Application of paeoniflorin in preparation of medicine for preventing or treating acute graft versus host disease

Abstract

The invention relates to the technical field of biological medicine, and discloses application of paeoniflorin in preparation of medicine for preventing or treating acute graft versus host disease. The invention can promote hematopoietic recovery to regulate immune homeostasis. The donor hematopoietic stem cells are mobilized, glycometabolism, fatty acid metabolism and amino acid metabolism pathways of the hematopoietic stem cells are activated in a targeted manner, the activity of the transplanted hematopoietic stem cells is enhanced, and hematopoietic reconstruction is accelerated. The application disclosed by the invention can play a role in preventing or treating aGVHD by inhibiting amplification and activation of donor T cells, inhibiting release of inflammatory cytokines / chemotactic factors, improving the level of anti-inflammatory cytokines, relieving intestinal injury, balancing intestinal flora and other mechanisms.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of biological medicine, and particularly relates to application of paeoniflorin in preparation of a medicine for preventing or treating acute graft-versus-host disease. BACKGROUND

[0002] Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective method for treating various malignant and benign diseases of the blood system, but acute graft-versus-host disease (aGVHD) as one of the most common complications after allo-HSCT seriously affects the survival rate and quality of life of patients. aGVHD mainly occurs within 100 days after allo-HSCT, is an immune response in which the initial T cells of the donor are activated into effector T cells under the action of pro-inflammatory environment and antigen-presenting cells, and then cause damage to target organs, mainly involving organs such as skin, intestine and liver. Among all patients receiving allo-HSCT, 30-50% of the patients will develop aGVHD, and about 15% of the patients will develop severe aGVHD (grade III-IV). Therefore, exploring the prevention and treatment means of aGVHD is a hot research topic and a scientific problem that needs to be solved urgently in clinic.

[0003] The current standard prophylaxis regimen for aGVHD is a calcineurin inhibitor combined with methotrexate regimen, which can block the activation of donor T cells and prevent aGVHD in about 40%-60% of transplanted patients. However, this regimen still faces many challenges in clinical practice, such as obvious hepatorenal toxicity, possible infection, poor effect in unrelated donor transplantation, etc. In recent years, new aGVHD prevention drugs such as ruxolitinib, sirolimus, abatacept, etc. also still have many problems, such as large heterogeneity of patient response, narrow application, limited long-term safety data, etc. At the same time, in terms of aGVHD treatment, clinical medication is greatly dependent on the glucocorticoid-based regimen, but hormone therapy also causes metabolic disorders, severe immunosuppression, irreversible organ damage and other side effects. In addition, about 40%-60% of patients do not respond to hormone therapy, and the prognosis of this part of patients is very poor. Due to the double dilemma of aGVHD in prevention and treatment, it is necessary to continuously develop and explore new aGVHD prevention or treatment drugs to improve the prognosis of transplanted patients. Monomeric compounds derived from botanical drugs have a clear chemical structure, which is conducive to mechanism research, standardized production and clinical application, and many compounds have been reported to play a strong anti-inflammatory role, so they are expected to be candidates for aGVHD prevention or treatment drugs. For example, paeoniflorin, as a monoterpenoid glycoside compound derived from the peony family, has the characteristics of fast absorption, wide distribution and low toxicity, and has been proven to play a protective role in various inflammatory and autoimmune diseases such as contact dermatitis, lupus nephritis and ulcerative colitis. However, the role of paeoniflorin in aGVHD has not been reported. SUMMARY

[0004] Therefore, the present application aims to provide an application of paeoniflorin in preparing a drug for preventing or treating acute graft-versus-host disease, which can prevent or treat aGVHD by inhibiting the expansion and activation of donor T cells, inhibiting the release of inflammatory cytokines / chemokines, increasing the level of anti-inflammatory cytokines, reducing intestinal injury and balancing intestinal flora, and other mechanisms.

[0005] The present application solves the above technical problems by the following technical means:

[0006] In a first aspect, the present application provides an application of paeoniflorin in preparing a drug for preventing or treating acute graft-versus-host disease.

[0007] Preferably, the paeoniflorin is used for mobilizing donor hematopoietic stem cells to prevent or treat acute graft-versus-host disease.

[0008] The paeoniflorin of the present application promotes hematopoietic recovery to regulate immune homeostasis. By mobilizing donor hematopoietic stem cells, targeting the glycometabolism, fatty acid metabolism and amino acid metabolism pathways of activated hematopoietic stem cells, the activity of hematopoietic stem cells after transplantation is enhanced, and hematopoietic reconstruction is accelerated (manifested as increasing the levels of blood routine indexes WBC, RBC, HGB, PLT, increasing the number of bone marrow mononuclear cells and hematopoietic stem cells, and increasing the levels of serum hematopoietic stimulating factors IL-3, G-CSF, GM-CSF). Successful hematopoietic recovery can reverse the hematopoietic delay caused by aGVHD, and at the same time, by restoring the immune system homeostasis, the pathological process of aGVHD is reversed.

[0009] Preferably, the paeoniflorin is used for preventing or treating acute graft-versus-host disease by inhibiting the expansion and activation of donor T cells.

[0010] Preferably, the donor T cells include CD8 + T cells and CD4 + T cells.

[0011] Preferably, the paeoniflorin is used for regulating cytokine levels to prevent or treat acute graft-versus-host disease, specifically including inhibiting the release of inflammatory cytokines and chemokines, and increasing the release of anti-inflammatory factors.

[0012] Preferably, the inflammatory cytokines include TNF-α, IFN-γ, IL-2, IL-6, IL-17A, the chemokines include CCL2, CCL3, CCL4, CCL5, CXCL1, and the anti-inflammatory factors include IL-4, IL-10.

[0013] The paeoniflorin of the present application inhibits excessive immune response to reduce inflammatory injury. By reducing donor-derived CD4+ T cells and CD8 + Abnormal expansion of T cells in the recipient, over-activation of inflammation-related pathways such as JAK / STAT signaling pathway, chemokine signaling pathway, thereby reducing the release of pro-inflammatory cytokines (TNF-alpha, IFN-gamma, IL-2, IL-6, IL-17A) and chemokines (CCL2, CCL3, CCL4, CCL5, CXCL1), while increasing the levels of anti-inflammatory cytokines (IL-4, IL-10), ultimately reducing immune-mediated target organ damage.

[0014] Preferably, the paeoniflorin is used to prevent or treat acute graft-versus-host disease by restoring intestinal flora balance.

[0015] The paeoniflorin of the present application restores intestinal flora homeostasis to protect the intestinal barrier. By improving intestinal microecological diversity (improving Chao1 index, Simpson index, Shannon index, and Observed Species index), regulating intestinal flora structure under aGVHD pathological state, making the species ratio of phylum level (Firmicutes_D, Bacteroidota, Firmicutes_A) and genus level (Lactobacillus, Duncaniella, etc.) tend to be normalized, while up-regulating the biosynthesis pathways of butirosin and neomycin, and down-regulating the epithelial bacterial invasion pathway, thereby maintaining intestinal flora homeostasis and reducing aGVHD-related intestinal damage.

[0016] In a second aspect, the present application provides a medicine for preventing or treating acute graft-versus-host disease, the medicine comprising paeoniflorin.

[0017] Preferably, the administration route of the medicine comprises one or more of oral administration, intraperitoneal injection, subcutaneous injection, intravenous injection, and intramuscular injection.

[0018] The beneficial effects of the present application are:

[0019] (1) The present application first discovers that paeoniflorin can effectively prevent or treat acute graft-versus-host disease, reduce aGVHD score, and improve survival and weight loss.

[0020] (2) The present application effectively reverses the damage to hematopoietic reconstruction caused by aGVHD, increases the number and activity of hematopoietic stem cells, and accelerates the recovery of blood routine indexes and hematopoietic stimulating factor levels, laying a foundation for the reconstruction of immune system homeostasis.

[0021] (3) Paeoniflorin, as a natural plant-derived monomeric compound, has the characteristics of fast absorption, wide distribution, and low toxicity, and compared with existing chemical drugs, can reduce adverse reactions such as liver and kidney toxicity and infection risk. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 is an experimental graph showing that paeoniflorin prophylaxis can significantly improve mouse aGVHD and promote hematopoietic recovery after transplantation. Among them, (A) aGVHD mouse modeling schematic diagram. (B) Bone marrow chimerism rate of mice in each group. (C) Clinical score of mice in each group. (D) Survival time of mice in each group. (E-H) Blood routine count of mice in each group, including (E) white blood cell count, (F) red blood cell count, (G) hemoglobin count, (H) platelet count. (I) Bone marrow mononuclear cell number of mice in each group. (J-K) Bone marrow hematopoietic stem cell number of mice in each group. (L-N) Serum hematopoietic factor levels of mice in each group, including (L) IL-3, (M) G-CSF, (N) GM-CSF. Paeoniflorin (PF) administration dose is 30 mg / kg / day, and cyclosporine A (CsA) administration dose is 10 mg / kg / day. * P <0.05 (compared with BMT group), ** P < 0.01 (compared with BMT group), # P < 0.05 (compared with aGVHD group), ##P < 0.01 (compared with aGVHD group)

[0023] Figure 2 is an experimental graph showing that whole-process paeoniflorin administration can enhance the aGVHD prophylaxis effect. Among them, (A) whole-process paeoniflorin (EP-PF) administration schematic diagram. (B) Bone marrow chimerism rate of mice in each group. (C) Clinical score of mice in each group. (D) Body weight change of mice in each group. (E) Survival time of mice in each group. (F) Skin, liver, small intestine, colon pathological changes of mice in each group. * P <0.05, ** P < 0.01.

[0024] Figure 3 is an experimental graph showing that paeoniflorin prophylaxis can reduce the number of CD8 + T and CD4 + T cells in the spleen and inhibit the pro-inflammatory function. Among them, (A-D) Paeoniflorin significantly reduces the number of (A) total T cells, (B) CD8 + T cells, (C) CD4 + T cells in the spleen, and increases (D) CD4 + T / CD8 + T cell ratio. (E) CD8 + T cell and CD4 + T cell gene expression heat map of each group. (F) Pathway changes of CD8 + T cells and CD4 + T cells in the aGVHD group compared with the BMT group. (G) CD8 + T cells and CD4+ Pathway changes in T cells compared to aGVHD group. (H) Pae administration throughout reversed the gene expression pattern in aGVHD mice. (I) Pae administration throughout reversed the gene expression pattern in CD8 + T cells and CD4 + KEGG enrichment analysis of genes reversed in CD8

[0025] Figure 4 are experimental graphs showing that pae prevention can reduce proinflammatory cytokine / chemokine levels and increase anti-inflammatory cytokine levels. Among them, (A-E) pae reduces serum proinflammatory cytokine levels, including (A) TNF-a, (B) IFN-g, (C) IL-2, (D) IL-6, (E) IL-17A. (F-G) Pae increases serum anti-inflammatory cytokine levels, including (F) IL-4, (G) IL-10. (H-L) Pae reduces serum chemokine levels, including (H) CCL2, (I) CCL3, (J) CCL4, (K) CCL5, (L) CXCL1. * P < 0.05 (compared to BMT group), ** P < 0.01 (compared to BMT group), # P < 0.05 (compared to aGVHD group), ## P < 0.01 (compared to aGVHD group).

[0026] Figure 5 are experimental graphs showing that pae prevention can significantly reduce aGVHD-related intestinal damage. Among them, (A) diarrhea performance of mice in each group, the more serious the anal fecal adhesion, the more serious the diarrhea. (B) The rate of loose stool in mice in each group. (C) The loose stool index of mice in each group. (D) The fecal water content of mice in each group. (E) Intestinal permeability of mice in each group. (F-I) Intestinal apoptosis-related gene expression of mice in each group, including (F) Caspase 3, (G) Caspase 9, (H) Bax, (I) Bcl2. * P < 0.05 (compared to BMT group), ** P < 0.01 (compared to BMT group), # P < 0.05 (compared to aGVHD group), ## P < 0.01 (compared to aGVHD group).

[0027] Figure 6Figure 8 is an experimental diagram that paeoniflorin prevents intestinal flora disorder associated with recoverable aGVHD. Among them, (A-D) are the intestinal flora diversity indexes of mice in each group, including (A) Chao1 index, (B) species number, (C) Simpson index, and (D) Shannon index. (E) Venn diagram of ASVs intersection among the three groups. (F) LEfSe analysis reveals the representative species of each group (LDA score > 2, p < 0.05). (G-H) are the species structure diagrams of each group at (G) door level and (H) genus level. (I) differential metabolic pathway analysis of the paeoniflorin administration group compared with the aGVHD group. *P < 0.05 (compared with the BMT group), **P < 0.01 (compared with the BMT group), #P < 0.05 (compared with the aGVHD group), ##P < 0.01 (compared with the aGVHD group).

[0028] Figure 7 Figure 9 is an experimental diagram that paeoniflorin treatment can significantly improve mouse aGVHD. Among them, (A) is the clinical score of mice in each group. (B) is the survival time of mice in each group. *P < 0.05, **P < 0.01. DETAILED DESCRIPTION

[0029] The technical solutions in the embodiments of the present application will be clearly and completely described below in combination with specific implementation examples of the present application. Obviously, the described embodiments are only some of the embodiments of the present application, not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application:

[0030] I. Construction of aGVHD mouse model and grouping and administration

[0031] Donor and recipient selection: C57BL / 6 mice were used as donors, and BALB / c mice were used as recipients.

[0032] Pre-treatment: The recipient received a dose of 8.5 Gy of 60 Co source gamma rays whole body irradiation 8 hours before transplantation.

[0033] Cell transplantation: After irradiation, the recipient was injected with bone marrow cells (8.0 x 10 6 per mouse) and spleen cells (8.0 x 10 6 per mouse) from the donor through the tail vein to induce aGVHD; the simple bone marrow transplantation group (BMT group, healthy control) was only injected with bone marrow cells (8.0 x 10 6 per mouse).

[0034] Grouping and administration: the aGVHD-induced recipient was randomly divided into 4 groups, at least 6 in each group:

[0035] aGVHD group: intraperitoneal injection of normal saline from day 1 to day 14 after transplantation;

[0036] Paeoniflorin prevention group (PF group): intraperitoneal injection of paeoniflorin from day 1 to day 14 after transplantation, the dose is 30 mg / kg / day;

[0037] Cyclosporine A prevention group (CsA group, positive control): intraperitoneal injection of cyclosporine A from day 1 to day 14 after transplantation, the dose is 10 mg / kg / day.

[0038] The above is shown in Figure 1 A.

[0039] Whole-process administration group setting: In order to optimize the prevention effect, an additional whole-process paeoniflorin administration group (EP-PF group) is set up: the donor mice are continuously intraperitoneally injected with paeoniflorin (30 mg / kg / day) for 7 days before transplantation, and the recipient mice are continuously intraperitoneally injected with paeoniflorin (30 mg / kg / day) from day 1 to day 14 after transplantation, and the transplanted cells are bone marrow and spleen cells from the donor mice pretreated with paeoniflorin.

[0040] Paeoniflorin treatment group setting: In order to explore the treatment effect of paeoniflorin on aGVHD that has already occurred, an additional paeoniflorin treatment group (PF-Treat group) is set up: the recipient mice are intraperitoneally injected with paeoniflorin at a dose of 30 mg / kg / day for 14 days starting from the 7th day after transplantation when obvious aGVHD symptoms are observed.

[0041] II. Detection of aGVHD-related indicators

[0042] All detection indicators are performed on day 14 after transplantation, and the specific methods are as follows:

[0043] 1. Clinical scoring and survival analysis: Observe the state of mice daily, and perform aGVHD clinical scoring according to symptoms such as humpback, curly hair, diarrhea, etc. (0-12 points, the higher the score, the more severe the symptoms), and the specific scoring criteria are shown in the table below. Record the body weight change and survival time synchronously.

[0044]

[0045] 2. Blood routine test: 0.5 mL of orbital blood is collected, and a blood cell automatic counter is used to detect the levels of white blood cells (WBC), red blood cells (RBC), hemoglobin (HGB), and platelets (PLT).

[0046] 3. Hematopoietic function evaluation:

[0047] Flow cytometry is used to detect the number of hematopoietic stem / progenitor cells (Lineage - Sca1 + cKit + cells) in bone marrow;

[0048] The levels of hematopoietic stimulating factors IL-3, G-CSF, and GM-CSF in serum were detected by a liquid suspension chip system (Luminex 200).

[0049] 4. Target organ pathological detection: skin, liver, small intestine, and colon tissues were taken, fixed with 4% paraformaldehyde, embedded in paraffin, sectioned (4 μm), and subjected to HE staining, and the tissue damage (such as liver lobule disorder and small intestinal villus shedding) was observed under an optical microscope.

[0050] 5. Immune function detection:

[0051] The number of total T cells (CD3 + ), CD4 + T cells, CD8 + T cells, and the ratio of CD4 + T cells / CD8 + T cells in the spleen were detected by flow cytometry.

[0052] The levels of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-2, IL-6, and IL-17A), anti-inflammatory cytokines (IL-4 and IL-10), and chemokines (CCL2, CCL3, CCL4, CCL5, and CXCL1) in serum were detected by a multi-factor detection kit.

[0053] 6. Intestinal function evaluation:

[0054] Diarrhea evaluation: the rate of loose stool, loose stool index, and fecal water content were calculated;

[0055] Intestinal permeability detection: 4 hours after intragastric administration of FITC-dextran (400 mg / kg), the FITC fluorescence intensity in serum was detected;

[0056] Real-time fluorescent quantitative PCR was used to detect the mRNA expression levels of apoptosis-related genes (Caspase3, Caspase9, Bax, and Bcl2) in intestinal tissues (the primer sequences are shown in the following table)

[0057]

[0058] Intestinal flora analysis: fecal samples were collected, genomic DNA was extracted by CTAB method, the V3-V4 region of 16S rRNA gene was amplified by PCR, NovaSeq PE250 platform sequencing was performed, and the flora diversity (Chao1, Simpson, and Shannon indices) and species composition (phylum level and genus level) were analyzed.

[0059] III. Statistical analysis

[0060] Data analysis was performed using Graphpad Prism 10.1.2 software. Measurement data were expressed as mean ± standard deviation. One-way ANOVA was used for multiple comparisons. Log-rank test was used for survival analysis. P<0.05 was considered statistically significant (*P<0.05, **P<0.01).

[0061] IV. Experimental results and analysis

[0062] 1. Paeoniflorin can improve aGVHD symptoms and prolong survival

[0063] Figure 1 B and Figure 2 B shows that the average bone marrow chimerism rate of each group can reach 99.0%, indicating that the myeloablation is complete and donor cells are successfully engrafted, and the model is reliable.

[0064] Figure 1 C shows that the clinical score (including symptoms such as humpback, curly hair, diarrhea, etc.) of the aGVHD group is significantly higher than that of the BMT group, while the scores of the PF group and the CsA group are significantly reduced. Figure 2 C further shows that the score of the EP-PF group is significantly lower than that of the PF group and the CsA group.

[0065] Figure 1 D and Figure 2 E shows that the survival time of the aGVHD group is the shortest, the survival time of the PF group and the CsA group is significantly prolonged, and the survival time of the EP-PF group is significantly better than that of the other drug groups (the median survival time is 29.5 days).

[0066] Figure 2 D shows that the body weight of each group rapidly decreases at 1-7 days after transplantation, and the body weight of the aGVHD group does not significantly recover subsequently, while the body weight of the PF group and the CsA group significantly recovers, and the body weight recovery of the EP-PF group is the most obvious.

[0067] Figure 2 F shows that the liver lobule of the aGVHD group is disordered, the small intestinal villi are swollen and shed, the whole layer structure of the colon is damaged, and the goblet cells are reduced. The pathological damage of the PF group and the CsA group is improved to some extent, while the EP-PF group is the most improved, close to the BMT group.

[0068] Therefore, compared with the aGVHD group, the clinical score of the PF group and the CsA group is significantly reduced (P<0.01), the survival time is significantly prolonged (P<0.01), and the target organ damage is significantly reduced. The effect of the whole process drug group (EP-PF group) is better.

[0069] 2. Paeoniflorin can promote hematopoietic reconstitution

[0070] Figure 1E-H showed that the levels of WBC, RBC, HGB and PLT in aGVHD group were significantly decreased, and the levels of the indicators in PF group and EP-PF group were significantly increased, and the levels of the indicators in EP-PF group were close to the levels in BMT group.

[0071] Figure 1 I-K showed that the number of BMMCs and HSPCs in aGVHD group was significantly reduced, and the number of cells in EP-PF group was recovered most significantly.

[0072] Figure 1 L-N showed that the levels of IL-3, G-CSF and GM-CSF in aGVHD group were significantly reduced, and the levels of the factors in EP-PF group were increased most significantly.

[0073] Therefore, the levels of WBC, RBC, HGB and PLT, the number of BMMCs and HSPCs, and the levels of IL-3, G-CSF and GM-CSF in PF group and EP-PF group were significantly higher than those in aGVHD group (P<0.01), and the recovery speed of hematopoiesis in EP-PF group was the fastest.

[0074] 3. Paeoniflorin can reduce immune injury and inflammatory response

[0075] Figure 3 A-D showed that the number of total T cells, CD4 + T cells and CD8 + T cells in aGVHD group was significantly increased, the ratio of CD4 + / CD8 + T cells was inverted, and the number of cells in EP-PF group was reduced most significantly, and the ratio was restored to normal.

[0076] Figure 3 F-G showed that the inflammatory signaling pathways closely related to aGVHD, such as JAK-STAT pathway and chemokine pathway, in aGVHD group were significantly up-regulated, and the activation of the pathways in EP-PF group was significantly inhibited.

[0077] Figure 4 It was shown that the levels of pro-inflammatory factors (TNF-α, IFN-γ, etc.) and chemokines (CCL2, CXCL1, etc.) in serum in aGVHD group were significantly increased, and the levels of anti-inflammatory factors (IL-4, IL-10) were significantly reduced, and the levels of the factors in EP-PF group were reversed most significantly.

[0078] Therefore, PF group and EP-PF group can significantly reduce the number of total T cells, CD4 + T cells and CD8 + T cells in spleen, and restore the ratio of CD4 + / CD8 + T cells (P<0.01).

[0079] The levels of pro-inflammatory cytokines and chemokines in serum were significantly reduced, and the levels of anti-inflammatory cytokines were significantly increased (P < 0.01), and the EP-PF group had stronger inhibitory effect on inflammatory pathways (JAK-STAT, chemokine signaling pathway).

[0080] 4. Paeoniflorin can prevent and protect intestinal function and regulate the balance of intestinal flora

[0081] Figure 5 A-E shows that the rate of loose stool, fecal water content and intestinal permeability of aGVHD group were significantly increased, and the indicators of EP-PF group were significantly reduced, and the improvement of diarrhea was the most obvious.

[0082] Figure 5 F-I shows that the expression of intestinal apoptosis genes (Caspase3, Bax) in aGVHD group was significantly up-regulated, and Bcl2 was significantly down-regulated, and the gene expression of EP-PF group was the closest to that of BMT group.

[0083] Figure 6 A-D shows that the intestinal flora diversity (Chao1, Shannon index) of aGVHD group was significantly reduced, and the diversity of EP-PF group was the most significant.

[0084] Figure 6 G-H shows that Firmicutes_D and Lactobacillus in aGVHD group were over-expanded, Bacteroidota and Duncaniella were reduced, and the proportion of intestinal flora in EP-PF group tended to be normal.

[0085] Therefore, the diarrhea symptoms (loose stool rate, water content) of EP-PF group mice were significantly improved, the intestinal permeability was reduced (P < 0.01), the expression of intestinal apoptosis genes (Caspase3, Bax) was down-regulated, and the expression of anti-apoptotic gene Bcl2 was up-regulated (P < 0.01);

[0086] The diversity of intestinal flora was significantly restored, the over-expansion of Firmicutes_D and the reduction of Bacteroidota were reversed, and the proportion of Lactobacillus and Duncaniella tended to be balanced (P < 0.01).

[0087] 5. Paeoniflorin treatment can improve aGVHD symptoms and prolong survival

[0088] Figure 7A shows that there is no significant difference in clinical score between aGVHD group and PF-Treat group at 1-7 days after transplantation, and both are significantly higher than that of BMT group. After the symptoms of aGVHD are observed in PF-Treat group at 7 days after transplantation and the treatment of paeoniflorin is applied, the clinical score is significantly lower than that of aGVHD group (P<0.01).

[0089] Figure 7 B shows that the survival time of PF-Treat group is significantly longer than that of aGVHD group.

[0090] Therefore, the treatment of paeoniflorin after the occurrence of aGVHD also has good effect.

[0091] The above examples are only used to illustrate the technical solutions of the present application but not limit the present application. Although the present application is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solutions of the present application can be modified or replaced equivalently without departing from the purpose and scope of the present application, and all should be covered in the scope of the claims of the present application. The technical, shape and structure parts not described in detail in the present application are all known technologies.

Claims

1. Use of paeoniflorin in the preparation of a drug for preventing or treating acute graft-versus-host disease.

2. Use according to claim 1, characterized in that: The paeoniflorin is used for mobilizing donor hematopoietic stem cells to prevent or treat acute graft-versus-host disease.

3. Use according to claim 1, characterized in that: The paeoniflorin is used for preventing or treating acute graft-versus-host disease by inhibiting the expansion and activation of donor T cells.

4. Use according to claim 3, characterized in that: The donor T cells comprise CD8 + T cells and CD4 + T cells.

5. The use according to claim 1, characterized in that: The paeoniflorin is used for regulating cytokine levels to prevent or treat acute graft-versus-host disease, specifically including inhibiting the release of inflammatory cytokines and chemokines, and increasing the release of anti-inflammatory factors.

6. Use according to claim 5, characterized in that: The inflammatory cytokines include TNF-α, IFN-γ, IL-2, IL-6, IL-17A, the chemokines include CCL2, CCL3, CCL4, CCL5, CXCL1, and the anti-inflammatory factors include IL-4, IL-10.

7. The use according to claim 1, characterized in that: The paeoniflorin is used for preventing or treating acute graft-versus-host disease by restoring the balance of intestinal flora.

8. A medicament for preventing or treating acute graft-versus-host disease, characterized by, The drug includes paeoniflorin.

9. The medicament according to claim 8, characterized in that, The administration route of the drug includes one or more of oral administration, intraperitoneal injection, subcutaneous injection, intravenous injection, and intramuscular injection.

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