Crosstalk of human mesenchymal stromal cells with the cellular components of the immune system

Using the
potential 
of immune regulatory cell populations 
for
c
ellular therapy 
constitutes 
an attractive tool to obliterate imbalances of immune responses
in 
inflammatory disorde
rs. 
In this context, adoptive transfer of m
esenchymal stromal cells 
(MSCs) 
represents
a relatively novel approach 
and its
impact on the immune system 
has not been completely clarified. In this thesis we aimed 
to study
the 
effects
of 
MSCs
on key immune 
cell
types, 
which 
led us
amongst others
to investigate 
regulatory 
T
-
cell
s 
(T
Regs
), 
and myeloid cells. 




We show that 
MSC
s
utilize the 
anti
-
oxidative, immune regulatory enzyme 
hemeoxygenase
-
1 (HO
-
1) 
for 
suppressing 
T
-
cell
activation 
directly 
and for inducing
T
Re
gs
(=indirect 
T
-
cell
suppression)
. 
An i
nflammatory 
milieu generated by alloreactive 
T
-
cell
s led to the so
-
called 
‘licensing’ 
of the MSCs boosting their regulatory capacity. 
Interestingly, HO
-
1 expression was substantially diminished during this process and
its 
functions were taken over by other (up
-
regulated) molecules such as cyclooxygenase
-
2 
thereby highlighting (functional) MSC plasticity.




Most MSC
-
based trials lack a systemic 
immune monitoring, which is 
key for 
interpreting the 
in vivo
effects of MSCs. 
Performing a comprehensive flow cytometry
-
based immune screening in patients with acute graft
-
versus
-
host disease (aGVHD)
,
treated with either third
-
party MSC or placebo infusions (in a double
-
blinded fashion)
,
we 
were 
-
most importantly 
-
able to further 
corroborate the notion that MSCs function 
in vivo
partly
by promoting 
T
Reg
-
subsets
.
Thereby, our data underscores the need for 
accompanying 
extens
ive immune analyses 
to better comprehend
such 
“bench
-
to
-
bedside” approaches. 
Accordingly, we carried out thoro
ugh
,
laboratory investigations 
when we 
were the first to apply MSCs in a patient with treatment
-
refractory 
hemophagocytic lymphohistocytosis
. 
Upon MSC infusion 
we could observe an 
increase of the immune modulating cytokine 
i
nterleukin (
IL
)
-
10 
in the serum 
and a 
preferential appearance of regulatory 
type 2 macrophages in the patients’ bone marrow. 
Altogether, this data confirmed previous findings from 
in vitro
and animal model 
studies
regarding the MSCs
’
impact on myeloid cell populations
. Driven by these 
ob
servations we sought 
out 
to assess whether MSCs induce so
-
called myeloid derived 
suppressor cells 
(MDSCs) 
in 
aGVHD 
patients.
Although we did not find a
n
MSC
-
associate
d effect
,
we were the first to i
dentify monocytic CD14
+
HLA
-
DR
low/neg
MDSCs 
accumulating af
ter allogeneic hematopoietic transplantation. We characterized their 
suppressive 
function (
via
indoleamine
-
2,3
-
dioxygenase)
and 
established a significant 
association with inflammatory
cytokines
and aGVHD. In fact, our data indicates that 
MDSCs are part of 
an immune regulating feedback mechanism that is activated during 
hyper
-
inflammations (such as in aGVHD).




Overall, our results indicate that immune regulatory populations play a decisive role in 
various 
inflammatory 
diseases and 
MSCs could 
boost 
their
respo
nse
s
.
Furthermore our 
work suggests that combining basic and translational research is pre
-
requisite for 
understanding the MSCs’ multifaceted interactions and for optimizing their clinical use