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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Nat+Med
2016 ; 22
(3
): 319-23
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Transient inhibition of ROR-?t therapeutically limits intestinal inflammation by
reducing TH17 cells and preserving group 3 innate lymphoid cells
#MMPMID26878233
Withers DR
; Hepworth MR
; Wang X
; Mackley EC
; Halford EE
; Dutton EE
; Marriott CL
; Brucklacher-Waldert V
; Veldhoen M
; Kelsen J
; Baldassano RN
; Sonnenberg GF
Nat Med
2016[Mar]; 22
(3
): 319-23
PMID26878233
show ga
RAR-related orphan receptor-?t (ROR-?t) directs differentiation of
proinflammatory T helper 17 (TH17) cells and is a potential therapeutic target in
chronic autoimmune and inflammatory diseases. However, ROR-?t-dependent group 3
innate lymphoid cells ILC3s provide essential immunity and tissue protection in
the intestine, suggesting that targeting ROR-?t could also result in impaired
host defense after infection or enhanced tissue damage. Here, we demonstrate that
transient chemical inhibition of ROR-?t in mice selectively reduces cytokine
production from TH17 but not ILCs in the context of intestinal infection with
Citrobacter rodentium, resulting in preserved innate immunity. Temporal deletion
of Rorc (encoding ROR-?t) in mature ILCs also did not impair cytokine response in
the steady state or during infection. Finally, pharmacologic inhibition of ROR-?t
provided therapeutic benefit in mouse models of intestinal inflammation and
reduced the frequency of TH17 cells but not ILCs isolated from primary intestinal
samples of individuals with inflammatory bowel disease (IBD). Collectively, these
results reveal differential requirements for ROR-?t in the maintenance of TH17
cell and ILC3 responses and suggest that transient inhibition of ROR-?t is a safe
and effective therapeutic approach during intestinal inflammation.