GM-CSF is a Pro-Inflammatory Cytokine in Experimental ... · GM-CSF-producing T cells are...
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GM-CSF is a Pro-Inflammatory Cytokine in Experimental Vasculitis of Medium and
Large Arteries
Ryu Watanabe, Hui Zhang, Toshihisa Maeda, Mitsuhiro Akiyama, Rohan Gandhi, John F. Paolini, Gerald J. Berry, Cornelia M. Weyand
Stanford University School of Medicine
Kiniksa Pharmaceuticals Corp
2019 ACR/ARHP Annual Meeting, Atlanta November 11
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Disclosure
➢Study is funded by Kiniksa Pharmaceuticals Ltd
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Granulocyte-macrophage colony-stimulating factor (GM-CSF)
➢Cellular sourcesT cells, B cells, macrophages, neutrophils, endothelial cells and fibroblasts
➢FunctionsDevelopment and maintenance of macrophagesNeutrophil activationAngiogenesis
Nat Rev Rheumatol. 2016;12:37-48.
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Anti-GM-CSF receptor antibody as an immuno-regulatory agent
➢ Mavrilimumab (anti-GM-CSF receptor antibody) competes with GM-CSF for binding to the GM-CSF receptor α chain
➢ Therapeutic benefit in clinical trial of Rheumatoid arthritis (Burmester et al., Ann Rheum Dis 2013; 72: 1445-1452)
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Giant cell arteritis (GCA)
➢ Medium/large vessel vasculitis
➢ Affects the elderly ( >50 years)
➢ Infiltration of CD4 T cells and macrophages;giant cell formationvascular remodeling
➢ High expression of GM-CSF mRNAin temporal arteries affected by GCA
Temporal arteritis
Weyand CM, et al. Clin Immunol. 2019
Ann Intern Med. 1994
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GM-CSF functions as an amplifier of vascular inflammation
Hypothesis
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Methods
➢GM-CSF expression- in tissue biopsies from patients with GCA- in vivo: human artery-SCID chimeric mice.
➢Blocking GM-CSF activityMavrilimumab, KPL-301; a monoclonal anti-GM-CSFreceptor antibody(300 μg given over one week in established vasculitis)
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GM-CSF mRNA expression in temporal artery biopsies
GCA arteries
Non-inflamed arteries
GM-CSF
0
10
20
30
40
Rel
ativ
ee
x pre
ssio
n P<0.0001
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GM-CSF-producing T cells in vasculitic lesions
GM-CSF
IntMed
Adv
50μM
CD3
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GM-CSF-producing T cells are selectively recruited to the inflamed vessel wall
NSGmouse
GCA PBMCtransfer
Human artery engraftment
Vasculitis induction
Spleen Blood Artery0
10
20
30
% o
f G
M-C
SF+
CD
4+
T ce
lls P<0.001
P<0.05
* GM-CSF+ CD4+ T cells measured by intracellular cytokine stain
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Can Mavrilimumab suppress vasculitogenic activity in vivo?
NSGmouse
GCA PBMCtransfer
Human artery engraftment
300 μg mavri/mouse
300 μg iso control/mouse
Vasculitis
Explanted arteryDay 22
Gene expressionIHC
FACS
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Anti-GM-CSFR Ab reduces vessel wall inflammation
Anti-GM-CSFRα
No
. of
CD
3+
cells
/HP
F P<0.001
0
20
40
60
80
100
CD3
control IgG
100 μm
control IgG
Anti-GM-
CSFRα
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Anti- GM-CSFR Ab suppresses vessel wall inflammation
* P<0.05, ** P<0.01, *** P<0.001A B C D E F G H I J K L
123456789
101112 0
1
2
3
4
A B C D E F G H I J K L
123456789
101112 0
1
2
3
4TCRIFNγIL-17IL-21
CD163IL-1IL-6
TNFαCCL5
CCL22VEGF
Endothelin 0
1
2
3
4
Control IgG aGM-CSFRαP value
*****ns*****ns
****
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GM-CSF signaling promotes neoangiogenesisand intimal hyperplasia
(CD31/αSMA/DAPI)Control IgG Anti-GM-CSFRα
(CD31/αSMA/DAPI)
No
. of
mic
rove
ssel
s/H
PF
P<0.001
0
10
20
30
Inti
mal
th
ickn
ess
(μ
m)
P<0.001
0
50
100
150
Control IgGAnti-GM-CSFR
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Summary
1. GM-CSF mRNA is abundant in GCA-affected arteries.
2. The major sources of GM-CSF in the inflamed artery are CD4 T cells.
3. GM-CSF promotes innate and adaptive immunity in the vessel wall lesionsand amplifies tissue vascularization and intimal hyperplasia.
4. Mavrilimumab, an anti-GM-CSF receptor antibody, is highly effective in suppressing vasculitis and the vasculitis-associated wall remodeling.
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Acknowledgements
T Maeda, MD PhD
M Akiyama, MD PhD
H Zhang, MD PhD
CM Weyand. MD PhD JJ Goronzy, MD PhD
GJ Berry, MD
R Watanabe, MD PhD