B6-hIL12B Mice

Catalog Number: C001619

Strain Name: C57BL/6NCya-Il12b^em1(hIL12B)/Cya

Genetic Background: C57BL/6NCya

Reproduction: Homozygote x Homozygote

Strain Description

The IL12B gene encodes the p40 subunit, a component of both interleukin-12 (IL-12) and IL-23, which are formed through heterodimerization with IL-12p35 and IL-23p19, respectively ^[1]. Primarily secreted by activated monocytes, macrophages, dendritic cells, and B lymphocytes, these cytokines modulate Th1 and Th17 cell differentiation via the JAK-STAT signaling pathway, playing critical roles in immunity against intracellular pathogens and in inflammatory responses. IL-12 also enhances cellular immunity through the induction of interferon-gamma ^[1-2]. IL12B gene expression is regulated by NF-κB and IRF transcription factors, and aberrant activation is implicated in autoimmune pathogenesis. Notably, single nucleotide polymorphisms (SNPs) within IL12B and an overactive IL-12/IL-23 pathway are strongly associated with susceptibility to autoimmune diseases ^[1-3]. Monoclonal antibodies targeting IL-12B, such as ustekinumab, are clinically utilized for the treatment of moderate to severe psoriasis and Crohn's disease ^[4-5]. Within the tumor microenvironment, IL-12B exhibits a complex functional profile, potentially enhancing cytotoxic T and NK cell activity, promoting IFN-γ production, and driving anti-tumor immunity. However, it can also contribute to tumor progression by fostering angiogenesis, depending on the tumor type and microenvironmental context ^[6]. This duality underscores IL-12B as a key target for precise immunotherapy, particularly in combination therapies that simultaneously block IL-12 and IL-23 signaling, offering therapeutic potential across a spectrum of immune-related diseases and cancers ^[1-6].

B6-hIL12B mice are humanized models generated by gene editing technology, in which the entire base sequence of the mouse Il12b gene was replaced in situ with the corresponding sequence from the human IL12B gene. Homozygous B6-hIL12B mice are viable and fertile. This model can be used to study the pathological mechanisms and therapeutic methods of immune-related diseases and cancer, as well as the screening and development of IL12B-targeted drugs, and preclinical efficacy and safety evaluations.

Strain Strategy

Figure 1. Gene editing strategy of B6-hIL12B mice. The sequences from ATG start codon to TAG stop codon of the endogenous mouse Il12b gene were replaced with the sequences from ATG start codon to TAG stop codon of the human IL12B gene.

Application

• Screening, development, and preclinical efficacy evaluation of IL12B-targeted drugs;
• Study of pathological mechanisms and therapeutic methods for immune-related diseases and cancer.

References
[1]Ullrich KA, Schulze LL, Paap EM, Müller TM, Neurath MF, Zundler S. Immunology of IL-12: An update on functional activities and implications for disease. EXCLI J. 2020 Dec 11;19:1563-1589.
[2]Wu PB, Wu XM, Qian R, Hong C, Yitian G, Zhang G, Yu YJ. Association between IL12B polymorphisms and inflammatory bowel disease in Caucasian population: A meta-analysis. Cytokine. 2020 Dec;136:155296.
[3]Manolova I, Ivanova M, Vasilev G, Stoilov R, Miteva L, Stanilova S. Impact of IL12B Polymorphisms on Genetic Susceptibility and IL-12p40 and IL-23 Serum Levels in Rheumatoid Arthritis. Immunol Invest. 2020 Feb;49(1-2):1-14.
[4]Kocaaga A, Kocaaga M. Psoriasis: An Immunogenetic Perspective. Glob Med Genet. 2022 Jun 13;9(2):82-89.
[5]Benson JM, Peritt D, Scallon BJ, Heavner GA, Shealy DJ, Giles-Komar JM, Mascelli MA. Discovery and mechanism of ustekinumab: a human monoclonal antibody targeting interleukin-12 and interleukin-23 for treatment of immune-mediated disorders. MAbs. 2011 Nov-Dec;3(6):535-45.
[6]Zheng Y, Wang M, Tian T, Liu K, Liu X, Zhai Y, Lin S, Yang P, Li S, Dai Z, Lu J. Role of interleukin-12 gene polymorphisms in the onset risk of cancer: a meta-analysis. Oncotarget. 2017 May 2;8(18):29795-29807.