动物造模,药效评价,干眼病 z-bio 2024-09-03 438

　　Dry eye disease, also known as dry keratoconjunctivitis, is one of the most common eye diseases, which can cause damage to the ocular surface and blurred vision, affecting the quality of life of patients. At present, the etiology of most dry eye disease patients is unknown, but more severe dry eye diseases are often related to autoimmune factors. Animal experiments are an important means of studying the pathogenesis of dry eye disease. Previous models of dry eye disease mainly included removal of lacrimal glands, removal of nerve innervation on the ocular surface, and regulation of animal sex hormone secretion. Due to recent research findings showing that immune changes play an important role in the pathogenesis of dry eye, most of the established dry eye models are autoimmune related models that induce inflammatory responses on the ocular surface or lacrimal gland. The following mainly introduces a gene knockout mouse model.

　　A large number of experimental results have shown that dry eye disease is an inflammatory autoimmune disease, characterized by infiltration of autoimmune T cells on the ocular surface, long-term chronic inflammation of lacrimal gland functional units, which can lead to loss of corneal barrier function, apoptosis of ocular epithelial cells, loss of goblet cells, and squamous metaplasia of the ocular surface.

　　MRL/lpr mice were successfully cultivated by Murphy and Roths from Jackson Laboratories in the United States in 1978. They were produced by a series of complex hybridization of several different strains of mice, including LG/J, AKR/J, C3H/D, and C57BL/6, until the 12th generation. The retrotransposon was inserted into the intron of the Fas gene, resulting in abnormal Fas transcription expression and inability to induce apoptosis, leading to uncontrolled lymphocyte proliferation and T lymphocyte proliferation.

　　[Model features] Tear gland inflammation occurs in MRL/lpr mice at 1 month of age, while inflammatory infiltration in MRL/+mice occurs later and is not as severe as in MRL/lpr mice. However, tear gland inflammation also occurs at 3 months of age, indicating that the variation in lpr only exacerbates the occurrence of dry eye, rather than the cause of its formation. The apoptosis of defective lymphocytes in MRL/lpr mice is caused by variations in the autosomal recessive gene lpr, which leads to the production of Fas antigen throughout the body except for the lacrimal gland. Therefore, it can be concluded that variations in the lpr gene are not the only factor causing changes in the lacrimal gland microenvironment. The mutation of the lpr gene does not cause severe autoimmune lesions, as no lymphocyte mutations were found in the lacrimal glands of male C3H/lpr mice and generalized lymphoproliferative disease mice. These findings seem to support the hypothesis that Fas antigen and Fas antibody are not key factors in immune damage to the lacrimal gland. The immunopathological mechanism of this model is unique, mainly due to the Th2 type hypersensitivity reaction between IL-4 and B7-2 in lacrimal gland tissue.

　　【 Model source 】 Both the Jackson Laboratory in the United States and the Model Animal Research Institute at Nanjing University can provide the model.

　　Model Evaluation and Application: MRL/+and MRL/lpr mice are commonly used in the study of systemic lupus erythematosus. Some studies have also found that MRL/+and MRL/Ip mice can develop lacrimal gland inflammation, sialadenitis, mumps, and sublingual gland inflammation, with CD4+T lymphocyte infiltration as the main feature of their lacrimal glands, and females showing more severe symptoms. MRL/+and MRL/lpr mice have always been one of the commonly used autoimmune disease models for salivary and lacrimal gland damage abroad.