Successful treatment of murine autoimmune cholangitis by parabiosis: Implications for hematopoietic therapy

Autor: Fang Ting Lu, Wei Yang, Yin Hu Wang, Zhi-Bin Zhao, Hong Di Ma, Zhe-Xiong Lian, William M. Ridgway, M. Eric Gershwin, Jing Bo Yang, Wei Tang, Koichi Tsuneyama, Yan Jie Jia
Rok vydání: 2016
Předmět:
Liver Cirrhosis
CD4-Positive T-Lymphocytes
Male
0301 basic medicine
Cholangitis
medicine.medical_treatment
Hematopoietic stem cell transplantation
CD8-Positive T-Lymphocytes
Inbred C57BL
Transgenic
Mice
0302 clinical medicine
Primary biliary cirrhosis
Transforming Growth Factor beta
Receptors
CD4(+) T cells
2.1 Biological and endogenous factors
Immunology and Allergy
Cytotoxic T cell
Aetiology
Bone marrow chimeric mice
Liver Cirrhosis
Biliary
Liver Disease
Biliary
Hematopoietic Stem Cell Transplantation
Regulatory T cells
Haematopoiesis
medicine.anatomical_structure
Liver
CD4 Antigens
Female
030211 gastroenterology & hepatology
Receptor
Parabiosis
Chronic Liver Disease and Cirrhosis
Immunology
Mice
Transgenic
Protein Serine-Threonine Kinases
Biology
Autoimmune Disease
Article
Autoimmune Diseases
03 medical and health sciences
Chimera (genetics)
Rare Diseases
medicine
Animals
Humans
Animal
Inflammatory and immune system
Receptor
Transforming Growth Factor-beta Type II
medicine.disease
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
Disease Models
Mutation
Bile Ducts
Bone marrow
Digestive Diseases
Receptors
Transforming Growth Factor beta
CD8
Transforming Growth Factor-beta Type II
Zdroj: Journal of Autoimmunity. 66:108-117
ISSN: 0896-8411
DOI: 10.1016/j.jaut.2015.09.002
Popis: There is a significant unmet need in the treatment of primary biliary cirrhosis (PBC) despite significant data on the effector pathways that lead to biliary duct damage. We focused attention on a murine model of PBC, the dominant negative transforming growth factor β receptor II (Tg) mice. To further define the pathways that lead to biliary pathology in these mice, we developed Tg mice deleted of CD4 cells (CD4(-/-)Tg). Interestingly, these mice developed more severe cholangitis than control Tg mice. These mice, which lack CD4 cells, manifested increased levels of IFN-γ produced by effector CD8 cells. It appears that increased cholangitis is due to the absence of CD4 Treg cells. Based on these data, we parabiosed CD4(-/-)Tg mice with established disease at 8-9 weeks of age with C57BL/6 control mice. Such parabiotic "twins" had a significant reduction in autoimmune cholangitis, even though they had established pathology at the time of surgery. We prepared mixed bone marrow chimera mice constructed from CD4(-/-)Tg and CD8(-/-) mice and not only was cholangitis improved, but a decrease in terminally differentiated CD8(+) T effector cells in the presence of wild type CD4 cells was noted. In conclusion, "correcting" the CD4 T cell subset, even in the presence of pathogenic CD8 T cells, is effective in treating autoimmune cholangitis.
Databáze: OpenAIRE
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