CN106474458A - Application in treatment C. difficile infection for the interleukin-22 7 - Google Patents
Application in treatment C. difficile infection for the interleukin-22 7 Download PDFInfo
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- CN106474458A CN106474458A CN201710007655.5A CN201710007655A CN106474458A CN 106474458 A CN106474458 A CN 106474458A CN 201710007655 A CN201710007655 A CN 201710007655A CN 106474458 A CN106474458 A CN 106474458A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
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Abstract
The present invention provides application in treatment C. difficile infection for the interleukin-22 7.The present invention finds IL 27 through interior animal experiment（Interleukin-22 7）There is to CDI preferable therapeutical effect, be a kind of medicine with broad prospect of application, provide another kind of feasible selection for preferably curing CDI, improve the quality of life of patient.
Description
Technical field
The present invention relates to the application in treatment C. difficile infection of pharmaceutical technology field, more particularly to interleukin-27.
Background technology
Clostridium difficile (Clostridium difficile, Cd) is Grain-positive anaerobic spore-bearing bacilli, is in human intestine
One of normal flora, be distributed widely in natural environment and animal wastes.1978, Britain BARTLETT etc. confirmed Cd first
For the main pathogenic fungi of antibiotic-associated diarrhea (AAD), cardinal symptom includes asymptomatic carrier, mild to moderate diarrhoea and serious
Pseudomembranous enteritiss (Pseudomembrannous Colitis, PMC).Since calendar year 2001, due to C. difficile infection rate
Rising, the appearance of strong virus force strain (BI/NAP1/027/ toxin III type) and Outbreak, lead to this sick several cases number, answer
The rate of sending out and case fatality rate all substantially increase, and Resistant strain is also increasing, and the treatment of this disease causes global researcher and medical personnel
Great attention.
At present, the primarily strategy for the treatment of C. difficile infection is off antibiotic, uses other treatment measure instead, corrects simultaneously
Water and rock-soil coupling, corrects hypoproteinemia etc..Main antibacterials for Cd are metronidazole, vancomycin.Treating
Cheng Zhong, can apply some microbial ecological agent as the adjuvant drug of antimicrobial drug simultaneously, such as take lactobacilluss, bacillus bifiduss or ferment
Female bacterium etc., helps recover normal intestinal flora, contributes to shortening the course for the treatment of of antibiotic, reduces recurrence.But, in the past more than 20
Nian Li, Endodontic failure, infection and recurrence probability significantly raised, particularly infected strong virus force strain (BI/NAP1/027/ toxin III
Type) patient, develop more effective and more targeted CDI (C. difficile infection) Therapeutic Method remain control difficult shuttle
One of popular necessary means of bacterium.
IL-27 is a kind of heterodimeric cytokine, secreted by the antigen-presenting cell activating, have proinflammatory disease and
The effect of anti-inflammatory, closely related with multi-infection disease and diseases associated with inflammation.It pass through to promote inmature CD4+T cell to
The early stage of the special pedigree of Th1 submits to and facilitates inflammation.In contrast, it suppresses Th17 differentiation Th1 the and Th2 effect in differentiation again
The activity as induction regulatory T cells (Tr1) in cell is answered to suppress inflammation.Using the TCCR/ having infected various pathogen
The research that WSX-1 deficient mice is carried out shows, the signal of IL-27 is also to prevent excessive T cell activity and limit proinflammatory disease
Cytokine discloses important function played in anti-microbial infection for the IL-27 necessary to producing.But with regard to IL-
The 27 concrete researchs playing therapeutical effect in C. difficile infection need to be goed deep into.
Content of the invention
The shortcoming of prior art in view of the above, it is an object of the invention to provide interleukin-27 is treating difficult shuttle
Application in bacterium infection, for solve in prior art good to the therapeutic effect of C. difficile infection the problems such as.
For achieving the above object and other related purposes, first aspect present invention provide interleukin-27 in preparation treatment or
Application in the medicine of prevention C. difficile infection.The object of interleukin-27 treatment, can be also not by C. difficile infection
Object, can be but without showing related indication object or by clostridium difficile sense by C. difficile infection
Dye, reaches the object causing relevant disease.
In some embodiments of the invention, described interleukin-27 be selected from human interleukin-2 7, RhIL-2 7,
One or more of Mus interleukin-27, recombinant murine interleukin-27 combine.
In some embodiments of the invention, interleukin-27 is used for treating the disease that C. difficile infection causes.
In some embodiments of the invention, described disease includes the antibiotic associated abdomen that C. difficile infection causes
Rush down.
In some embodiments of the invention, described disease includes the pseudomembranous enteritiss that C. difficile infection causes.
In some embodiments of the invention, described disease also includes pyelonephritis, the meninges that C. difficile infection causes
Inflammation, abdominal cavity and vaginal infection, bacteremia, gas gangrene.
Second aspect present invention provides a kind for the treatment of or the medicine of prevention C. difficile infection, contains effectively in described medicine
The interleukin-27 of amount.
In some embodiments of the invention, described interleukin-27 be selected from human interleukin-2 7, RhIL-2 7,
One or more of Mus interleukin-27, recombinant murine interleukin-27 combine.
As described above, application in treatment C. difficile infection for the interleukin-27 of the present invention, there is following beneficial effect
Really：Through interior animal experiment, the present invention finds that IL-27 (interleukin-27) has preferable therapeutical effect to CDI, be a kind of tool
There is the medicine of broad prospect of application, provide another kind of feasible selection for preferably curing CDI, improve the life of patient
Quality.
Brief description
Fig. 1 be shown as Il-27 in C. difficile infection patients serum and feces containing spirogram.
After Fig. 2 is shown as C. difficile infection, the body weight of tri- groups of mices of PBS, WT, KO is schemed over time.
After Fig. 3 is shown as C. difficile infection, the survival rate of tri- groups of mices of PBS, WT, KO is schemed over time.
Fig. 4 is shown as colon's HE colored graph of mice.
Fig. 5 is shown as the survival rate variation diagram with mice after normal saline and rmIL-27 process respectively.
Fig. 6 is shown as rmIL-27 treatment group and control group mice cecal content colony counting result figure.
Specific embodiment
Below by way of specific instantiation, embodiments of the present invention are described, those skilled in the art can be by this specification
Disclosed content understands other advantages and effect of the present invention easily.The present invention can also be by addition different concrete realities
The mode of applying is carried out or applies, and the every details in this specification can also be based on different viewpoints and application, without departing from
Carry out various modifications and changes under the spirit of the present invention.
Alcohol concentration in following examples refers both to volumetric concentration.
Embodiment 1
IL-27 detection in the patients serum of C. difficile infection and feces
The stool sample of clinical patient censorship, is carried out the coherent detection of clostridium difficile by microbial room of clinical laboratory, to be detected
After finishing, collect remaining stool sample and the serum specimen on patient's censorship same day；Meanwhile, serum and the feces of Healthy People are collected
Specimen, as comparison, is stored in -80 DEG C of refrigerators immediately, treats that subsequent experimental is used.All patients are divided into 2 groups：The diarrhoea positive and group
Clostridium difficile culture positive (CDI group), the diarrhoea positive and the negative group (Diarrhea group) of clostridium difficile culture, Healthy People is as right
According to group (Control group).Using human IL-2's 7ELISA test kit (purchased from R＆D Systems company), detect patients serum and excrement
Just the content of middle IL-27 albumen, concrete operation step strict reference reagent box description.
Result shows：Healthy People and diarrhoea but the patient of no C. difficile infection, almost detect not in its serum and feces
Go out IL-27；And it is then significantly raised with the patients serum of C. difficile infection and the content of IL-27 in feces to suffer from diarrhoea, relatively diarrhoea but
No C. difficile infection patient and Healthy People statistically significant (as shown in Figure 1), illustrates that IL-27 sends out in C. difficile infection
Wave certain effect.
Embodiment 2
The foundation of C. difficile infection mouse model and identification
For probing into the effect that IL-27 plays during C. difficile infection further, the present invention builds clostridium difficile sense
The mouse model of dye.Experiment mice includes 20 6-8 week old female IL-27 receptor deficient (WSX-1-/-) mice is randomly divided into
Experimental group (KO+CDI group) and matched group (KO+PBS)；Wild type (WT) the female C57BL/6 mice of 20 6-8 week old (is purchased from
Medical University Of Chongqing's Experimental Animal Center), it is randomly divided into experimental group (WT+CDI group) and two groups of matched group (WT+PBS group), every group
10.Mice all accept mix antibiotic (purchased from Sangon Biotech (Shanghai) Co., Ltd.) treatment, including card that
Mycin (0.4mg/mL), gentamycin (0.035mg/mL), polymyxin (850U/mL), metronidazole (0.215mg/mL) and ten thousand
Ancient mycin (0.045mg/mL), above-mentioned antibiotic is made into drinking water in the desired amount and drinks 5 days to mice, then change into common
Drinking water, after drinking 2 days, that is, fills bacterium the previous day, all mices give clindamycin (10mg/kg) lumbar injection.Experimental group gives
0.2mL clostridium difficile (purchased from American Type Culture Collecti type strain ATCC43255) bacteria suspension (108CFU/mL) gavage, comparison
Group mice gives same volume aseptic PBS gavage.Then, weigh daily, observe pellet morphology, mice mobility, have or not the back of a bow, abdomen
Rush down, wet tail or death；Simultaneously by leaving and taking mouse Colon tissue, it is carried out with HE dyeing, check intestinal tissue pathologic condition.Observe
Terminal is animal moribund condition or to filling the 7th day after bacterium, by above index, verifies mice C. difficile infection model whether structure
Build up work(.
Result shows：Compared with two matched groups, KO experimental group and WT experimental mice are the 1st day after C. difficile infection
Start, mice mobility is deteriorated, weight loss (as shown in Figure 2), and stool is dilute soft, or even be in watery stool, wet tail, bow occur
Back posture gesture, above-mentioned symptom becomes apparent from KO group mice, seriously, and KO group mouse death rate is high (as Fig. 3) compared with WT group.Separately
Outward, the mice of all survivals the 3rd day body weight is the lightest after infection, start after the 4th day recover；Two control group mice body weight change are not
Greatly, the related symptoms of no C. difficile infection, body weight change situation is as shown in Fig. 2 the mouse model of explanation C. difficile infection
Successfully construct, and IL-27 plays an important role during C. difficile infection.
Embodiment 3
Colon's pathological examination
Observe during dead mouse or to observe terminal, anaesthetize respectively and take off neck put to death mice after, leave and take reality respectively
Test group (CDI) and the colon of matched group (PBS) mice, every group has 5 samples (n=5), specific organized processing step respectively
Suddenly as follows：
1) fixing：Tissue is added in the neutral formalin of 10% (mass concentration), fixing general 1 day；
2) it is dehydrated：Take out the tissue fixing, being sequentially placed into graded ethanol and being dehydrated (is 70% ethanol respectively
1h, 80% ethanol 1h, 95% ethanol 1h and 100% ethanol 1h)；
3) transparent：First use dimethylbenzene I to soak 10mim, then use dimethylbenzene II to soak 20min；
4) waxdip：First soak 1h at 60 DEG C with soft wax, then soak 2h at 60 DEG C with hard wax；
5) embed：Hard wax embeds；
6) section and paster：Carry out tissue slice, about 4 μm of the thickness of section in paraffin slicing machine；It is put into heating
Plate in water, then be attached on microscope slide, put in 45 DEG C of calorstats and dry.
7) dewaxing dyeing：The paraffin section being dried is positioned in dimethylbenzene, (100% ethanol in graded ethanol successively
3min, 95% ethanol 3min, 80% ethanol 3min, 70% ethanol 3min) carry out dewaxing treatment, finally enter distilled water.Entered
Dyeing several minutes in hematoxylin aqueous solution are put in section after distilled water；Color separation in sour water and ammonia, each several seconds, using flowing water
Enter distilled water a moment after rinsing 1 hour, then enter to be dehydrated in 70% and 90% ethanol each 10 minutes, finally enter ethanol eosin stains
Liquid dyes 23 minutes.Section after dyeing is dehydrated through absolute alcohol, then makes section transparent through dimethylbenzene, drips upper natural gum and is sealed
Gu, carry out image acquisition using microscope.
C. difficile infection is observed after terminating, and carries out pathology detection, assessment colon inflammatory cell infiltration, the congestion of blood vessel
Situation with tissue edema, epithelial cell damage.Result shows：The mice of C. difficile infection, its colon is substantially congested,
Edema, epithelial cell damage is serious, and with substantial amounts of inflammatory cell infiltration, and KO group mice is more serious；The knot of control group mice
The no above-mentioned change of intestinal tissue, is shown in Fig. 4.
Embodiment 4
Mus IL-27 recombiant protein (recombinant IL-27) improves the C. difficile infection symptom of mice
Antibiotic pretreatment and difficult is carried out using the method for embodiment 2 to wild type (WT) mice and control group mice
Clostridium gavage is processed, after CDI the 0th day and the 3rd day of wild type (WT) mice, uses isoflurane light anesthesia, and then abdominal cavity is noted
Penetrate the injection containing IL-27 (rmIL-27 group), the injection measurement of the present embodiment is 100 μ L, in injection, contain 10 μ g/mL
Recombined small-mouse IL-27 albumen, IL-27 albumen be purchased from R＆D Systems company, article No.：NYA0915111, specification：10μg/
, the IL-27 albumen of every 10 μ g is dissolved in the aseptic PBS solution of 1mL, and described injection is obtained；Matched group is only to inject equal agent
The mouse model (Saline group) of the C. difficile infection of normal saline (sodium chloride mass concentration is 0.9%) of amount (100 μ L),
Whether the related symptoms observing two groups of mouse infection clostridium difficiles are improved, and specifically include diarrhoea, the back of a bow, body weight, wet tail, work
Dynamic degree etc., specifically describes and sees result part.At the end of observation, pathological examination does in the colon leaving and taking mice, is embodied as
Method is as described in Example 3.
, as shown in figure 5, the mouse survival rate through IL-27 treatment increases, the amplitude that loses weight is little, and mobility is preferable for result,
The symptom of the C. difficile infection such as no hunchbacked, wet tail；After pathological examination results (as Fig. 4) show IL-27 treatment, the damage of intestinal tissue
Wound, edema and inflammatory infiltration lesser extent, and non-treatment group is the related symptoms ratio of the wild mouse CDI of normal saline treatment group
More apparent, after illustrating to treat through IL-27, mice C. difficile infection symptom is improved, and improves the survival rate of mice.
Embodiment 5
Mice intestinal contentses colony counting
After the observation of mice C. difficile infection terminates, take rmIL-27 treatment group and control group mice cecal content, contain
Be put in the microcentrifugal tube of 1.5mL and weigh, then plus the aseptic PBS of 1mL (PH7.4) be vortexed mix, 1500g centrifugation 30s obtain
Suspension, its 10 times is diluted, serial dilution 4 times (10-1to 10-4), the suspension of each concentration respectively inoculates 50uL in cephalo
On western butyl- D-Cycloserine-cefoxitin-cycloserine-fructose agar flat board (CCFA), after 37 DEG C of Anaerobic culturel 48h, carry out colony counting.
Result shows：Treat through rmIL-27 after C. difficile infection, in mice intestinal contentses, clostridium difficile carrying capacity relatively compares
Group substantially reduces (being illustrated in figure 6 rmIL-27 treatment group and control group mice cecal content colony counting result figure), explanation
IL-27 contributes to removing clostridium difficile in intestinal, has significant therapeutic effect to mice.
In sum, through interior animal experiment, the present invention finds that IL-27 has preferable therapeutical effect to CDI, is one
Plant the medicine with broad prospect of application, provide another kind of feasible selection for preferably curing CDI, improve patient's
Quality of life.
Above-described embodiment only principle of the illustrative present invention and its effect, not for the restriction present invention.Any ripe
The personage knowing this technology all can carry out modifications and changes without prejudice under the spirit and the scope of the present invention to above-described embodiment.Cause
This, those of ordinary skill in the art is complete with institute under technological thought without departing from disclosed spirit such as
All equivalent modifications becoming or change, must be covered by the claim of the present invention.
Claims (8)
1. application in preparation treatment or prevention C. difficile infection medicine for the interleukin-27.
2. according to claim 1 application it is characterised in that：Described interleukin-27 is selected from human interleukin-2 7, recombined human
One or more of interleukin-27, Mus interleukin-27, recombinant murine interleukin-27 combine.
3. according to claim 1 application it is characterised in that：Interleukin-27 is used for treating what C. difficile infection caused
Disease.
4. according to claim 1 application it is characterised in that：Described disease includes the antibiotic that C. difficile infection causes
Induced diarrhea.
5. according to claim 1 application it is characterised in that：It is pseudomembranous that described disease includes that C. difficile infection causes
Enteritis.
6. according to claim 1 application it is characterised in that：Described disease also includes the renal pelvis that C. difficile infection causes
Nephritis, meningitiss, abdominal cavity and vaginal infection, bacteremia, gas gangrene.
7. treat or prevention C. difficile infection medicine it is characterised in that：Interleukin containing effective dose in described medicine-
27.
8. medicine according to claim 7 it is characterised in that：Described interleukin-27 is selected from human interleukin-2 7, recombined human
One or more of interleukin-27, Mus interleukin-27, recombinant murine interleukin-27 combine.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710007655.5A CN106474458B (en) | 2017-01-05 | 2017-01-05 | Application of interleukin-27 in treatment of clostridium difficile infection |
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| CN201710007655.5A CN106474458B (en) | 2017-01-05 | 2017-01-05 | Application of interleukin-27 in treatment of clostridium difficile infection |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102844027A (en) * | 2009-11-23 | 2012-12-26 | 培力(香港)健康产品有限公司 | Novel therapeutic methods for treating inflammation and immune system disorders |
| CN103409465A (en) * | 2013-08-29 | 2013-11-27 | 武汉大学 | Preparation method and application of recombinant human leucocyte interleukin 27 |
| WO2014169344A1 (en) * | 2013-04-19 | 2014-10-23 | Immuron Limited | Methods and compositions for the treatment and/or prophylaxis of clostridium difficile associated disease |
| WO2015095241A3 (en) * | 2013-12-16 | 2015-10-15 | Seres Therapeutics, Inc. | Bacterial compositions and methods of use thereof for treatment of immune system disorders |
| CN105949234A (en) * | 2011-09-29 | 2016-09-21 | 苏黎世联邦理工学院 | Pharmaceutical compounds for use in the therapy of clostridium difficile infection |
-
2017
- 2017-01-05 CN CN201710007655.5A patent/CN106474458B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102844027A (en) * | 2009-11-23 | 2012-12-26 | 培力(香港)健康产品有限公司 | Novel therapeutic methods for treating inflammation and immune system disorders |
| CN105949234A (en) * | 2011-09-29 | 2016-09-21 | 苏黎世联邦理工学院 | Pharmaceutical compounds for use in the therapy of clostridium difficile infection |
| WO2014169344A1 (en) * | 2013-04-19 | 2014-10-23 | Immuron Limited | Methods and compositions for the treatment and/or prophylaxis of clostridium difficile associated disease |
| CN103409465A (en) * | 2013-08-29 | 2013-11-27 | 武汉大学 | Preparation method and application of recombinant human leucocyte interleukin 27 |
| WO2015095241A3 (en) * | 2013-12-16 | 2015-10-15 | Seres Therapeutics, Inc. | Bacterial compositions and methods of use thereof for treatment of immune system disorders |
Non-Patent Citations (3)
| Title |
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| 曾昭静；吕小平: "IL-27在炎症性肠病中的免疫调节作用", 《山东医药》 * |
| 肖新云；赵先平；谭周进；: "艰难梭菌相关肠道疾病的研究进展", 《世界华人消化杂志 》 * |
| 郭月英；李国忠: "白细胞介素-27研究进展", 《中华临床医师杂志》 * |
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