induction of persistent tolerance to lung … und...induction of persistent tolerance to lung...
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![Page 1: Induction of persistent tolerance to lung … und...Induction of persistent tolerance to lung transplants by IL-2 complex-stimulated regulatory T cells in vivo Walter Brendel Award](https://reader036.vdocuments.net/reader036/viewer/2022081406/5f1539c91051b30ae24e9de2/html5/thumbnails/1.jpg)
Induction of persistent tolerance to lung transplants
by IL-2 complex-stimulated regulatory T cells in vivo
Walter Brendel Award Session
Wolfgang Jungraithmayr, MD PhD University Hospital Zurich, Switzerland, and Medical University Brandenburg, Germany
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Acute cellular rejection (ACR) after lung transplantation (Tx)
Scientific Registry of Transplant Recipients, USA, 2014
Incidence of ACR Pathology of ACR
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Orthotopic single lung transplantation (Tx)
Jungraithmayr et al. J Thorac Cardiovascular Surg, 2009
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Course of rejection after mouse lung Tx
days after transplantation
Human Mouse
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Activation of immune cells after lung Tx
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Stimulation of T cells by IL-2 complexes (cx) for Treg proliferation
High affinity IL-2Rα + AB bind selectively on CD25+ T cells
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Experimental set up – 3 times of IL-2cx treatment before Tx
at day 5, 15, 28 and 56
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Il-2cx treated recipients showed macroscopic normal appearance
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Histologically (H&E) preserved grafts in IL-2cx-treated recipients
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Background
Lymphocytes infiltrated less in IL-2cx treated recipients
AR score
Day 5 15 28 560
1
2
3
4
5
ControlIL-2cx
* * * *
* p<0.05
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Background
IL-2cx – treated recipients showed better compliance and improved PaO2
day 5
Lung compliance of allograft( µ
l/ cm
H2O
)
Control IL-2cx0
2
4
6
8 * PaO2 from allograft
(mm
Hg)
Control IL-2cx0
100
200
300
400
500 *
* p<0.05
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Background
Foxp3+CD4+CD25+ cells in IL-2 cx treated allografts
% C
D4+ C
D25+ F
oxP3
+ce
lls
Day 5 15 28 560
20
40
60
80ControlIL-2cx
*
* * *
Day 5
Control IL-2cx
Allograft
* p<0.05
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% C
D4+ C
D25+ F
oxP3
+ce
lls
Day 5 15 28 560
20
40
60
80
ControlIL-2cx*
Background
Naïve right lungs had increased numbers of Foxp3+ cells early after Tx
Day 5
Naïve right lung
Control IL-2cx
* p<0.05
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% C
D4+ C
D25+ F
oxP3
+ce
lls
Day 5 15 28 560
20
40
60
80
ControlIL-2cx
*
*
Control IL-2cx
Background
Spleens had increased numbers of Foxp3+ cells early after Tx
Day 5 Spleen
* p<0.05
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Background
Loss of function experiments
B6-Foxp3DTR
B6-Foxp3DTR
Harvest IL-2cx Allo Tx
Day -4 -3 -2 -1 0
BALB/c
15 3 14 1 2
Diphtheria toxin (DT)
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Background
IL-2cx-treated B6-Foxp3DTR receiving diphterie toxin develop severe ACR
B6-Foxp3DTR
allograft on day 15
IL-2cx+ DT IL-2cx
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Background
Summary & Conclusion
• IL-2 cx treatment before lung transplantation induces long term
acceptance, histologically and functionally
• The presence of Tregs within allografts suggests that this cell population
is responsible for allograft acceptance
• Preliminary data from loss of function experiments confirms the
tolerogenic role of Tregs
• These data may have implications for immune protocols for Treg
modulation in human lung transplantation
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Thanks to
Shampa Chatterjee, USA
Walter Weder
Beatrice Beck
Ilhan Inci
Ingrid de Meester (Belgium
Christian Münz
Andreas Boss
Jae Hwi Jang
Alex Soltermann
Yoshito Yamada
Florian Janker
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Thank from Zurich
to Amsterdam
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Background
CD4+ Foxp3+ cells were increased in IL-2cx allografts
Foxp
3+ Control
IL2cx Day 28 Foxp3+
Inte
nsity
(0-4
)
Day 5 15 28 560
1
2
3
4
5
ControlIL2cx
* * *
CD
4+
Day28 IL-2cx CD4+
Inte
nsity
(0-4
)
Day 5 15 28 560
1
2
3
4
5 ControlIL-2cx* * *