CN114686427A - Spleen-regulating B lymphocyte and preparation method and application thereof - Google Patents
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- C12N5/06—Animal cells or tissues; Human cells or tissues
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- 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
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
- G01N33/56966—Animal cells
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- C12N2509/00—Methods for the dissociation of cells, e.g. specific use of enzymes
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- G—PHYSICS
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- G01N2469/00—Immunoassays for the detection of microorganisms
- G01N2469/10—Detection of antigens from microorganism in sample from host
Abstract
The invention provides spleen regulation type B lymphocytes and a preparation method and application thereof. The invention provides spleen regulatory B lymphocytes, wherein the proportion of the CD1d, CD5 and CD21/35 antibody positive regulatory B lymphocytes in the cells is more than 94.6%. In a second aspect, the present invention provides a method for preparing spleen-regulated B lymphocytes. The method for preparing spleen regulatory B lymphocytes comprises the following steps: taking spleen cell suspension, and marking the spleen cell suspension by using surface antibodies CD1d, CD5 and CD 21/35; fluorescence activated cell sorting labeled cells. The third aspect of the invention provides application of the spleen-regulating B lymphocytes in preparation of a preparation for targeted engraftment on bilateral kidneys. The fourth aspect of the invention provides application of the spleen regulatory B lymphocytes in preparing products for kidney protection.
Description
Technical Field
The invention relates to spleen-regulating B lymphocytes and a preparation method and application thereof, in particular to fluorescence activated cell sorting, belonging to the field of cell biology.
Background
In recent years, the role of B lymphocytes in fibrosis has been gaining increasing attention. The B lymphocyte depletion therapy has potential regulation effect on immune cell subgroup constitution and fibroblast phenotype expression, and may be one of the ways of playing the anti-fibrosis effect.
Given the complexity of the B lymphocyte subpopulation phenotype, B lymphocyte depletion therapy against a single surface antigen may not be universally applicable to all types of glomerulonephritis and its induced interstitial fibrosis. B lymphocyte depletion therapies targeting a single surface antigen, particularly a single broad-spectrum surface antigen, are therefore not applicable in part of the disease and in patients, and may be associated with subpopulations of B lymphocytes that have different functions themselves.
Of particular note is a particular subset of B lymphocytes with immunomodulatory functions, called regulatory B lymphocytes (Breg), also known as B10 cells. Breg cells account for only about 10% of all B lymphocytes in the human blood circulation, but Breg has an essential role in the maintenance of immune tolerance and immune homeostasis. Breg cells are reported to be the major cell type producing the cytokine IL-10, which is also responsible for their sometimes called B10 cells. Breg cell can inhibit Th1 immune response, inhibit Th17 cell differentiation, and convert CD4+T cells are transformed into suppressor T lymphocytes (tregs) and type 1 regulatory cells (Tr 1).
Among the currently known subpopulations of B lymphocytes Breg cells exhibit the following characteristics:
a. phenotypic plasticity (plasticity): can differentiate to plasma cells producing immunoglobulin and to memory B lymphocytes which are remained for a long time;
b. has the regulation function on other types of immune cells: the differentiation of Treg cells can be induced, and the stability of Treg cell communities is maintained;
c. has the secretion function: breg cells are the major contributors to the regulatory cytokine IL-10;
d. has shown promising treatment effect in animal models of various immune-related diseases, such as experimental autoimmune encephalomyelitis (one of animal models of human multiple sclerosis), rheumatoid arthritis and experimental lupus nephritis, and Breg cells show good treatment potential.
Qin Yao, a Master thesis of Nanjing medical university published in 2014 5/1, CD19+CD5+CD1dhiThe regulation effect and mechanism research of the B cell on the islet transplantation immune response uses the conventional method for preparing Breg cells: MACS (Magnetic-activated cell sorting) sorting of mouse CD19＋B cells, activated in vitro for 48h, further sorted by FACS to obtain CD19+CD5+CD1dhiB cells.
Disclosure of Invention
An object of the present invention is to provide spleen-regulated B lymphocytes.
Another object of the present invention is to provide a method for preparing spleen-regulated B lymphocytes.
The invention also aims to provide application of spleen-regulating B lymphocytes in preparing a preparation for targeted engraftment on bilateral kidneys.
The invention also aims to provide application of the spleen-regulated B lymphocytes in preparing products for kidney protection.
In one aspect, the invention provides spleen-regulated B lymphocytes comprising CD1d, CD5 and CD21/35 antibody-positive regulated B lymphocytes.
In another aspect, the present invention provides a method for preparing spleen-regulated B lymphocytes, wherein the method comprises the steps of:
taking spleen cell suspension, and marking by using surface antibodies CD1d, CD5 and CD 21/35;
and (3) sorting cells positive to surface antibodies CD1d, CD5 and CD21/35 by fluorescence activated cell sorting to obtain the spleen regulating B lymphocyte.
According to a specific embodiment of the present invention, the method further comprises the process of crushing, filtering and resuspending the isolated spleen to obtain a spleen cell suspension.
According to a specific embodiment of the present invention, wherein the method further comprises a process of purity determination of the sorted surface antibody CD1d, CD5 and CD21/35 positive cells.
According to a particular embodiment of the invention, wherein the process of purity determination comprises the following steps:
the sorted cells were re-labeled with CD1d, CD5, and CD21/35 surface antibodies, after which the purity of the regulatory B lymphocytes positive for CD1d, CD5, and CD21/35 antibodies was determined by flow cytometry.
According to a specific embodiment of the present invention, wherein the purity of the regulatory B lymphocytes positive for CD1d, CD5 and CD21/35 antibodies is 94.6% -99.7%; preferably, the purity of the CD1d, CD5 and CD21/35 antibody positive regulatory B lymphocytes is 97.5%.
On the other hand, the invention provides application of spleen-regulating B lymphocytes in preparation of a preparation for targeted engraftment on bilateral kidneys.
According to a specific embodiment of the present invention, wherein said splenic regulated B lymphocytes are derived from autofluorescent mT/mG mice.
In another aspect, the invention provides an application of spleen-regulated B lymphocytes in preparing a product for kidney protection. The product is mainly a kit containing the regulatory B lymphocyte or other pharmaceutical products containing the regulatory B lymphocyte and used for protecting the kidney.
According to a particular embodiment of the invention, wherein the renal protection comprises a reduction of the degree of obstruction-side renal tubulointerstitial fibrosis.
According to a particular embodiment of the invention, wherein the renal protection comprises a reduction of renal cortex thinning of the ileus side kidney.
The invention provides spleen regulatory B lymphocytes, wherein the purity of the regulatory B lymphocytes positive to CD1d, CD5 and CD21/35 antibodies can reach 94.6-99.7%. The spleen-regulating B lymphocyte provided by the invention has good adoptive transfer, can be remained in the renal cortex within a certain time, and further shows the treatment effect on experimental renal tubule interstitial fibrosis. When the spleen-regulating B lymphocyte provided by the invention is applied to a UUO model mouse, the appearance of the obstructed side kidney can be obviously fuller than that of a control group, the renal cortex thinning degree is reduced, and the tubulointerstitial fibrosis degree is reduced; the spleen-regulated B lymphocyte provided by the invention shows good treatment potential in a mouse UUO model. Therefore, it is easy to see that the conditioning B lymphocyte prepared by sorting has a protective effect on obstructed kidney after adoptive transfer.
Drawings
FIG. 1 is a FACS sorting of CD1d, CD5 and CD21/35 antibody positive regulatory B lymphocytes.
FIG. 2 is a purity measurement of FACS sorted CD1d, CD5 and CD21/35 antibody positive, regulated B lymphocytes.
FIG. 3 is a graph showing the distribution of CD1d, CD5, and CD21/35 antibody positive regulatory B lymphocytes in the bilateral kidneys of mice following adoptive transfer.
FIG. 4 shows the interstitial fibrosis of the renal tubules and the deposition of collagen.
FIG. 5 is a pathological change in the major internal organs of mice following adoptive transfer of Breg cells.
Detailed Description
The technical solutions of the present invention will be described in detail below in order to clearly understand the technical features, objects, and advantages of the present invention, but the present invention is not limited to the practical scope of the present invention.
Example 1
This example provides a method for sorting mouse spleen CD1d, CD5, and CD21/35 antibody positive, regulated B lymphocytes.
Step 1: mouse spleen cells were collected. The spleen tissue was minced to 1mm using freshly harvested mouse spleen on ice using pre-cooled sharp ophthalmic scissors3The fragments were filtered through a 100 μm nylon mesh and resuspended in RPMI1640 cell culture medium.
Step 2: the surface antibody labeled mouse spleen cells. Performing flow cytometry surface antibody Staining on the cells obtained in the step 1 in a stabilizing Buffer (eBioscience) system; dyeing markers: CD1d, CD5 and CD 21/35; dyeing incubation conditions: room temperature, protected from light, 20 min.
And step 3: the FACS method sorts the target cells. The cells stained in step 2 were immediately subjected to FACS cell sorting on a MoFlo XDP ultra-rapid flow cytometry sorting system (Beckman Coulter Co.) to sort CD1d, CD5 and CD21/35 antibody-positive regulatory B lymphocytes (hereinafter, abbreviated as CR 1)+Breg cells). Cell sorting is shown in FIG. 1.
And 4, step 4: CR1+Breg cell purity assay. Labeling CR1 sorted in step 3 with CD1d, CD5, and CD21/35 surface antibodies again+Breg cells, then CR1 determined by flow cytometry+Purity of Breg cells. The results of the purity measurement are shown in FIG. 2. As can be seen from FIG. 2, in the cells sorted in steps 1 to 3, CR1 was found+The Breg cell accounts for 94.6-99.7% and has average purity of 97.5%.
Example 2
This example provides the use of regulatory B lymphocytes in adoptive transfer to the kidney. The application relates to a method for adoptively transferring the regulatory B lymphocyte and tracking and observing the distribution of the B lymphocyte in the kidney.
Step 1: obtaining mT/mG mouse-derived spleen CR1 with spontaneous red fluorescence+Breg cells. The cells were sorted as described in example 1.
Step 2: autored fluorescent mT/mG mouse-derived spleen CR1+Adoptive transfer of Breg cells. Spleen CR1 from mT/mG mouse with spontaneous red fluorescence+Breg cells were adoptively transferred using the left renal intravenous method.
And step 3: and detecting the fluorescence signal after the adoptive transfer. At 15 minutes after the injection operation in step 2, bilateral kidneys were exposed from the abdomen, the kidney envelopes were removed with a pair of tweezers, and CR1 was observed with a two-photon microscope while maintaining the survival of the animals+Distribution of Breg cells in bilateral kidneys of mice. The results are shown in FIG. 3, in which FIG. 3 shows the control group on the left, and FIG. 3 shows the adoptive transfer CR1+Left kidney 15min after Breg cells, FIG. 3 right for adoptive transfer CR1+Right kidney 15 minutes after Breg cells.
As can be seen from FIG. 3, CR1+Breg cells had a clearly visible distribution in the superficial cortical layers of both bilateral kidneys (two-photon microscopy at a sample depth of detection of about 100 μm) after 15min of renal intravenous injection, mainly in perivascular capillary vessels. This part of the results suggest that after renal intravenous injection, CR1 was obtained according to the present invention+Breg cells are able to enter the kidney and persist, at least transiently, within the renal cortex.
Example 3
This example provides the use of regulatory B lymphocytes for renal protection. In particular to the application of the adjusting B lymphocyte in the adoptive transfer treatment of experimental renal tubular interstitial fibrosis.
Step 1: spleen CR1 was obtained+Breg cells. The cells were sorted as described in example 1.
Step 2: and constructing a UUO model mouse. UUO model mice were obtained by unilateral ureteral ligation.
And step 3: spleen CR1+Adoptive transfer of Breg cells. Immediately after the ureteral ligation operation in step 2, 5X 10 cells were inserted5A CR1+Breg cells were injected into the ileus side kidney of UUO model mice via renal vein, and gauze pressed after injectionHemostasis was performed under pressure for 3 minutes.
And 4, step 4: and (6) dyeing and observing. And (4) on the 7 th day after the treatment in the step 3, taking the obstructed lateral kidney of the mouse, preparing a paraffin pathological section of kidney tissue with the thickness of 2 mu m, performing Masson staining, and observing the interstitial fibrosis of the renal tubules and the deposition condition of collagen. The results are shown in FIG. 4.
As can be seen from FIG. 4, CR1+The Breg cell treated group had a fuller appearance of the kidney, a reduced thinning of the renal cortex and a reduced degree of tubulointerstitial fibrosis compared to the untreated group; it can also be seen that the CR1 obtained by the present invention+The treatment effect of the Breg cells is better than that of the conventional CD1d and CD5 double-positive Breg cell treatment group. The results suggest that CR1 is obtained according to the invention+Breg cells have shown initially good therapeutic potential in the mouse UUO model. It was further concluded that the sorted CR1 of the present invention was prepared+The Breg cells have protective effect on the obstructed kidney after adoptive transfer.
Example 4
This embodiment provides CR1+Animal body weight, cardiac ultrasound observations, and pathology observations of major internal organs 12 days after Breg cell transplantation.
This embodiment acquires CR1+Breg cell, UUO model construction and spleen CR1+The procedure for adoptive transfer of Breg cells was the same as in example 3, steps 1-3.
CR1+12 days after the adoptive transfer of Breg cells, mice of blank control group, mice of UUO model group and CR1 were observed+Body weights of mice in the Breg cell transplant group were recorded as shown in table 1; and observing CR1 using cardiac ultrasound+Effect of adoptive transfer of Breg cells on mice, cardiac ultrasound observations are recorded in table 2.
TABLE 1
TABLE 2
As is clear from tables 1 and 2, CR1 was found+Adoptive transfer of Breg cells had no significant effect on the body weight and cardiac ultrasound observation indices of the mice.
CR1+Pathological changes in the major internal organs of the mice were observed 12 days after adoptive transfer surgery of Breg cells using hematoxylin and eosin staining, and the results are shown in fig. 5. As can be seen from FIG. 5, CR1+There were no significant pathological changes in the major internal organs of the mice after 12 days of adoptive transfer surgery for Breg cells.
Claims (10)
1. A spleen regulatory B lymphocyte, wherein the purity of the regulatory B lymphocyte positive for CD1d, CD5 and CD21/35 antibody in the cell is more than 94.6%.
2. A method of preparing the spleen-regulated B lymphocyte of claim 1, comprising the steps of:
taking spleen cell suspension, and marking by using surface antibodies CD1d, CD5 and CD 21/35;
and (3) sorting cells positive to surface antibodies CD1d, CD5 and CD21/35 by fluorescence activated cell sorting to obtain the spleen regulating B lymphocyte.
3. The method of claim 2, further comprising the step of obtaining a spleen cell suspension by crushing, filtering, and resuspending the isolated spleen.
4. The method according to claim 2 or 3, wherein the method further comprises a process of performing purity measurement on the sorted cells;
the process of purity determination comprises the following steps:
the sorted cells were re-labeled with CD1d, CD5, and CD21/35 surface antibodies, after which the purity of the regulatory B lymphocytes positive for CD1d, CD5, and CD21/35 antibodies was determined by flow cytometry.
5. The method of claim 2, wherein said spleen cells are mouse spleen cells.
6. Use of the spleen-regulated B lymphocytes of claim 1 in the preparation of a formulation for targeted engraftment in bilateral kidneys.
7. The use according to claim 6, wherein said spleen-regulated B lymphocytes are derived from autofluorescent mT/mG mice.
8. Use of spleen-regulated B lymphocytes according to claim 1 for the preparation of a product for renal protection.
9. The use of claim 8, wherein the renal protection comprises a reduction in the degree of tubulointerstitial fibrosis or a reduction in the degree of renal cortex thinning on the side of the obstruction.
10. The use of claim 8, wherein said spleen-regulated B lymphocytes are mouse spleen-regulated B lymphocytes.
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| 王斌等: "丹酚酸B对高脂日粮小鼠抗氧化与淋巴细胞亚群免疫功能调节的研究", 《天然产物研究与开发》 * |
| 秦瑶: "CD19+CD5+CD1dhi B细胞对胰岛移植免疫应答的调节作用及机制研究", 《中国优秀博硕士学位论文全文数据库(硕士) 医药卫生科技辑》 * |
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| 赵鲁汀等: "B淋巴细胞刺激因子的研究进展", 《国际免疫学杂志》 * |
| 龙康霞等: "肾组织B 淋巴细胞浸润及其异位淋巴样组织形成在狼疮肾炎诊治中的意义", 《中华临床免疫和变态反应杂志》 * |
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