Programmed cell death protein 1 (PDCD1/PD-1) is a member of the B7-CD28 costimulatory receptor family. It is an inhibitory receptor expressed on activated T cells and plays a role in regulating the function of effector T cells, including CD8+ T cells, and promoting the differentiation of CD4+ T cells into regulatory T cells. PD-1 is expressed in a variety of tumors and plays an important role in antitumor immunity. In addition, PD-1 is involved in the defense against autoimmune diseases and has inhibitory effects on antitumor and antimicrobial immunity ^[1]. PD-1 binds to programmed death ligands 1 and 2 (PD-L1 and PD-L2) to inhibit T cell activation, reduce the production of corresponding cytokines, and regulate T cell survival ^[2]. Drugs targeting this pathway can reactivate T cells to activate antitumor immune responses ^[3]. The Vascular Endothelial Growth Factor (VEGF) family is a group of particular endothelial growth factors intimately associated with angiogenesis. These factors promote increased vascular permeability, extracellular matrix degeneration, vascular endothelial cell migration and proliferation, and are capable of stimulating angiogenesis and increasing the permeability of existing vessels. As such, they play a pivotal role in normal vascular development and wound healing. The VEGF family comprises VEGFA, VEGFB, VEGFC, VEGFD, VEGFE, and PLGF ^[4]. Of these, VEGFA is the most commonly targeted in research related to neovascular ophthalmic diseases due to its crucial role in the proliferation, migration, and formation of endothelial cell microvessels ^[5]. Overexpression of VEGFA in the eye can result in abnormal vascular growth and leakage, leading to various ophthalmic diseases such as Age-Related Macular Degeneration (AMD), Diabetic Retinopathy (DR), and corneal neovascularization ^[5-6]. The progression of solid tumors depends on vascularization and angiogenesis within malignant tissues, with VEGFA playing a crucial role among various pro-angiogenic factors. The VEGFA gene is upregulated in many known tumors, correlating with tumor staging and progression. Blocking VEGFA may lead to vascular network regression, inhibiting tumor growth ^[7]. Thus, VEGFA is an important target for anti-angiogenic cancer therapies. The B6-hPD-1/hVEGFA mouse is a humanized model obtained by crossbreeding hPD-1 mice (Catalog No. C001524) with B6-hVEGFA mice (Catalog No. C001555). This model can be used for research in drug development, efficacy and safety evaluation, tumor immunotherapy evaluation, and immune system mechanisms related to human PD-1/VEGFA.

PD-1 and CTLA-4 are checkpoint receptors that critically modulate T cell immunity. The genes PDCD1 and CTLA4 encode PD-1 and CTLA-4 respectively, with CTLA4 expression largely restricted to T cells, while PDCD1 is evident in activated T cells, B cells, and myeloid populations ^[1]. These transmembrane proteins function as key negative regulators of T cell activation ^[2]. CTLA-4 primarily operates in lymphoid tissues during early immune responses to restrain T cell proliferation, whereas PD-1 predominantly acts in peripheral tissues during the effector phase to dampen T cell activity and limit immunopathology, particularly in chronically stimulated or ‘exhausted’ T cells ^[2-3]. Aberrant regulation of PD-1 and CTLA-4 is implicated in the pathogenesis of cancers, including melanoma, non-small cell lung cancer, and renal cell carcinoma, as well as chronic viral infections such as hepatitis B and C ^[1][4]. Clinically, monoclonal antibodies targeting CTLA-4 (e.g., ipilimumab) and PD-1 (e.g., nivolumab, pembrolizumab) are established immunotherapeutic agents that enhance anti-tumor responses. By blocking these negative signaling pathways, these monoclonal antibodies restore the anti-tumor activity of T cells, significantly enhancing anti-tumor responses ^[1-2]. These drug applications have not only improved the treatment outcomes for various cancers but also offer new strategies for the treatment of chronic viral infections. B6-hPD-1/hCTLA4 mouse is a dual humanized model of PD1 and CTLA4 constructed by humanizing the mouse Pdcd1 gene based on the CTLA4 humanized mouse model (Catalog No. C001413), due to the fact that the mouse Pdcd1 gene and Ctla4 gene are on the same chromosome. These mice express human CTLA4 and PDCD1 genomic sequences under the control of mouse promoters. This model is capable of reproducing the human PD-1/CTLA4 signaling pathway and is a valuable tool for studying cancers and chronic viral infections. Furthermore, this model provides a powerful preclinical research platform for evaluating the efficacy and mechanism of therapeutic drugs targeting the PD-1/CTLA4 signaling pathway.

TNF-like ligand 1A (TL1A), also known as TNF superfamily member 15 (TNFSF15), is a member of the tumor necrosis factor (TNF) family encoded by the TNFSF15 gene in humans. TL1A acts as a ligand for death receptor 3 (DR3) and decoy receptor 3 (DcR3), providing a stimulatory signal for downstream pathways. It regulates the proliferation, activation, and apoptosis of effector cells, as well as cytokine and chemokine production. TL1A is expressed in various immune cells, including monocytes, macrophages, dendritic cells, and T cells, as well as in non-immune cells such as synovial fibroblasts and endothelial cells. It plays a crucial role in modulating immune responses by promoting the differentiation and survival of T cells, particularly Th17 cells involved in inflammatory processes ^[1]. TL1A enhances IL-2 responses in anti-CD3/CD28-stimulated T cells and synergizes with IL-12 and IL-18 to augment IFN-γ release in human T and NK cells, biasing T cell differentiation toward a Th1 phenotype ^[2]. Dysregulation of TL1A expression is implicated in autoimmune diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), primary biliary cholangitis (PBC), systemic lupus erythematosus (SLE), and ankylosing spondylitis (AS) ^[1]. TL1A has emerged as a promising therapeutic target, with ongoing research focused on developing monoclonal antibodies and other biologics to neutralize TL1A and reduce inflammation in autoimmune disorders. Clinical trial results suggest that TL1A inhibition can be used in the treatment of various autoimmune diseases, particularly IBD ^[3-5]. The IL23A gene encodes the p19 subunit, a component of interleukin-23 (IL-23), which forms a heterodimer with the p40 subunit (encoded by IL12B) to generate the functional IL-23 cytokine ^[1]. Primarily expressed by activated dendritic cells, macrophages, and monocytes, IL-23 signals through the IL-23 receptor (IL-23R) complex, activating the JAK-STAT pathway to promote Th17 cell differentiation and maintain IL-17 production. This process drives inflammatory responses and mucosal immunity against extracellular pathogens ^[6-7]. Genetic polymorphisms within IL23A are strongly associated with autoimmune and inflammatory diseases, including psoriasis, Crohn's disease, and inflammatory bowel disease, due to dysregulated Th17 activity and chronic inflammation ^[6-7]. Monoclonal antibodies targeting IL-23, such as risankizumab and guselkumab, selectively block the p19 subunit, demonstrating therapeutic efficacy in psoriasis and inflammatory bowel diseases by suppressing pathogenic IL-17/Th17 pathways ^[8]. While IL-23 plays a role in protective immunity, its overactivation contributes to tissue damage in autoimmune settings, highlighting its dual function in immune regulation and disease pathogenesis ^[6-9]. B6-hTL1A/hIL23A mice are humanized models generated by crossing B6-hTL1A (TNFSF15) mice (Catalog No.: C001603) with B6-hIL23A mice (Catalog No.: C001618). These mice are suitable for studying the pathological mechanisms and therapeutic strategies of allergic and inflammatory diseases, immune-related disorders, and cancer, as well as for the screening, development, and preclinical evaluation of TL1A/IL23A-targeted drugs.

Cluster of differentiation 3 (CD3) is a multimeric protein complex that is essential for T cell activation and antigen recognition. It consists of five different polypeptide chains (γ, δ, ε, ζ, and η) that are noncovalently associated with the T cell receptor (TCR). The TCR is responsible for recognizing antigens presented by antigen-presenting cells (APCs), while CD3 transduces the activation signal into the T cell and activates helper T-cells and cytotoxic T-cells ^[1-2]. The CD3-TCR complex is expressed on the surface of all mature T cells, and its assembly is required for T cell development and function. CD3 plays a crucial role in stabilizing the TCR and facilitating its interaction with antigens. It also recruits signaling molecules to the TCR, which initiates a cascade of events that leads to T cell activation. CD3 is a highly specific T cell marker, and its expression is increased upon T cell activation. This makes it a valuable tool for identifying and characterizing T cells in tissues and blood samples. CD3 staining is also used to diagnose T-cell lymphomas and leukemias. Due to its essential role in T cell activation, CD3 is a promising target for immunosuppressive therapy. Several anti-CD3 monoclonal antibodies have been developed and are being tested in clinical trials for the treatment of autoimmune diseases, such as type 1 diabetes and rheumatoid arthritis ^[3]. The TNFRSF17 gene, also known as BCMA, encodes a protein belonging to the tumor necrosis factor receptor superfamily. This protein is predominantly expressed in mature B lymphocytes, particularly plasma cells, with lower expression in early B cells and non-B cells ^[4-5]. As a type III transmembrane glycoprotein, TNFRSF17 plays a critical role in B cell survival and differentiation, acting as a key regulator of B cell maturation ^[5]. Functionally, TNFRSF17 primarily acts as a receptor for the B cell-activating factor (BAFF). Upon BAFF binding, it activates both the classical NF-κB pathway and the non-classical MAPK8/JNK pathway, subsequently regulating downstream gene expression to promote B cell survival, proliferation, and antibody secretion. Furthermore, TNFRSF17 can interact with TNFR-associated factors (TRAFs) 1, 2, and 3, further mediating physiological processes related to cell differentiation and growth ^[4-5]. Multiple studies have demonstrated that the TNFRSF17 gene and its protein are associated with various B cell-related diseases. Notably, this gene exhibits abnormally high expression in diseases such as multiple myeloma and systemic lupus erythematosus, rendering it a potential therapeutic target for these conditions ^[6-7]. The B6-hCD3/hBCMA mouse is a dual-gene humanized model generated by crossing B6-hCD3 mice (Catalog No.: C001325) with B6-hBCMA (TNFRSF17) mice (Catalog No.: C001630). This model can be used for researching the pathological mechanisms and therapeutic approaches of diseases such as autoimmune diseases and multiple myeloma, as well as for the development of CD3/BCMA-targeted drugs.

The CD40 gene encodes CD40, a transmembrane protein belonging to the tumor necrosis factor receptor (TNFR) superfamily. Primarily expressed on antigen-presenting cells (APCs) such as B lymphocytes, macrophages, and dendritic cells, CD40 is also found on a variety of non-immune cells including endothelial cells, fibroblasts, epithelial cells, and smooth muscle cells, as well as many tumor cells ^[1]. The CD40LG gene is located on the X chromosome (Xq26.3) and encodes CD40 ligand (CD40L, also known as CD154), a type II transmembrane protein mainly expressed on activated T cells, platelets, and some B cells. Under inflammatory conditions, monocytes, natural killer cells, mast cells, and basophils can also be induced to express CD40L ^[2-4]. The interaction of CD40 with its ligand, CD40L (CD154), is a critical costimulatory signal essential for T-dependent humoral and cell-mediated immunity. This interaction triggers downstream signaling pathways, including NF-κB, JNK, and JAK/STAT, leading to B cell activation, proliferation, differentiation, isotype switching, memory B cell development, germinal center formation, and enhanced APC function and cytokine production ^[5]. Dysregulation of CD40/CD40L signaling pathway is implicated in the pathogenesis of numerous diseases, including autoimmune disorders like inflammatory bowel disease (IBD), type 1 diabetes (T1D), multiple sclerosis, and rheumatoid arthritis (RA), as well as cardiovascular diseases such as atherosclerosis, certain neurological conditions including Alzheimer's disease (AD) and traumatic brain injury, and various cancers ^[5-7]. Due to the important role of the CD40/CD40L interaction in immune activation, CD40/CD40L has been an important target for immunotherapy. In recent years, significant progress has been made in CD40/CD40L-targeted therapy. Various drugs have been developed, including agonistic/antagonistic monoclonal antibodies, cellular vaccines, adenoviral vectors, and protein antagonists, and have shown therapeutic potential in malignant tumors, autoimmune diseases, and allograft rejection ^[1]. The B6-hCD40/hCD40LG mouse is a dual-gene humanized model (for CD40 and CD40LG) generated by crossing B6-hCD40 mice (Catalog No.: C001721) with B6-hCD40LG mice (Catalog No.: C001720). The B6-hCD40/hCD40LG mouse model can be used for research on the mechanisms and therapeutic approaches of diseases such as autoimmune diseases, cancer, and cardiovascular diseases, as well as for the development of CD40/CD40L-targeted drugs.