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Application of RANK<+> macrophages in preparation of medicament for treating spontaneous abortion and preventing miscarriage

A technology for spontaneous abortion and use, applied in the field of medicine, can solve the problem of the specific mechanism to be elucidated and so on

Inactive Publication Date: 2018-02-06
THE OBSTETRICS & GYNECOLOGY HOSPITAL OF FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This differential effect may be related to the local microenvironment of mucosal tissue, but the specific mechanism remains to be elucidated

Method used

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  • Application of RANK&lt;+&gt; macrophages in preparation of medicament for treating spontaneous abortion and preventing miscarriage
  • Application of RANK&lt;+&gt; macrophages in preparation of medicament for treating spontaneous abortion and preventing miscarriage
  • Application of RANK&lt;+&gt; macrophages in preparation of medicament for treating spontaneous abortion and preventing miscarriage

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Example 1 Analysis of the expression levels of RANKL and RANK at the maternal-fetal interface

[0049] 1) RANKL is highly expressed in Tros and DSCs at the maternal-fetal interface in normal early pregnancy

[0050] Firstly, by immunohistochemical staining, it was found that both Tros and DSCs at the maternal-fetal interface in normal early pregnancy highly expressed RANKL (both RANKL and RANK immunohistochemical antibodies were from R&D companies) (eg figure 1 Shown in A); Tros and DSCs are obtained by primary isolation and culture subsequently, utilize ELISA detection (ELISA kit comes from R&D company) to find that Tros and DSCs all can secrete soluble RANKL (such as figure 1 B, shown in 1C), and the secretion level of soluble RANKL was the highest when the two cells were co-cultured (as shown in figure 1 C shown);

[0051] 2) High expression of RANK, and RANK + More towards the M2 phenotype

[0052] Normal early pregnancy decidual tissues were collected, and ...

Embodiment 2

[0053] Example 2 Adoptive transfer of RANK + induced pregnant mouse uterus In vivo differentiation towards the M2-tolerant phenotype

[0054] By plasmid transfection (transfection reagent comes from Invitrogen company), construct the DSCs and JEG-3 cell that RANKL overexpresses, it is combined with After co-culture, it was found that Tros and DSCs overexpressing RANKL could promote Differentiate to M2 phenotype (the levels of CD163, CD206, CD209 and IL-10 were all increased; CD86, IL-12, etc. were all decreased) (flow antibodies were purchased from Biolegend) (such as image 3 A, 3B shown), then, as image 3 As shown in C, spleen CD45 was obtained by flow sorting + F4 / 80 + RANK + and CD45 + F4 / 80 + RANK - (The flow-type antibodies were all purchased from Biolegend), and the above-mentioned two kinds of cells were labeled with PKH-67 dye (green fluorescence, sigma company), and healthy C57B / L6 mice (Shanghai Slack Experimental Animal Co., Ltd.) The suppositor...

Embodiment 3

[0055] Example 3 Adoptive transfer of RANK + Induction of Th2 immune bias in pregnant mouse uterus in vivo

[0056] Co-cultured with or without Tros and DSCs, respectively Co-culture with decidual naiveT cells (eg Figure 4 Shown in A), the results show that after training with RANKL derived from Tros and DSCs can be further induced Differentiation of T cells to Th2 phenotype (increased expression of IL-4, IL-10 and GATA-3; conversely, decreased levels of TNF-α, IFN-γ and T-bet) (ELSIA kit from R&D company) (eg Figure 4 Shown in B-4E), found by the above method, relative to PKH-67-RANK - group, PKH-67-RANK + CD4+ T cells in the uterus of pregnant mice in the transfusion group were biased toward Th2 differentiation (GATA-3 expression increased; on the contrary, T-bet level decreased) (flow cytometry antibodies were purchased from Biolegend) (eg Figure 4 F shown).

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Abstract

The invention belongs to the technical field of medicaments, and relates to application of RANK<+> macrophages, in particular to the application of the RANK<+> macrophages in preparation of a medicament for treating spontaneous abortion and preventing miscarriage. According to the application of the RANK<+> macrophages in the preparation of the medicament for treating the spontaneous abortion andpreventing the miscarriage, in-vitro experiments and in-vivo animal experiments show that an RANKL / RANK signal in an early pregnant mother-fetal interface can obviously induce differentiation from decidual macrophages to an M2 phenotype so as to induce Th2 immune deviation of the early pregnant mother-fetal interface, which is beneficial to establishment and maintenance of normal pregnancy; adoptively transferred RANK<+> macrophages can remarkably reverse fetal resorption of a pregnant mice caused by dysfunction of the macrophages, and can be further used for the preparation of the medicamentfor treating the spontaneous abortion and preventing the miscarriage.

Description

technical field [0001] The invention belongs to the technical field of medicine and relates to RANK + Use of macrophages, specifically related to RANK + Use of macrophages in the treatment of spontaneous abortion and miscarriage protection. In vitro experiments and in vivo animal experiments have shown that the RANKL / RANK signal at the maternal-fetal interface during early pregnancy can significantly induce the differentiation of decidual macrophages to the M2 phenotype, thereby inducing the Th2 immune shift at the maternal-fetal interface, which is conducive to the establishment and development of normal pregnancy. maintain. Adoptive transfer RANK + Macrophages can significantly reverse the absorption of mouse embryos caused by abnormal macrophage function, and can be further used as a miscarriage therapy for spontaneous abortion. Background technique [0002] Studies have shown that normal pregnancy is similar to successful allogeneic transplantation. The mother not on...

Claims

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Application Information

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IPC IPC(8): A61K35/15A61P15/06
CPCA61K35/15
Inventor 李明清李大金孟玉菡周文洁金莉萍杜美蓉
Owner THE OBSTETRICS & GYNECOLOGY HOSPITAL OF FUDAN UNIV
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