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Animal experiment service: introduction of SCID mice

2020-06-17
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The appearance of SCID mice is not much different from ordinary mice, with hair, white coat, and normal weight development. However, the weight of thymus, spleen, and lymph nodes was less than 30% of normal, and histologically showed significant lymphocyte defects. The thymus is surrounded by adipose tissue, there is no cortical structure, only medulla remains, mainly composed of epithelioid cells and synthetic fibroblasts, and occasionally focal lymphocyte groups. The white pulp of the spleen is not obvious, the red pulp is normal, and there is no lymphocyte accumulation in the spleen body, mainly composed of reticulocytes. There is no obvious cortical area in the lymph nodes, and the bran cortex area is missing, and reticular cells are occupied. Submucosa of small intestine and bronchial lymph nodes are rare, and there is no lymphatic accumulation in the structure. It is particularly noteworthy that a small number of SCID mice may have a certain degree of immune function recovery during adolescence, which is the leakage phenomenon of SCID mice. The leakage phenomenon is not hereditary, but is related to the age, strain and breeding environment of the mice. SCID mice are highly susceptible to infection and can survive for more than one year in a highly clean SPF environment, with litters of 3-5 litters. SCID mice are another valuable immunodeficiency animal discovered by humans after the appearance of nude mice.

SCID mice

source:

SCID mice are derived from autosomal recessive mutations (scid).

In 1980, Bosma discovered the mutation in a group of C.B-17/lcr mice raised at the Fox Chase Cancer Center.

The strain showed severe symptoms of combined immunodeficiency, and B-cell and T-lymphocyte functions were lost.

At the same time, this strain has normal NK cells, macrophages and granulocytes.

Charles River was introduced from Iffa Credo in 1991.

Coat: no hair, white background

Features and uses:

It is widely used in the research of human immunology and virology, oncology, physiology, hematology, pathology, etc. It can accept the transplantation of human normal tissues and become a chimeric mouse (ie SCID-hu model) for human body Research on immune function reconstruction and oncology.

1. Many human parasites that cannot infect other strains of mice can infect SCID mice. The lesions are similar to humans and are animal models for studying human filariasis.

2. The survival rate of human tumor transplantation is as high as 36.9%, while that of nude mice is 16.9%. It has a high rate of metastasis to leukemia and malignant tumors, and can spread widely. It is very similar to the biological behavior of human tumors. Tumor infiltration and metastasis are similar to spontaneous metastasis of human tumors.

3. It is the main model for studying the differentiation and regulation of lymphocytes and the main model for studying the relationship between immunodeficiency and spontaneous lymphoma.

Reference data:

Coat colorAlbino
Maturity (male)6-8 weeks
Maturity (female)6-8 weeks
Mating ratio1:2
Estrous cycle3-5 days
Pregnancy17-21 days
Average litters per litter4-5 only
Birth weight1-2g
Weaning weight (male)9-12g
Weaning weight (female)9-12g
Lactation21 days
Average daily feed consumption5g (per 100g body weight)
Average daily water consumption6-7ml (per 100g body weight)
Rat elimination cycle (male)May-June
Breeding rat elimination cycle (female)May-June
Feeding temperature21±2℃
Relative humidity40-70%
Photoperiod12/12 hours
Weight loss during transportation10%

SCID mice breeding

Due to the severe deficiency of the immune function of SCID mice, it is necessary to keep them in a state free of specific pathogens (SPF) to avoid the infection of pathogenic microorganisms. In the general environment where mouse hepatitis virus or Pasteurellap Pneumotropica is present, SCID mice cannot be reared successfully. SCID mice are easily susceptible to Pneumocystis carinii infection, which makes them unable to reproduce normally, shorten their lifespan, and lose the value of experimental application. There is no doubt that the deficiency of T and B lymphocytes will cause the mouse to be susceptible to a variety of pathogenic microorganisms.

Under SPF conditions, SCID mice can live longer than 1 year. For mice homozygous for the SCID gene, siblings between homozygotes can be used for breeding. SCID mice have a weak reproductive capacity, with an average of 3.4 pups per litter, an infertility rate of about 30℅, and a survival rate of about 70℅. In addition to the indirect influence of the SCID gene on the reproduction of mice due to immunodeficiency, the animals are susceptible to infection by pathogens. Whether or not it directly affects the reproductive function of animals needs further study.

In order to maintain the SPF status of animals, SCID mice should be housed in a barrier system with air filtration devices. Animal feed, drinking water, bedding, cages and surgical instruments must be sterilized before they can be used. In order for SCID mice to reproduce successfully, the animal feed should be a full-price balanced feed with a protein content of not less than 20℅. The temperature of the feeding environment should be controlled at 20~30℃ and the humidity at 40~70℅.

SCID mouse biological characteristics

1. Anatomical features:

The appearance of SCID mice is no different from that of common mice, and the body weight development is normal, but the development of lymphoid organs is defective. The relative weight of the thymus is only about 6℅ of the normal control mice of the same age, and the relative weight of the spleen is only 3℅ of the normal. The lymph nodes are extremely small and often scattered in the fat tissue. It is difficult to see with the naked eye. Only 1/3 of normal.

2. Histological characteristics:

The histological characteristics of SCID mice are prominently expressed in the tissue structure related to immunodeficiency. The lymphoid tissue in the body is extremely abnormal, and it obviously shows the symptoms of lymphocyte deficiency, but the distribution of granulocytes and macrophages is normal. SCID mice have fewer peripheral blood leukocytes, mainly due to the decrease of lymphocyte components. The lymphocyte meter accounts for 10 to 20℅ of the total number of white blood cells. In contrast, the lymphocytes of the control animals accounted for about 70℅ of the total. The thymus of SCID mice had no cortical structure and only retained the remaining medulla, mainly composed of reticulocytes and fibroblasts. The white pulp of the spleen is not obvious, and the red pulp is normal. The spleen body has no lymphocyte aggregation, and is mainly composed of reticulocytes. There is no obvious cortical area in the lymph nodes, and the paracortical area is missing. It appears as lymphocyte emptying and is occupied by reticular cells. The intestinal submucosa and bronchial bamboo lymph node aggregation are rare, and there is no lymphocyte aggregation in the structure. However, the bone marrow tissue structure of SCID mice is normal.

3. Spontaneous tumor:

The incidence of spontaneous T-cell lymphoma (mainly in the thymus) in SCID mice is around 15℅. However, the normal control animals had no cases of this tumor. Lymphoma clearly originates in the thymus, and can metastasize to the lung, lymph nodes, spleen, liver, and kidney. The tumor is composed of large and uniform lymphoblasts. The cells are large, rich in chromatin, contain large nucleoli, and the cytoplasm is basophilic. Tumor cells carry T-cell surface marker antigens. After the tumor mass or cultured cell suspension of this tumor is transplanted into a histocompatible host body, it can grow well and be passaged. At present, it is not clear: the relationship between the SCID mutation gene and the high incidence of T-cell thymoma.

4. Immunological characteristics:

SCID mice were negative in all T and B lymphocyte function tests. Its splenocytes had no proliferative response to T and B cytokinins and in the same mixed lymphatic reaction test, and lacked B cell and cytotoxic T cell colony forming units. There is no antibody and cellular immune response to foreign antigens. The same kind of skin transplant cannot be excluded. The body lacks cells that carry surface markers of pre-B cells, B cells, and T cells.

 The differentiation of non-lymphoid hematopoietic cells in SCID mice was not affected by the mutant gene. Macrophages, granulocytes, megakaryocytes and red blood cells are in a normal state. Mast cell precursors are normal, but due to the lack of lymphokines produced by T cells, they cannot differentiate normally and have defective functions. SCID antigen presenting cells function normally. Macrophages were induced by T cell lymphokine and Listeria monocytogenes, and their major histocompatibility antigen Ia was normally expressed. The differentiation and function of natural killer cells (Nk cells) and lymphokine-activated killer cells (LAK cells) are also normal in SCID mice.

5. Reconstruction of the lymphatic system:

After SCID mice receive normal bone marrow or fetal hepatocytes with the same histocompatibility, their lymphoid tissue will be partially or completely reconstructed and normal functions will be restored. Long-term culture of lymphocytes from bone marrow can also restore the immune system of SCID mice. The reconstructed lymphocytes come from the donor rather than the host. In contrast, normal mice that received bone marrow cells from SCID mice (treated with radiation) did not detect lymphocytes from donors. The results of these experiments further prove that the immunodeficiency of SCID mice is caused by the mutation gene directly affecting the differentiation and development of lymphocytes, rather than the defects of the lymphocyte development microenvironment. Furthermore, adult SCID mice can avoid incomplete lymphatic system reconstruction after receiving non-lethal radiation treatment.

6. Molecular biological characteristics:

In the lymphoid organs of SCID mice, mRNA transcripts of Ig and T cell receptor (Tcr) genes can be detected. Therefore, it is proved that SCID mice have germline cells of B and T cell lineages. The effect of SCID gene on lymphocyte differentiation occurs after stem cells differentiate into B and T lineage cells. During the development of lymphocytes, the recombination of antigen-responsive genes (Ig and Tcr sites) of SCID mice is abnormal and cannot be rearranged normally, so that the cells cannot produce functional antigen receptor proteins. The affected lymphocytes will die before maturation or be eliminated by macrophages, granulocytes or NK cells in the body.

At present, it is believed that the recombinase activity of the VDJ coding sequence of the antigen receptor gene of SCID mice is abnormal, so that when the VDJ region is rearranged, its split ends cannot be connected normally, resulting in the deletion and abnormality of the antigen receptor gene after rearrangement. The results of long-term cultivation of bone marrow B cells are consistent with the above hypothesis.

7. Leakage characteristics:

Not all SCID mice lack functional lymphocytes, 2~23℅ individuals have a limited number of T and B cells, and their immune function has a minimal degree of functional recovery, namely: the so-called leaky SCID mice (leak SCID mice). Although these individuals carry the homozygous SCID gene, a small number of their lymphocytes can mature without being affected by the mutant gene. Animal pedigree analysis and selective breeding experiments prove that the leakage characteristics of SCID mice are not inherited, and the number of occurrences in the population depends on the age of the animals and the feeding environment. Interestingly, the incidence of thymic lymphoma in leaking individuals is 40℅, which is higher than that of individuals with complete immune deficiency (10℅).

A certain level of immunoglobulin can be detected in the serum of leaking SCID mice. A small number of B cell clones can be detected in their tissues. 50℅ leaky individuals can reject allogeneic skin transplants. Thymus cells have rearrangement of T cell receptor (TCR) gene, and can detect cells carrying T cell specific antigen markers. However, leaky SCID mice are far from being similar to normal individuals. The spleen cells could not express lymphocyte antigens, and did not respond to lymphokine. The histological structure of the lymphatic system is also similar to ordinary SCID mice.

At present, there are two hypotheses about the leakage characteristics and mechanisms of SCID mice. One is that during the development of lymphocytes in SCID mice, although the recombinase system is abnormal, the antigen receptor gene will occasionally undergo normal and functional rearrangement. This leads to the production of functional lymphocytes. The other is that during the development of lymphocytes in SCID mice, due to some late changes or the reversion of the SCID gene locus, the recombinase activity of some lymphocytes returned to normal. At present, the experimental evidence obtained is in favor of these two hypotheses that are not mutually exclusive. Therefore, the leakage mechanism of SCID mice needs further study.

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