CN111544592B - Application of pattern recognition receptor Dectin-1 inhibitor in immunoprotection of receptor graft and induction of immune tolerance - Google Patents
Application of pattern recognition receptor Dectin-1 inhibitor in immunoprotection of receptor graft and induction of immune tolerance Download PDFInfo
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Abstract
The invention discloses application of a pattern recognition receptor Dectin-1 inhibitor in immunoprotection of a receptor graft and induction of immune tolerance, and comprises application of laminarin in inhibiting rejection reaction of a mouse graft and induction of immune tolerance. The invention firstly proposes that the laminarin can inhibit rejection reaction after organ transplantation, obviously prolongs the survival time of the transplant, induces immune tolerance under the synergistic action of tacrolimus and has better combined effect; it is also proposed that laminarin inhibits graft rejection and induces immune tolerance by inhibiting dectin-1. The Dectin-1 inhibitor laminarin and low-dose tacrolimus are combined for the first time, so that immune tolerance is induced, the using dose of the tacrolimus can be reduced, the side effect of singly using the full-dose tacrolimus is reduced, the economic burden of a patient is also reduced, the life quality of an organ transplantation patient is improved, the application prospect is good, and meanwhile, a new target spot and a new way are provided for regulating and controlling the rejection reaction of a transplant organ and inducing the immune tolerance of a receptor.
Description
Technical Field
The invention belongs to the technical field of medicines. Relates to the immunoprotection effect of a pattern recognition receptor Dectin-1 inhibitor on a receptor graft and application thereof in inducing immune tolerance, in particular to application of laminarin in inhibiting rejection reaction of a transplant receptor and inducing immune tolerance, and application of laminarin combined with an anti-rejection medicament in inhibiting rejection reaction of the transplant receptor and inducing immune tolerance.
Background
Organ transplantation is one of the most effective means for treating various terminal diseases at present, China is the second major organ transplantation of the world at present, through ten years of efforts, the organ donation work of China has great progress, and the demand of the organ supply is increased day by day, so the demand and the development potential of the organ transplantation in China are huge.
However, organ transplantation is prone to graft rejection (transplant rejection), and is one of the major factors affecting graft survival. Transplant rejection (transplant rejection) means that after the recipient has undergone an allogeneic tissue or organ transplant, the foreign tissue or organ or other transplant is recognized by the recipient's immune system as a "foreign component" that initiates an immunological response to attack, destruction and removal of the transplant. The mechanism of rejection mainly includes cellular immunity and humoral immunity. The most common clinical acute rejection is mediated primarily by cellular immunity, while hyperacute and chronic rejection are mediated primarily by humoral immunity. Therefore, patients after organ transplantation need to take anti-rejection drugs for a long period of time to suppress the occurrence of rejection.
The existing anti-rejection drug which is clinically used is tacrolimus, and long-term use of the anti-rejection drug can cause a plurality of adverse reactions, such as neurotoxicity, induction of opportunistic infection or tumorigenesis, and the like, and influence the long-term prognosis of a transplant recipient. Moreover, the anti-rejection medicine has higher price, and the economic burden of patients is heavy after long-term administration. Therefore, how to induce persistent immune tolerance in transplantation remains one of the hot topics studied in the transplantation community.
Disclosure of Invention
The invention aims to provide a novel drug selection capable of inhibiting rejection reaction of a transplant recipient and inducing immune tolerance. The research of the invention provides that the laminarin can inhibit rejection reaction after transplantation and induce the immune tolerance of islet transplants under the synergistic action of tacrolimus.
The invention aims to provide application of a pattern recognition receptor Dectin-1 as a target for inhibiting rejection reaction of a receptor on a transplanted organ and inducing immune tolerance.
The invention also aims to provide application of the pattern recognition receptor Dectin-1 inhibitor in preparing a medicament capable of inhibiting rejection reaction of a receptor on a transplanted organ and inducing immune tolerance.
It is still another object of the present invention to provide the use of laminarin for the preparation of a medicament capable of inhibiting rejection of transplanted organs by a recipient and inducing immune tolerance.
Still another object of the present invention is to provide the use of laminarin in combination with an anti-rejection drug for the preparation of a medicament capable of inhibiting rejection of a recipient to a transplanted organ and inducing immune tolerance.
It is still another object of the present invention to provide a drug capable of inhibiting rejection of a recipient to a transplanted organ and inducing immune tolerance.
The above purpose of the invention is realized by the following technical scheme:
the invention takes a mouse islet transplantation model as an example to research the protective effect of laminarin and tacrolimus on islet transplants, the laminarin can inhibit rejection reaction after transplantation, and the laminarin can induce the immune tolerance of the islet transplants under the synergistic effect of tacrolimus. The invention discloses the effect of laminarin in inducing immune tolerance in the field of organ transplantation for the first time, the combined use effect of laminarin and tacrolimus is better, the long-term survival time of the low-dose (0.25mg/kg/d) and full-dose (0.5mg/kg/d) tacrolimus in inducing mouse islet transplants has no obvious difference, the combined use of laminarin can reduce the dosage of tacrolimus to achieve similar curative effect, can avoid various side effects caused by long-term use of the full-dose tacrolimus, also reduces the economic burden of patients, and improves the life quality. Meanwhile, the research of the invention also shows that the inhibition of graft rejection reaction and the induction of immune tolerance by laminarin are realized by inhibiting dectin-1; dectin-1 is a target for inhibiting rejection of the recipient on the transplanted organ and inducing immune tolerance, and can inhibit rejection of the recipient on the transplanted organ and induce immune tolerance by inhibiting Dectin-1.
Accordingly, the present invention provides the following applications:
the application of the pattern recognition receptor Dectin-1 as a target for inhibiting rejection reaction of the receptor on transplanted organs and inducing immune tolerance.
The application of the pattern recognition receptor Dectin-1 inhibitor in preparing a medicament capable of inhibiting rejection reaction of a receptor to a transplanted organ and inducing immune tolerance.
The application of a pattern recognition receptor Dectin-1 inhibitor and an anti-rejection drug in preparation of a drug capable of inhibiting rejection reaction of a receptor on a transplanted organ and inducing immune tolerance.
Application of laminarin in preparing medicine for inhibiting rejection reaction of transplanted organ and inducing immunological tolerance is provided.
Application of laminarin combined with anti-rejection medicine in preparing medicine for inhibiting rejection reaction of transplanted organ and inducing immunological tolerance of recipient is provided.
In addition, a drug capable of inhibiting rejection of a transplanted organ by a recipient and inducing immune tolerance, which contains a pattern recognition recipient Dectin-1 inhibitor, is also provided.
Preferably, the pattern recognition receptor Dectin-1 inhibitor is laminarin.
Preferably, the medicament further comprises an antirejection drug.
More preferably, the antirejection drug is tacrolimus.
More preferably, the mass ratio of laminarin to tacrolimus is 10: 0.1-1.
More preferably, the mass ratio of laminarin to tacrolimus is 10: 0.2-0.5.
More preferably, the mass ratio of laminarin to tacrolimus is 10: 0.25-0.5.
More preferably, the mass ratio of laminarin to tacrolimus is 10: 0.25.
in addition, the invention also researches the mechanism of the graft protection effect of laminarin and tacrolimus, and the laminarin can up-regulate the content of Th2 and Treg, inhibit the content of Th1 cells, increase the secretion of the cell factor IL-10, reduce the secretion of the cell factor IFN-gamma, thereby inhibiting rejection reaction, inducing transplantation immune tolerance and prolonging the survival time of the islet graft of the mouse.
The invention has the following beneficial effects:
(1) the invention firstly proposes that the laminarin can inhibit rejection reaction after organ transplantation and obviously prolong the survival time of the transplant.
(2) The invention firstly provides that the laminarin can induce the immune tolerance under the synergistic action of the tacrolimus.
(3) The invention combines laminarin and low-dose tacrolimus for the first time to induce immune tolerance.
(4) The laminarin and the tacrolimus are used cooperatively, so that the dosage of the tacrolimus is reduced, the side effect of singly using the full dosage of the tacrolimus is reduced, the economic burden of a patient is also reduced, and the life quality of a patient subjected to organ transplantation is improved.
(5) The invention also provides that laminarin inhibits graft rejection and induces immune tolerance by inhibiting dectin-1; dectin-1 is a target for inhibiting rejection of the recipient on the transplanted organ and inducing immune tolerance, and can inhibit rejection of the recipient on the transplanted organ and induce immune tolerance by inhibiting Dectin-1. Provides a new target and a new way for regulating and controlling the rejection reaction of the receptor to the transplanted organ and inducing the immune tolerance.
Drawings
FIG. 1 shows that laminarin alone, in combination with tacrolimus, can prolong the survival time of islet transplants in mice.
FIG. 2 shows the detection of the number of mouse spleen T lymphoid subtypes Th1, Th2 and Treg by flow cytometry.
FIG. 3 shows the detection of cytokines IL-10 and IFN-. gamma.in peripheral blood of mice by ELISA.
FIG. 4 is a photograph of immunohistochemistry for Dectin-1 of islet grafts, with A representing the control group with PBS and B representing the group with laminarin.
Detailed Description
The invention is further described with reference to the drawings and the following detailed description, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
The following examples of the invention use a mouse islet transplantation model to observe the protective effect of laminarin and tacrolimus on islet transplants.
Example 1 Experimental methods
1. Experimental animal model
A diabetes model was established by intraperitoneal injection of STZ using a single 200mg/kg dose of 6-8 week C57BL/6 mice as islet transplant recipients. Balb/c mice were used for 6-8 weeks as islet transplant donors.
2. The method for islet transplantation comprises the following steps:
(1) fully anesthetizing a donor mouse Balb/c mouse, reversely perfusing 2-2.5ml collagenase through common bile duct, after digestion gradient centrifugation, selecting 250-300 islets under a microscope, and putting the islets into an incubator at 37 ℃ for culturing for 12-24 hours.
(2) The recipient mouse is black C57BL/6, fully anesthetized, prepared for skin in the intercostal region, in the right lateral decubitus, padded with an empty insulin syringe or a cylinder of similar shape to the waist, fully exposed to the kidney, sterilized and draped, and vertically cut open the skin incision in the longitudinal direction, with a length of about 1.5cm, exposed to the kidney, lightly scratched with the tip of a needle on the recipient kidney capsule, opened with a gap of 0.15-0.3cm, and then gently pushed between the kidney capsule and parenchyma in the direction of the long axis of the kidney, to the position of the suprarenal pole, taking care not to damage the adrenal gland, to form a subconvelopment channel for implantation of islets. Drawing out the capillary glass tube, discharging liquid in the channel, advancing the PE50 hose along the channel, slowly withdrawing after reaching the suprarenal pole, slightly pushing a micro sample injector needle core, completely placing the pancreatic island in the tunnel, slightly gathering the pancreatic island tissue by using a glass minute needle, and finally slightly burning the notch of the envelope by using a bipolar needle to stop bleeding without damaging the renal envelope and leaking the pancreatic island. Care was taken to keep the kidney capsule moist. After the operation is finished, the abdominal wall of the incision is lifted slightly, and the 3-0 operation suture with the needle is used for closing the abdomen and sewing the skin layer by layer after the kidney is automatically retracted. After the operation, the mice are subjected to heat preservation until the anesthesia is clear.
3. Method of administration
Daily laminarin was administered by intraperitoneal injection and tacrolimus by intramuscular injection for one week, and the C57BL/6 mice after islet transplantation were divided into the following six groups:
the first group was a blank group (PBS injected once),
the second group was the laminarin group alone (10mg/kg/d),
the third group was a low dose tacrolimus alone group (0.25mg/kg/d),
the fourth group was the full dose tacrolimus alone group (0.5mg/kg/d),
the fifth group was the laminarin + low dose tacrolimus group (10mg/kg/d +0.25mg/kg/d),
the sixth group was the laminarin + Tacrolimus full dose group (10mg/kg/d +0.5 mg/kg/d).
After transplantation and the above-mentioned drug-treated C57BL/6 mice were raised for the corresponding time, and then the detection of the corresponding index was performed.
Example 2 evaluation of the immunoprotective Effect of laminarin on islet transplants
The test was performed according to the method of example 1, and daily blood glucose after transplantation was recorded in the above six groups of mice. A rejection was considered to occur when the blood glucose of the mouse was twice at >300mg/kg (16.7 mmol/L). Islet graft survival time was recorded and a survival curve was generated (fig. 1).
As can be seen from fig. 1:
the mean survival time of islets (29) in the laminarin group was longer in the PBS group (11) (n-5, p < 0.05).
The mean islet survival time (35) days in mice in the low dose tacrolimus group was longer than in the PBS group (11) (n-5, p < 0.05).
The mean survival time of islets (41) in mice in the high dose tacrolimus group was longer (n-5, p <0.05) than in PBS group (11).
The mean survival time of islets (62) in the laminarin + low dose tacrolimus group was longer (n-5, p <0.05) than in the PBS group (11).
The mean survival time of islets (64) days was longer in the laminarin + high dose tacrolimus group than in the PBS group (11) (n-5, p < 0.05).
The average survival time of islets of mice in the laminarin + low dose tacrolimus group (62) days was not significantly different from that in the laminarin + high dose tacrolimus group (64) days (n ═ 5, p ═ 0.3472)
Mean islet survival time in mice in the laminarin + low dose tacrolimus group (62) days lower dose tacrolimus (35) days long (n ═ 5, p < 0.05).
Mean survival time of islets in mice in the laminarin + low dose tacrolimus group (62) days higher dose tacrolimus (41) days long (n-5, p < 0.05).
The results show that laminarin can prolong the survival time of islet transplants of mice, and the treatment effect of the laminarin combined with tacrolimus is better, and the high dose and the low dose have no obvious difference.
Example 3 Effect of laminarin on the number of T cell subsets Th1, Th2 and Tregs
The test was carried out in the same manner as in example 1.
Collecting spleen of mice 7 days after islet transplantation, grinding with injection piston, filtering with 70 μm nylon mesh, treating with erythrocyte lysate, collecting T lymphocytes, treating with Golgi inhibitor, collecting T cells, staining intracellularly and extracellularly, and detecting Th1(CD 3)+CD8-IFN-γ+)、Th2(CD3+CD8-IL4+) And Treg (CD 4)+CD25+FoxP3+) Number of (mean ±) (SD, n ═ 5). The results of the analysis are shown in FIG. 2:
the content of Th1 in laminarin group is lower than that in PBS group (19.64 + -1.115 VS23.36 + -0.7301, P0.0002)%, the content of Th2 in laminarin group is higher than that in PBS group (2.882 + -0.4755 VS1.686 + -0.2798, P0.0013)%, and the content of Treg in laminarin group is higher than that in PBS group (3.504 + -0.2986 VS 2.630 + -0.1400, P0.0004)%.
The content of Th1 in the low-dose tacrolimus group is lower than that in the PBS group (16.68 +/-0.9257 VS23.36 +/-0.7301 and P < 0.0001)%, the content of Th2 in the low-dose tacrolimus group is higher than that in the PBS group (3.452 +/-0.4083 VS1.686 +/-0.2798 and P < 0.0001)%, and the content of Treg in the low-dose tacrolimus group is higher than that in the PBS group (5.602 +/-0.8195 VS 2.630 +/-0.1400 and P < 0.0001)%.
The content of Th1 in the full dose tacrolimus group is lower than that in the PBS group (14.16 +/-1.074 VS23.36 +/-0.7301, P < 0.0001)%), the content of Th2 in the full dose tacrolimus group is higher than that in the PBS group (4.594 +/-0.5960 VS1.686 +/-0.2798, P < 0.0001)%, and the content of Treg in the full dose tacrolimus group is higher than that in the PBS group (7.136 +/-0.4396 VS 2.630 +/-0.1400, P < 0.0001)%.
The content of Th1 in the laminarin and low-dose tacrolimus group is lower than that in PBS group (10.88 + -0.1924 VS23.36 + -0.7301, P < 0.0001)%, the content of Th2 in the laminarin and low-dose tacrolimus group is higher than that in PBS group (7.236 + -0.4024 VS1.686 + -0.2798, P < 0.0001)%, and the content of Treg in the laminarin and low-dose tacrolimus group is higher than that in PBS group (9.238 + -1.192 VS 2.630 + -0.1400, P < 0.0001)%.
The content of Th1 in the laminarin + full dose tacrolimus group is lower than that in PBS group (11.24 + -0.2408 VS23.36 + -0.7301, P < 0.0001)%, the content of Th2 in the laminarin + full dose tacrolimus group is higher than that in PBS group (7.704 + -1.238 VS1.686 + -0.2798, P < 0.0001)%, and the content of Treg in the laminarin + full dose tacrolimus group is higher than that in PBS group (10.10 + -1.661 VS 2.630 + -0.1400, P < 0.0001)%.
The content of Th1 in the laminarin + low-dose tacrolimus group is lower than that in the laminarin + full-dose tacrolimus group (10.88 +/-0.1924 VS 11.24 +/-0.2408, P ═ 0.031)%, the content of Th2 in the laminarin + low-dose tacrolimus group is not obviously different than that in the laminarin + full-dose tacrolimus group (7.236 +/-0.4024 VS7.704 +/-1.238, P ═ 0.4446)%, and the content of Treg in the laminarin + low-dose tacrolimus group is not obviously different than that in the laminarin + full-dose tacrolimus group (9.238 +/-1.192 VS 10.10 +/-1.661, P ═ 0.3755)%.
The above results indicate that laminarin can up-regulate the amount of Th2 and Treg, down-regulate the amount of Th1, and thus inhibit the rejection of receptors. And the combined tacrolimus has better effect of inducing immune tolerance, but the effect of the low dose tacrolimus on Th2 and Treg is not obviously different compared with the full dose tacrolimus.
Example 4 Effect of laminarin on the secretion levels of cytokines IL-10 and IFN- γ
The test was carried out in the same manner as in example 1.
Peripheral blood of each group of mice was collected by tail vein bleeding on day 7 after the operation, serum was separated, and the expression levels of cytokines IL-10 and IFN- γ (mean ± SD, n ═ 5) in peripheral blood were measured by ELISA kit. The results of the analysis are shown in FIG. 3:
the IL-10 content of laminarin group was higher (164.3 + -8.468 VS93.26 + -9.995, P <0.0001) pg/ml than that of PBS group, and the IFN- γ content of laminarin group was lower (1627.0 + -64.59 VS2001.0 + -97.21, P <0.0001) pg/ml than that of PBS group.
The IL-10 content in the low-dose tacrolimus group is higher than that in the PBS group (189.6 + -5.907 VS93.26 + -9.995, P <0.0001) pg/ml, and the IFN-gamma content in the low-dose tacrolimus group is lower than that in the PBS group (1322.0 + -43.76 VS2001.0 + -97.21, P <0.0001) pg/ml.
The IL-10 content of the full dose tacrolimus group is higher than that of the PBS group (235.6 +/-17.93 VS93.26 +/-9.995, P <0.0001) pg/ml, and the IFN-gamma content of the full dose tacrolimus group is lower than that of the PBS group (1135.0 +/-77.88 VS2001.0 +/-97.21, P <0.0001) pg/ml.
The IL-10 content in the laminarin + low dose tacrolimus group is higher than that in PBS group (316.9 + -26.58 VS93.26 + -9.995, P <0.0001) pg/ml, and the IFN-gamma content in the laminarin + low dose tacrolimus group is lower than that in PBS group (641.4 + -27.77 VS2001.0 + -97.21, P <0.0001) pg/ml.
The IL-10 content in the laminarin + full dose tacrolimus group is higher than that in PBS group (339.1 + -26.80 VS93.26 + -9.995, P <0.0001) pg/ml, and the IFN-gamma content in the laminarin + full dose tacrolimus group is lower than that in PBS group (553.7 + -44.20 VS2001.0 + -97.21, P <0.0001) pg/ml.
The content of IL-10 in the laminarin + low dose tacrolimus group is not obviously different from that in the laminarin + full dose tacrolimus group (316.9 + -26.58 VS 339.1 + -26.80, P + -0.2246) pg/ml), and the content of IFN-gamma in the laminarin + low dose tacrolimus group is higher than that in the laminarin + full dose tacrolimus group (641.4 + -27.77 VS553.7 + -44.20, P ═ 0.0056) pg/ml.
The above results indicate that laminarin can induce the secretion of cytokine IL-10, reduce the secretion of cytokine IFN-gamma, and thus inhibit the rejection of the receptor. And the combined tacrolimus has better effect of inducing immune tolerance, but the influence of the low dose of tacrolimus on the IL-10 secretion is not obviously different than that of the full dose of tacrolimus.
Example 5 inhibition of dectin-1 by laminarin and immunoprotection of the graft
The test was carried out in the same manner as in example 1.
On the day of the occurrence of rejection reaction after transplantation, the kidneys with transplanted islets of langerhans of mice in the PBS group and the laminarin group were obtained and stored in 10% paraformaldehyde, then collectively sent to the pathology department of our hospital for slicing, the sliced tissue sections were baked in an oven at 60 ℃ for 30min, and then were respectively dewaxed with xylene (5min × 3 times), and dehydrated with 100% ethanol, 95% ethanol, and 70% ethanol for 3 times. Endogenous peroxidase activity was inhibited with 3% aqueous methanol dioxide, followed by tissue blocking with sheep serum for 1 h. The anti-Dectin-1 antibody was diluted 1: 200(PBS), incubated overnight at 4 deg.C, and then washed 4 times with PBS on a shaker. After addition of the secondary antibody, color development was performed with diaminobenzidine.
The results are shown in FIG. 4, in which FIG. 4A is PBS group and FIG. 4B is laminarin group. The results show that the expression of Dectin-1 is less in panel B than in panel A, indicating that laminarin inhibits the expression of Dectin-1 and that rejection is more severe in panel A than in panel B.
Meanwhile, the result also shows that Dectin-1 is a regulation target point influencing the rejection reaction of the recipient on the transplanted organ and inducing immune tolerance, and can inhibit the rejection reaction of the recipient on the transplanted organ and inducing immune tolerance by inhibiting Dectin-1.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (2)
1. Use of laminarin in combination with tacrolimus for the manufacture of a medicament capable of inhibiting rejection of a recipient of a transplanted organ and inducing immune tolerance.
2. The drug capable of inhibiting rejection reaction of a recipient on a transplanted organ and inducing immune tolerance is characterized by comprising laminarin and tacrolimus, wherein the mass ratio of the laminarin to the tacrolimus is 10: 0.1-1.
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