Name: huIL4/huIL4RA Mouse
Brand: サイヤジェン（Cyagen）
SKU: C001834

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huIL4/huIL4RA Mouse

製品名

huIL4/huIL4RA Mouse

製品ID

C001834

系統名

C57BL/6NCya-Il4^em1(hIL4)Il4ra^em1(hIL4R)/Cya

背景情報

C57BL/6NCya

状況

このマウス系統を論文で使用する場合は、「huIL4/huIL4RA Mouse（カタログ番号C001834）はサイアジェンから購入しました。」と引用してください。

HUGO-GT Humanized Models

Tumor Target Humanized Mouse Models

Immune Target Humanized Mouse Models

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遺伝子型

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HUGO-GT Humanized Models

Tumor Target Humanized Mouse Models

Immune Target Humanized Mouse Models

基本情報

検証 Data

系統詳細

Interleukin-4 (IL-4) and its receptor, IL-4R, are pivotal regulators of immune responses and inflammation. The IL4 gene encodes the IL-4 cytokine, a multifunctional protein predominantly secreted by Th2 cells, mast cells, and eosinophils, while the IL4R gene encodes the IL-4 receptor, which is expressed on a variety of immune cells, including B cells, T cells, macrophages, and endothelial cells. IL-4 binds to IL-4R, which exists in two distinct forms: Type I (comprising IL-4Rα and the common γ-chain) and Type II (comprising IL-4Rα and IL-13Rα1)^[1]. This interaction activates the JAK-STAT signaling pathway, driving Th2 cell differentiation, B cell class switching to IgE, and anti-inflammatory responses. The IL-4/IL-4R signaling axis is critically implicated in allergic diseases such as asthma, atopic dermatitis, and allergic rhinitis, as well as in parasitic infections and certain cancers^[2-5]. Dysregulation of this pathway underlies various pathological conditions, positioning IL-4Rα as a promising therapeutic target. For instance, dupilumab, a monoclonal antibody targeting IL-4Rα, has been approved for the treatment of atopic dermatitis, asthma, and chronic rhinosinusitis with nasal polyps, underscoring the therapeutic potential of modulating this pathway^[6-7].

The huIL4/huIL4RA mouse model is generated by crossing IL4 humanized mice (Catalog Number: C001628) with IL4R humanized mice (Catalog Number: C001629), resulting in a dual-humanized model. This model faithfully recapitulates the human IL-4/IL-4R signaling pathway, making it an invaluable tool for studying allergic diseases (e.g., asthma and atopic dermatitis), Th2 immune responses, parasitic infections, tumor immunology, and chronic inflammation. Furthermore, it serves as a robust preclinical platform for evaluating the efficacy and mechanisms of therapeutic agents targeting the IL-4/IL-4Rα pathway.

参考文献

Gandhi NA, Bennett BL, Graham NM, Pirozzi G, Stahl N, Yancopoulos GD. Targeting key proximal drivers of type 2 inflammation in disease. Nat Rev Drug Discov. 2016 Jan;15(1):35-50.

Oetjen LK, Mack MR, Feng J, Whelan TM, Niu H, Guo CJ, Chen S, Trier AM, Xu AZ, Tripathi SV, Luo J, Gao X, Yang L, Hamilton SL, Wang PL, Brestoff JR, Council ML, Brasington R, Schaffer A, Brombacher F, Hsieh CS, Gereau RW 4th, Miller MJ, Chen ZF, Hu H, Davidson S, Liu Q, Kim BS. Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch. Cell. 2017 Sep 21;171(1):217-228.e13.

Bankaitis KV, Fingleton B. Targeting IL4/IL4R for the treatment of epithelial cancer metastasis. Clin Exp Metastasis. 2015 Dec;32(8):847-56.

Davoodi P, Mahesh PA, Holla AD, Ramachandra NB. A preliminary study on the association of single nucleotide polymorphisms of interleukin 4 (IL4), IL13, IL4 receptor alpha (IL4Rα) & Toll-like receptor 4 (TLR4) genes with asthma in Indian adults. Indian J Med Res. 2015 Dec;142(6):675-80.

Choy DF, Hart KM, Borthwick LA, Shikotra A, Nagarkar DR, Siddiqui S, Jia G, Ohri CM, Doran E, Vannella KM, Butler CA, Hargadon B, Sciurba JC, Gieseck RL, Thompson RW, White S, Abbas AR, Jackman J, Wu LC, Egen JG, Heaney LG, Ramalingam TR, Arron JR, Wynn TA, Bradding P. TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma. Sci Transl Med. 2015 Aug 19;7(301):301ra129.

Muñoz-Bellido FJ, Moreno E, Dávila I. Dupilumab: A Review of Present Indications and Off-Label Uses. J Investig Allergol Clin Immunol. 2022 Apr 19;32(2):97-115.

Napolitano M, Ruggiero A, Patruno C. Dupilumab-associated inflammatory arthritis: a literature review. Clin Exp Dermatol. 2024 Mar 21;49(4):307-312.

系統作製戦略

Figure 1. huIL4 Mice Strategy. The sequences from the start codon to the stop codon of the endogenous mouse Il4 gene were replaced with the sequences from the start codon to the stop codon of the human IL4 gene.

Figure 2. huIL4RA Mice Strategy. The extracellular domain of the mouse Il4ra was replaced with the corresponding human IL4R extracellular domain, while retaining the murine signal peptide.

適用分野

Investigation of immune regulation and Th2 responses, allergic diseases, parasitic infections, and tumor immunology;

Preclinical development, screening, and efficacy evaluation of IL4/IL4R-targeted therapeutic agents;

Studies on inflammation and autoimmune diseases.

検証 Data

1. Gene Expression (RT-qPCR)

Transcript levels of hIL4, hIL4RA, mIl4, and mIl4ra were analyzed in the spleen and thymus of huIL4/huIL4RA and wild-type (WT) mice using species-specific primers. mβ-actin was used as the internal reference gene, and the relative expression level of each gene in each tissue was calculated. Data are presented as mean±SD. hIL4 and hIL4RA transcripts were detected in the spleen and thymus of huIL4/huIL4RA mice, whereas mIl4 and mIl4ra transcripts were not detected. In contrast, mIl4 and mIl4ra transcripts were detected in the spleen and thymus of WT mice, whereas hIL4 and hIL4RA transcripts were not detected.

Figure 3. RT-qPCR analysis of human IL4 and IL4RA transcripts and mouse Il4 and Il4ra transcripts in huIL4/huIL4RA and wild-type (WT) mice (8–9 weeks old, homozygous, female, n=4).

2. IL4RA Protein Expression (FACS)

Splenocytes were isolated from homozygous huIL4/huIL4RA and wild-type (WT) mice under basal or anti-mCD3ε-stimulated conditions to evaluate hIL4RA and mIL4RA protein levels using specific antibodies. Under basal conditions, hIL4RA was detected in splenic B cells of huIL4/huIL4RA mice but not in WT mice. Following anti-mCD3ε stimulation, the proportion of hIL4RA-positive B cells increased in huIL4/huIL4RA mice, with no mIL4RA detected. Conversely, WT mice expressed only mIL4RA, with no hIL4RA signal observed.

Figure 4. Flow cytometric analysis of human and mouse IL4RA protein expression in splenic B cells of huIL4/huIL4RA and wild-type (WT) mice. (7–9-week-old female homozygous mice, n ≥ 4).

3. IL-4 Protein Expression in the OXA-induced Atopic Dermatitis Model (ELISA)

(A) Schematic of the experimental procedure. Six-week-old female mice (n=3) were sensitized with a high dose of oxazolone (OXA) on Day 0, followed by repeated low-dose OXA ear challenges from Day 7 to 25. Mice were sacrificed on Day 26. Ear tissues were collected, snap-frozen, and homogenized to measure mouse and human IL-4 protein levels via ELISA.

(B) Mouse IL-4 protein was detected in the ear tissues of wild-type (WT) mice but not in huIL4/huIL4RA mice, confirming successful replacement of the endogenous mouse Il4 gene.

(C) Human IL-4 protein was detected in the ear tissues of huIL4/huIL4RA mice but not in WT mice, demonstrating that the human IL4 gene is functionally expressed under OXA-induced inflammatory conditions.

Figure 5. ELISA quantification of human and mouse IL-4 protein levels in ear tissues of huIL4/huIL4RA and wild-type (WT) mice in the OXA-induced atopic dermatitis model (6-week-old female homozygous mice, n=3. Data are presented as mean±SD).

4. Pharmacodynamics (PD) evaluation of Dupilumab in the OVA-induced allergic asthma model

(A) Schematic of the experimental procedure. An OVA-induced allergic asthma model was established in 6-week-old female huIL4/huIL4RA mice and treated with varying doses of Dupilumab.

(B) Growth curves indicated no significant differences in body weight among the groups during the experimental period.

(C–E) FACS analysis revealed that OVA stimulation significantly increased the infiltration of CD45⁺ immune cells and eosinophils in bronchoalveolar lavage fluid (BALF). Dupilumab treatment effectively attenuated this cellular infiltration in a dose-dependent manner, further reducing the proportion of eosinophils among CD45⁺ cells.

(F–H) ELISA results demonstrated that OVA stimulation significantly elevated the levels of hIL-4, mCCL17 (TARC) in BALF, and total serum IgE. These markers were significantly reduced following Dupilumab treatment.

Collectively, these findings indicate that OVA-induced huIL4/huIL4RA mice exhibit a typical Th2-type airway inflammation phenotype and respond effectively to Dupilumab, making this model suitable for pharmacodynamics (PD) evaluation of drugs targeting the IL-4/IL-4RA pathway. (Data are presented as Mean±SEM, n=3–5. One-way ANOVA: *p<0.05, **p<0.01, ***p<0.001.)

Figure 6. Efficacy of Dupilumab treatment on airway inflammation in huIL4/huIL4RA mice in the OVA-induced allergic asthma model (6-week-old female mice).

huIL4/huIL4RA Mouse

基本情報

検証 Data

関連リソース

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さらに

データシート

系統詳細

参考文献

系統作製戦略

適用分野

1. Gene Expression (RT-qPCR)

2. IL4RA Protein Expression (FACS)

3. IL-4 Protein Expression in the OXA-induced Atopic Dermatitis Model (ELISA)

4. Pharmacodynamics (PD) evaluation of Dupilumab in the OVA-induced allergic asthma model

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