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Method of immune modulation by modulating ABCF1

A technology for immune response and autoimmune diseases, applied in the field of immune regulation, which can solve problems such as lack of transmembrane domains

Pending Publication Date: 2021-12-24
太平洋米科生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unlike other ABC family members, ABCF1 lacks a transmembrane domain and does not appear to function as a transporter

Method used

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  • Method of immune modulation by modulating ABCF1
  • Method of immune modulation by modulating ABCF1
  • Method of immune modulation by modulating ABCF1

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Example 1: A novel ubiquitin E2-conjugating enzyme, ABCF1, reverse-regulates TLR4 endocytosis and cytokine storm during sepsis

[0072] ABCF1 counter-regulates inflammation through TLR2 and TLR9. It binds to OAS1, regulates dsRNA viral cleavage and controls viral infection. After LPS stimulation, ABCF1 regulates ITAM phosphorylation in FcyR II A and regulates E. coli phagocytosis in BMDM.

[0073] Materials and methods

[0074]Mice and cells: Bone marrow cells were isolated from the femur and tibia of C57BL / 6 mice and matured into macrophages as described (Trouplin et al., 2016). Abcf1+ / - mice (Het) were prepared as previously described (Wilcox et al., 2017), and C57BL / 6J (Jackson Laboratories; 000664) mice were used as wild-type (WT) controls for in vivo experiments.

[0075] Transfection: All gene knockdown in cells with liposomes TM RNAiMAX transfection reagent (Thermo Fisher Scientific; 13778075) was accomplished by RNAi interference according to the manufactur...

Embodiment 2

[0111] Example 2: ABCF1 controls endocytosis of TLR4 through its E2-binding activity

[0112] Here, ABCF1 is described as an E2 ubiquitin-conjugating enzyme, a novel activity among ABC transporters involved in regulating and controlling key elements of cytokine secretion through ubiquitination, modulating TLR4 endocytosis and controlling sepsis-mediated Leading ET period.

[0113] result

[0114] ABCF1 switches macrophage polarization to the M2b phenotype: To investigate whether ABCF1 regulates the switch in macrophage polarization, LPS-stimulated Abcf1 siRNA-treated and overexpressed BMDMs were analyzed for M1 and M2 specificity by flow cytometry Levels of cell surface markers. The levels of M1-specific markers such as CD86 and MHC-II were highest in Abcf1 siRNA-treated cells, followed by ABCF1-overexpressed cells ( Figure 8 A). On the other hand, the levels of M2a-specific CD206 in Abcf1 siRNA-treated and ABCF1-overexpressed cells were the same or slightly lower than th...

Embodiment 3

[0142] Example 3: ABCF1 regulates the transition from SIRS to ET phase during sepsis:

[0143] Sepsis is a biphasic disease characterized by an initial hyperinflammatory phase, also known as systemic inflammatory response syndrome (SIRS), followed by an immunocompromised phase, termed endotoxin tolerance (ET). The SIRS phase showed massive production of pro-inflammatory cytokines such as IL1β, TNFα, IL-6, and downregulation of anti-inflammatory cytokines such as IL-10, IL-4, IL-1Rα, while the ET phase showed the complete opposite. In SIRS, intense inflammatory insults often lead to impaired contractility, reduced cardiac index and ejection fraction, leading to circulatory collapse. Persistent circulatory failure leads to disruption of the microcirculation and vasculature, leading to multiple organ dysfunction syndrome (MODS), a major determinant of sepsis mortality. Transition to the ET phase suppresses the overall inflammatory response, and death during this phase may be due...

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Abstract

The present invention relates to methods of immune modulation. In particular, the present invention relates to regulation of inflammation and immune responses by modulation of ABCF1. Modulation of ABCF1 may be useful in the treatment of sepsis, autoimmune diseases, cancer or infections.

Description

technical field [0001] The present invention relates to methods of immunomodulation. In particular, the present invention relates to the modulation of inflammatory and immune responses through modulation of ABCF1. Background technique [0002] Inflammation and immune responses are tightly regulated cellular mechanisms that help maintain cellular homeostasis. These mechanisms are controlled by several proteins that regulate downstream effector cascades. Modulation of these downstream effectors can be used in the treatment of diseases, including the treatment of sepsis, inflammatory bowel disease, Crohn's disease and cancer. ABCF1, a protein of the ABC transporter family that has been shown to regulate innate immune responses, is a risk gene for autoimmune pancreatitis and arthritis. Unlike other ABC family members, ABCF1 lacks a transmembrane domain and does not appear to function as a transporter. The ABCF1 gene is located in the class I region of the major histocompatib...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/17A61P29/00A61P37/02C07K14/47C12N15/12C12N15/85G01N33/48
CPCA61P29/00A61P37/02G01N2333/9015G01N2800/24G01N2800/065G01N2800/042C12Q1/25G01N2500/00A01K2217/075A01K2227/105A01K2267/0337A61K38/177C07K14/705C07K2319/60A61P19/02A61P1/18C12Q1/68C12Q2600/158
Inventor 威尔弗雷德·杰弗里斯希特什·阿罗拉萨拉·威尔科克斯隆纳·蒙罗谢丽尔·菲弗
Owner 太平洋米科生物科技有限公司
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