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B-hPD-1/hPD-L1/hGITR mice
Strain Name C57BL/6-Pdcd1tm1(PDCD1) Cd274tm1(CD274) Tnfrsf18tm1(TNFRSF18)/Bcgen Common Name  B-hPD-1/hPD-L1/hGITR mice  
Background C57BL/6 Catalog number  131108
Related Genes 
PDCD1 also known as PD1; PD-1; CD279; SLEB2; hPD-1; hPD-l; hSLE1.
 CD274 also known as B7-H; B7H1; PDL1; PD-L1; hPD-L1; PDCD1L1; PDCD1LG1.
 TNFRSF18  also known as AITR; GITR; CD357; GITR-D; ENERGEN

Gene description


PD-1 (Programmed death-1) is mainly expressed on the surface of T cells and primary B cells. The two PD-1 ligands, PD-L1 and PD-L2, are widely expressed on antigen-presenting cells (APCs). PD-1 interacts with its ligands and plays an important role in the negative regulation of the immune response. PD-L1 protein expression is detected in many human tumor tissues. PD-L1 expression in tumor cells could be induced by the microenvironment of tumor cells. PD-L1 expression is favorable for tumorigenesis and growth, for induction of anti-tumor T Cell apoptosis, and for escaping responses by the immune system. Inhibition of PD-1 binding to its ligand can result in tumor cells that are exposed to the killing version of the immune system, and thus is a target for cancer treatments. 
PD-L1 (Programmed cell death ligand-1), also known as B7-H1 and CD274, is mainly expressed in antigen-presenting cells (APCs) and activated T cells, and is one of the two ligands of PD-1. The interaction between PD1 and PD-L1 plays an important role in the negative regulation of the immune response. PD-L1 is highly expressed in a variety of solid tumors. PD-1 and PD-L1 interactions can reduce T Cell activation and promote tumor immune escape. The PD-1/PD-L1 signaling pathway can be blocked and antitumor immune response can be restored by using by anti-PD-1 or anti-PD-L1 antibodies to block the binding of PD1 to PD-L1. 

TNFRSF18 (TNF Receptor Superfamily Member 18) is also known as Glucocorticoid-induced TNFR-related protein (GITR), which is expressed on many immune cells including T cells. As a co-stimulatory signal of T cells, TNFRSF18 is upregulated upon the activation of T cells, and in turn promotes T cell proliferation. CD25+/CD4+ regulatory T cell is known to mediate immune tolerance, and GITR agonist antibodies can reverse this immune tolerance, and show anti-tumor effect in multiple tumor models.


Protein expression analysis


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Strain specific PD-1, PD-L1 and GITR expression analysis in homozygous B-hPD-1/hPD-L1/hGITR mice by flow cytometry. Splenocytes were collected from wild-type mice (+/+) and homozygous B-hPD-1/hPD-L1/hGITR mice (H/H) stimulated with anti-CD3ε in vivo, and analyzed by flow cytometry with species-specific antibody. Mouse PD-1, PD-L1 and GITR were detectable in wild-type mice but not in homozygous B-hPD-1/hPD-L1/hGITR mice. Human PD-1, PD-L1 and GITR were exclusively detectable in homozygous B-hPD-1/hPD-L1/hGITR mice but not in wild-type mice.


Analysis of leukocytes subpopulation in B-hPD-1/hPD-L1/hGITR mice


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Analysis of spleen leukocyte subpopulations by FACS. Splenocytes were isolated from female C57BL/6 and B-hPD-1/hPD-L1/hGITR mice (n=3, 6-week-old). Flow cytometry analysis of the splenocytes were performed to assess leukocyte subpopulations. A. Representative FACS plots. Single live cells were gated for the CD45+ population and used for further analysis as indicated here. B. Results of FACS analysis. Percent of T cells, B cells, NK cells, dendritic cells, granulocytes, monocytes and macrophages in homozygous B-hPD-1/hPD-L1/hGITR mice were similar to those in the C57BL/6 mice, demonstrating that PD-1/PD-L1/GITR humanized does not change the overall development, differentiation or distribution of these cell types in spleen. The same results were obtained in lymph nodes and blood (data not shown). Values are expressed as mean ± SEM.


Analysis of T cell subpopulations in B-hPD-1/hPD-L1/hGITR mice


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Analysis of spleen T cell subpopulations by FACS. Splenocytes were isolated from female C57BL/6 and B-hPD-1/hPD-L1/hGITR mice (n=3, 6-week-old). Flow cytometry analysis of the splenocytes ere performed to assess leukocyte subpopulations. A. Representative FACS plots. Single live CD45+ cells were gated for CD3+ T cell population and used for further analysis as indicated here. B. Results of FACS analysis. The percent of CD8+ T cells, CD4+ T cells and Tregs in homozygous B-hPD-1/hPD-L1/hGITR mice were similar to those in the C57BL/6 mice, demonstrating that introduction of hPD-1/hPD-L1/hGITR in place of its mouse counterpart does not change the overall development, differentiation or distribution of these T cell subtypes in spleen. The same results were obtained in lymph nodes and blood (data not shown). Values are expressed as mean ± SEM.


Combination therapy of anti-human PD-1 antibody and anti-human GITR antibody


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Antitumor activity of anti-human PD-1 antibody combined with anti-human GITR antibody in B-hPD-1/hPD-L1/hGITR mice. (A) Anti-human PD-1 antibody combined with anti-human GITR antibody inhibited MC38 tumor growth in B-hPD-1/hPD-L1/hGITR mice. All antibodies used in the experiment were prepared in-house. Murine colon cancer MC38 cells were subcutaneously implanted into homozygous B-hPD-1/hPD-L1/hGITR mice (female, 6-7 weeks old, n=5). Mice were grouped when tumor volume reached approximately 100 mm3, at which time they were treated with human PD-1 and human GITR antibodies (in house) indicated in the panel. (B) Body weight changes during treatment. As shown in panel A, the antibodies were efficacious in controlling tumor growth in B-hPD-1/hPD-L1/hGITR mice, demonstrating that the B-hPD-1/hPD-L1/hGITR mice provide a powerful preclinical model for in vivo evaluation of PD-1 and GITR antibodies. Values are expressed as mean ± SEM.