclodextrin and corn oil. The concentration of ABT-263 in the injection is preferably 1-10 mg/ml, more preferably 1-5 mg/ml, and most preferably 1.25 mg/ml. The injection amount of the ABT-263 is 50mg/kg body weight of the mouse. The frequency of ABT-263 injection is preferably 1 time/2 d.
The application of ABT-263 provided by the present invention in the preparation of a medicament for suppressing immune rejection in corneal transplantation will be described in detail with reference to the following examples, but they should not be construed as limiting the scope of the present invention.
Example 1
Immunological rejection experiment after allogeneic cornea transplantation
1. 18 BALB/c mice (6-8 weeks old) were randomly divided into the following 3 groups:
A. normal group (Nor);
B. syngeneic corneal transplantation group (Syn-transplantation, Syn);
C. allogeneic corneal transplantation (donor of C57BL/6 mice of the same week old) group (Allo-transplantation, Allo).
The penetrating corneal transplantation model was constructed as follows: all animals select the right eye as an operation eye, perform slit lamp examination before the operation, know the condition of the operation eye, and give the operation eye drop levofloxacin for preventing infection. After donor mice are anesthetized by injecting sodium pentobarbital into abdominal cavities, the donor mice are disinfected and paved by a conventional method, a central full-layer graft of a cornea with the thickness of 2.25mm is taken under an operation microscope, a central penetrating graft bed of the cornea of the receptor mice with the thickness of 2.25mm is immediately implanted, 8 needles are intermittently sutured by using 11-0 Japanese MANI nylon thread, a small amount of sterile air is injected into an anterior chamber after the operation to form the anterior chamber, and ofloxacin eye ointment is applied to local 2d after the operation and is applied by the conventional method 1 time a day. And (4) observing the mice by using a slit lamp every day after the operation for 30d, and removing the mice with other eye complications such as anterior iris adhesion, cataract or iris obstruction and the like after the operation. The time at which each group of rejection occurred was recorded and no observation was made after rejection occurred.
2. At 10d, the mice were sacrificed, the 3 groups of mice were individually harvested for eye balls, corneal cups were carefully excised along the corneal limbus, in situ histochemical staining was performed using a senescence-associated β -galactosidase (SA- β -Gal) kit (petit sky), incubated overnight at 37 ℃, stained corneal endothelium was applied with the corneal endothelium facing upward, and staining was observed by microscope.
The results show that: corneal endothelial cells were clearly positive for β -Gal staining in the Allo group compared to the Nor and Syn groups and were predominantly distributed in the center of the corneal graft and at the intersection of the corneal graft and the graft bed (a in fig. 1).
After 3 groups of the stained corneal implants were OCT embedded, frozen sections were taken, the thickness of the sections was 7 μm, and then the staining of each group of corneal tissues by β -Gal was observed under a phase contrast microscope.
In the Allo group, there were a large number of cells staining positive for β -Gal in the corneal stroma layer compared to the Nor and Syn groups (B in FIG. 1).
The above results indicate that the stromal and endothelial layers of corneal implants are of the senescent phenotype during immune rejection in corneal transplantation.
3. At 10d, the mice are sacrificed, the 3 groups of mouse eyeballs are taken, 3 samples of each group are taken, each group of mouse cornea implant is cut, RIPA lysate and PMSF protease inhibitor are added according to the Western Blotting specification proportion, each group of sample protein is extracted after grinding and ultrasonic treatment, after SDS-PAGE electrophoresis is carried out, the protein is electrically transferred to a PVDF membrane from gel, strips are cut, rabbit anti-mouse p16 antibody (1: 1000 dilution), rabbit anti-mouse p21 antibody (1: 1000 dilution) and mouse anti-mouse beta-actin antibody (1: 2000 dilution) are respectively added, after incubation and membrane washing, goat anti-rabbit IgG-HRP and goat anti-mouse IgG-HRP secondary antibody are respectively added, after incubation and membrane washing, a Bio-Rad fast luminescence camera is adopted, and ECL luminescence kit is used for luminescence.
The results show that: under the condition that beta-actin is used as a standard internal reference, the protein expression levels of p16 and p21 in corneal transplants of the Allo group are obviously increased compared with those of the Nor group and the Syn group (C in FIG. 1). Since both p16 and p21 belong to cyclin-dependent kinase inhibitors (CDKI), they are key markers of cellular senescence. Their high expression suggests a significant senescence phenotype for corneal transplants.
It can be seen that the allogeneic corneal graft showed an obvious aging phenotype after corneal transplantation.
Example 2
The deletion of the senescence gene p16 from the corneal donor significantly prolonged the survival time of corneal transplants.
The cellular senescence process is mainly realized through two signal pathways of p16INK4a/Rb and p19ARF/p53/p21 Cipl. In order to determine the key role of aging in corneal transplantation immune rejection, the invention constructs a penetrating corneal transplantation model by taking a p 16-deleted C57BL/6(Frederick National Laboratory for Cancer Research (FNL)/SAIC-Frederick, Inc) mouse as a corneal donor and a Balb/C mouse as a corneal receptor, and evaluates the influence of aging on corneal transplantation immune rejection.
1. 12 BALB/c mice (6-8 weeks old) were randomly divided into the following 2 groups:
A. using wild type C57B/L6WTAllogeneic corneal transplant group (WT) which is a donor;
B. p16 knockout mouse C57B/L6p16KOAllogeneic corneal transplant group as a graft donor (p16 KO).
A model of penetrating corneal transplantation was established and the procedure was as described in example 1.
And (4) observing by using a slit lamp every day after the operation, recording the time when each group of rejection occurs and drawing a rejection survival curve of the corneal implant.
The research finds that: the significant prolongation of survival of corneal grafts in group p16KO (A and B in FIG. 2) compared to the WT group was preliminary evidence that corneal graft senescence significantly promoted immune rejection following corneal transplantation.
2. At 30d, the mice were sacrificed, the eyeballs of the 2 groups of mice were removed, and after OCT embedding, cryo-sections were taken with a slice thickness of 7 μm, and then immunofluorescent staining was performed using an anti-CD 45 antibody, and the staining results were observed by photographing under an immunofluorescent microscope.
The results show that: CD45 in p16KO corneal transplants compared to WT corneal transplant group+Infiltration of immune cells was significantly reduced (C in fig. 2). These results further indicate that p16 gene knockout can effectively delay corneal transplantation immune rejection.
Example 3
The anti-aging drug ABT-263 intervenes and treats to obviously inhibit the immune rejection reaction of corneal transplantation
1. 12 BALB/c mice (6-8 weeks old) were randomly divided into the following 2 groups:
A. allogeneic corneal transplant group (Allo);
B. the allogenic cornea transplantation and ABT-263 injection group (Allo + ABT-263).
A penetrating corneal transplant model was constructed as described in example 1.
Postoperative 3d, different drug injections were applied according to the groups: group A PBS solution and group B ABT-263(50mg/kg, 1 time/2 d) were injected intraperitoneally 5 times on days 2, 4, 6, 8, and 10 after surgery, respectively. On the basis, the postoperative slit lamp observation is carried out every day, the time of each group of rejection reaction is recorded, and the survival curve of the corneal implant is drawn.
Through statistical discovery: the rejection time of corneal implants was significantly longer in the ABT-263 injected group (Allo + ABT-263) compared to the Allo group (A and B in FIG. 3), suggesting that anti-aging agent ABT-263 may be effective in prolonging corneal implant survival time.
2. At 30d, the mice were sacrificed, the eyeballs of the 2 groups of mice were removed, corneal cups were carefully cut along the corneal scleral rim, in situ histochemical staining was performed using an aging-related SA- β -Gal kit (bi yun day), incubation was performed overnight at 37 ℃, corneal endothelium was stained upward and corneal slides were observed under a microscope.
The results are shown in FIGS. 3A and B. The results show that: compared with the Allo group, the beta-Gal staining of the corneal graft endothelial layer in the ABT-263 injection group is obviously reduced after the intervention treatment of ABT-263. By cryosectioning in combination with phase contrast microscopy, results show: following ABT-263 intervention, the number of SA- β -Gal staining positive cells in the corneal stroma was significantly lower than in the Allo group.
The above results indicate that ABT-263 is effective in eliminating senescent cells from corneal transplants.
3. At 30d, the mice were sacrificed, the eyeballs of the normal control group (Nor), the unused drug group (Allo) and the drug intervention group (Allo + ABT-263) were removed,each group of 3 samples is cut to obtain each group of mouse cornea implant, total mRNA of each group of cornea tissue is respectively extracted by Trizol method, mRNA is reversely transcribed into cDNA by reverse transcription kit, H is reversely transcribed2O, SYBRPrimix Ex Taq II and primers are mixed uniformly according to a proportion, each group of cDNA is added, and the expression conditions of aging-related genes (p16, p21) and inflammation-related factors (IL-1 beta, IL-17A, TNF-alpha and IFN-gamma) in each group of corneal graft are detected by fluorescence quantitative PCR (detailed in attached tables 1-3).
TABLE 1 mouse RT-qPCR primer nucleotide sequences
TABLE 2PCR reaction System Table
TABLE 3PCR reaction procedure
Results Ct value (Threshold cycle) is defined as the number of cycles required to reach a detection Threshold that exceeds the fluorescence signal, and the data of the results are analyzed using ROTOR-GeneTMQ Series Software (v1.2.0.) from QIAGEN, Inc., at 2-ΔΔCtThe method of (3) is calculated with GAPDH as an internal reference.
Statistical analysis
Statistical analysis was performed using GraphPad Prism 8.0 software, data expressed as mean ± standard deviation, and multiple comparisons were analyzed using One-way variance (One-WayAnova), with significant differences of P <0.05, P <0.01, and P < 0.001.
The expression levels of senescence-associated genes (p16 and p21) in corneal transplants were significantly reduced following ABT-263 intervention compared to Nor and Allo groups, suggesting that ABT-263 intervention may significantly eliminate senescent cells. It was further found that the expression level of inflammation-related cytokines in corneal transplants was significantly lower on average than in the Allo group after ABT-263 intervention treatment, and the differences were statistically significant.
The above results indicate that the elimination of senescent cells can effectively delay the immune rejection reaction of corneal transplantation.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Sequence listing
<110> Shandong first medical university affiliated Qingdao ophthalmological Hospital (Shandong province institute of ophthalmology, Qingdao ophthalmological Hospital)
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Claims (10)
- Application of ABT-263 in preparing medicine for inhibiting cornea transplantation immunological rejection.
- 2. The use of claim 1, wherein the ABT-263 has a structural formula shown in formula I:
- 3. the use of claim 1, wherein the corneal transplant comprises an allogeneic corneal transplant.
- 4. The use of claim 1 or 3, wherein the inhibition of immune rejection in corneal transplantation comprises prolonging survival of a donor corneal graft and reducing inflammatory response in the corneal graft.
- 5. The use of claim 4, wherein the prolonging of the survival time of the donor corneal graft is by eliminating senescent cells via ABT-263, delaying corneal graft immune rejection, and maintaining the transparency of the corneal graft.
- 6. The use of claim 4, wherein the reduction of the inflammatory response in the corneal graft is a reduction in the expression level of an inflammation-associated cytokine in the corneal graft.
- 7. The use of claim 6, wherein the inflammation-associated cytokines comprise IL-1 β, IL-17A, TNF-a, and IFN- γ.
- 8. The use of any one of claims 1 to 3 and 5 to 7, wherein the medicament comprises an injection.
- 9. The use of claim 8, wherein the concentration of ABT-263 in the injection is 1-10 mg/ml.
- 10. The use of claim 9, wherein the concentration of ABT-263 is 1-5 mg/ml.
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| PCT/CN2022/099063 WO2023024664A1 (en) | 2021-08-26 | 2022-06-16 | Application of abt-263 in preparation of drug for inhibiting corneal transplant immune rejection |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023024664A1 (en) * | 2021-08-26 | 2023-03-02 | 山东第一医科大学附属眼科研究所(山东省眼科研究所、山东第一医科大学附属青岛眼科医院) | Application of abt-263 in preparation of drug for inhibiting corneal transplant immune rejection |
| CN116492462A (en) * | 2023-02-03 | 2023-07-28 | 山东第一医科大学附属眼科医院(山东省眼科医院) | Application of PAD4 inhibitor in preventing and treating immune rejection after cornea transplantation |
| WO2024011817A1 (en) * | 2022-11-28 | 2024-01-18 | 山东第一医科大学附属眼科研究所(山东省眼科研究所、山东第一医科大学附属青岛眼科医院) | Use of c-rel-specific ribonucleic acid in inhibiting corneal transplantation rejection |
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| CN101798292A (en) * | 2010-03-29 | 2010-08-11 | 无锡好芳德药业有限公司 | Method for preparing novel Bc1-2 protein inhibitor derived from ABT-263 |
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| JP2009542666A (en) * | 2006-06-30 | 2009-12-03 | シェーリング コーポレイション | Substituted piperidines that increase P53 activity and uses thereof |
| WO2008064116A2 (en) * | 2006-11-16 | 2008-05-29 | Abbott Laboratories | Method of preventing or treating organ, hematopoietic stem cell or bone marrow transplant rejection |
| CA2909380A1 (en) * | 2013-04-21 | 2014-10-30 | Yeda Research And Development Co. Ltd. | Agents for downregulation of the activity and/or amount of bcl-xl and/or bcl-w |
| BR112017020780A2 (en) * | 2015-03-30 | 2018-06-26 | Calithera Biosciences Inc | Glutaminase inhibitor administration methods |
| JP7279890B2 (en) * | 2019-01-15 | 2023-05-23 | 慶應義塾 | Graft-versus-host disease therapeutic or prophylactic agent |
| WO2020214993A1 (en) * | 2019-04-19 | 2020-10-22 | Buck Institute For Research On Aging | 25-hydroxycholesterol (25hc), cryab aggregation inhibitor, is a novel senolytic |
| CN113633642A (en) * | 2021-08-26 | 2021-11-12 | 山东第一医科大学附属青岛眼科医院(山东省眼科研究所、青岛眼科医院) | Application of ABT-263 in preparation of medicine for inhibiting corneal transplantation immune rejection |
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| WO2023024664A1 (en) * | 2021-08-26 | 2023-03-02 | 山东第一医科大学附属眼科研究所(山东省眼科研究所、山东第一医科大学附属青岛眼科医院) | Application of abt-263 in preparation of drug for inhibiting corneal transplant immune rejection |
| WO2024011817A1 (en) * | 2022-11-28 | 2024-01-18 | 山东第一医科大学附属眼科研究所(山东省眼科研究所、山东第一医科大学附属青岛眼科医院) | Use of c-rel-specific ribonucleic acid in inhibiting corneal transplantation rejection |
| CN116492462A (en) * | 2023-02-03 | 2023-07-28 | 山东第一医科大学附属眼科医院(山东省眼科医院) | Application of PAD4 inhibitor in preventing and treating immune rejection after cornea transplantation |
| CN116492462B (en) * | 2023-02-03 | 2023-09-22 | 山东第一医科大学附属眼科医院(山东省眼科医院) | Application of PAD4 inhibitor in preventing and treating immune rejection after cornea transplantation |
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