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2018 ; 9
(ä): 873
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gab.com Text
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English Wikipedia
Interleukin-27 Gene Therapy Prevents the Development of Autoimmune
Encephalomyelitis but Fails to Attenuate Established Inflammation due to the
Expansion of CD11b(+)Gr-1(+) Myeloid Cells
#MMPMID29740452
Zhu J
; Liu JQ
; Liu Z
; Wu L
; Shi M
; Zhang J
; Davis JP
; Bai XF
Front Immunol
2018[]; 9
(ä): 873
PMID29740452
show ga
Interleukin-27 (IL-27) and its subunit P28 (also known as IL-30) have been shown
to inhibit autoimmunity and have been suggested as potential immunotherapeutic
for autoimmune diseases such as multiple sclerosis (MS). However, the potential
of IL-27 and IL-30 as immunotherapeutic, and their mechanisms of action have not
been fully understood. In this study, we evaluated the efficacy of
adeno-associated viral vector (AAV)-delivered IL-27 (AAV-IL-27) and IL-30
(AAV-IL-30) in a murine model of MS. We found that one single administration of
AAV-IL-27, but not AAV-IL-30 completely blocked the development of experimental
autoimmune encephalomyelitis (EAE). AAV-IL-27 administration reduced the
frequencies of Th17, Treg, and GM-CSF-producing CD4(+) T cells and induced T cell
expression of IFN-?, IL-10, and PD-L1. However, experiments involving
IL-10-deficient mice and PD-1 blockade revealed that AAV-IL-27-induced IL-10 and
PD-L1 expression were not required for the prevention of EAE development.
Surprisingly, neither AAV-IL-27 nor AAV-IL-30 treatment inhibited EAE development
and Th17 responses when given at disease onset. We found that mice with
established EAE had significant expansion of CD11b(+)Gr-1(+) cells, and AAV-IL-27
treatment further expanded these cells and induced their expression of
Th17-promoting cytokines such as IL-6. Adoptive transfer of AAV-IL-27-expanded
CD11b(+)Gr-1(+) cells enhanced EAE development. Thus, expansion of
CD11b(+)Gr-1(+) cells provides an explanation for the resistance to IL-27 therapy
in mice with established disease.