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Successful treatment of murine autoimmune cholangitis by parabiosis: Implications
for hematopoietic therapy
#MMPMID26432598
Yang JB
; Wang YH
; Yang W
; Lu FT
; Ma HD
; Zhao ZB
; Jia YJ
; Tang W
; Tsuneyama K
; Ridgway WM
; Gershwin ME
; Lian ZX
J Autoimmun
2016[Jan]; 66
(?): 108-17
PMID26432598
show ga
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 ? 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-? 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.
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