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B-hPD-1/hTIM3 mice
Strain Name C57BL/6-Pdcd1tm1(PDCD1)Havcr2tm1(HAVCR2)/Bcgen Common Name  B-hPD-1/hTIM3 mice
Background C57BL/6 Catalog number  120524
Related Genes 
PD-1(Programmed death-1) ;
  HAVCR2
(hepatitis A virus cellular receptor 2)

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. T-cell immunoglobulin domain and mucin domain-3 (TIM3) is an activation-induced inhibitory molecule involved in immune tolerance and T-cell exhaustion in chronic viral infection and cancers. TIM3 maturation and cell surface expression is facilitated by forming a heterodimeric interaction with CD66a. Co-blockade of CD66a and TIM3 enhanced anti-tumor immune responses, and eliminated tumors in mouse colorectal cancer models.


mRNA expression analysis


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Strain specific analysis of PD-1/TIM3 gene expression in WT and hPD-1/hTIM3 mice by RT-PCR. Mouse Pd-1/Tim3 mRNA were detectable in splenocytes of wild-type (+/+) mice. Human PD-1/TIM3 mRNA were detectable only in H/H but not in +/+ mice.


Protein expression analysis

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Strain specific TIM3 expression analysis in homozygous B-hPD-1/hTIM3 mice by flow cytometry. Splenocytes were collected from WT and homozygous B-hPD-1/hTIM3 (H/H) mice stimulated with anti-CD3ε in vivo, and analyzed by flow cytometry with species-specific anti-TIM3 antibody. Mouse TIM3 was detectable in WT mice. Human TIM3 was exclusively detectable in homozygous B-hPD-1/hTIM3 but not WT mice.


Protein expression analysis
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Strain specific PD-1 expression analysis in homozygous B-hPD-1/hTIM3 mice by flow cytometry. Splenocytes were collected from WT and homozygous B-hPD-1/hTIM3 (H/H) mice stimulated with anti-CD3ε in vivo, and analyzed by flow cytometry with species-specific anti-PD-1 antibody. Mouse PD-1 was detectable in WT mice. Human PD-1 was exclusively detectable in homozygous B-hPD-1/hTIM3 but not WT mice.


Combination Therapy of PD-1 mAb (Keytruda) and TIM3 mAb


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Antitumor activity of anti-hTIM3 antibodies combined with anti-hPD-1 antibodies Keytruda in B-hPD-1/hTIM3 mice. (A) Anti-hTIM3 antibodies(Ab1/Ab2) combined with anti-hPD-1 antibodies Keytruda inhibited MC38 tumor growth in B-hPD-1/hTIM3 mice. Murine colon cancer MC38 cells (5×105) were subcutaneously implanted into homozygous B-hPD-1/hTIM3 mice (female, 6-8 week-old, n=6). Mice were grouped when tumor volume reached approximately 150±50 mm3, at which time they were treated with anti-hTIM3 antibodies and anti-hPD-1 antibodies Keytruda with doses and schedules indicated in panel, (B) Body weight changes during treatment. As shown in panel A, combination of anti-hTIM3 Ab2 and anti-hPD-1 antibody shows more inhibitory effects than individual groups, demonstrating that the B-hPD-1/hTIM3 mice provide a powerful preclinical model for in vivo evaluating combination therapy efficacy of hTIM3 antibodies and hPD-1 antibodies . Values are expressed as mean ± SEM.