2017
Immunomodulation by mesenchymal stem cells: Lessons from vascularized composite allotransplantation
Publication
Publication
Transplantation , Volume 101 - Issue 1 p. 30- 31
Mesenchymal stem cells (MSC) are under investigation
as a novel means of immunomodulation in solid organ
transplantation1 and encouraging data from early clinical trials
have been reported.2,3 Recently, it was demonstrated that
the beneficial immunomodulatory effects of MSC are not limited
to the transplantation of solid organs, but are also applicable
to vascularized composite allotransplantation (VCA).4 In
their elegant article, Plock et al5 explored the mechanisms of
MSC therapy in VCA, especially concerning timing and frequency
of MSC administrations. The timing of MSC administration
appears to be crucial for the therapeutic effect on
composite allograft survival, and repeated administrations
were shown to improve therapeutic efficacy.
There are a number of aspects to keep in mind in this
study that can help us understand the mechanisms of action
of MSC therapy in more detail. The first is that donor
MSC were used, which means that the possibility that the
observed prolongation of graft survival depends on
donor-specific desensitization cannot be ruled out. This
would still be an interesting finding and may indicate that
donor MSC administration could be used as a more controlled
alternative to donor-specific blood transfusions,
which have earlier been under investigation for inducing T
cell nonresponsiveness in organ recipients.6 MSC can be precisely
dosed, and furthermore, levels of HLA molecules,
which are at the basis of T cell nonresponsiveness induced
by donor cell infusion, can be controlled by treatment
of MSC with cytokines, such as IFNγ and TNFα. The
present study may suggest that the induction of T cell
nonresponsiveness by presentation of donor HLA by
MSC may deserve further investigation.
Second, Plock et al treated their recipient animals with
rabbit-antirat lymphocyte polyclonal serum (ALS) 4 days
before and 1 day after surgery. MSC were thus administered
in a partially lymphocyte depleted environment. This
may have played a role in the therapeutic effect of theMSC
administrations, and it may explain some of the differences
found between administration of MSC on postoperative
day 1 compared with MSC administered on day 4. On
day 1, MSC encountered a sharply reduced lymphocyte
population with dying lymphocytes, whereas at postoperative
day 4, MSC encountered a carefully recovering lymphocyte
population. The different conditions concerning
the lymphocyte compartment may be accompanied with
differences in cytokine profiles, which act upon the administered
MSC. Therefore, in addition to timing of
MSC administration in relation to the transplantation,
timing of MSC in relation to the ALS treatment may also
play a role in the observed therapeutic effects of the MSC
administrations. This is useful knowledge to take into
consideration for further studies.
Third, the observed peripheral blood cell chimerism in
the transplanted animals is intriguing. Chimerism is considered
to be associated with prolongation of graft survival,
and the data of the present study support this.
Because MSC do not circulate in the blood7,8 and intravenously
infused MSC disappear swiftly after administration,
the circulating donor cells have to represent
leukocytes derived from the vascularized composite transplant.
The data show that coadministration of MSC at
least temporarily increases the presence of donor cells in
the circulation. This would suggest that MSC therapy enhances
the survival of circulating donor derived leukocytes,
thereby supporting chimerism. If this is the case, it
could represent another mechanism of prolongation of
graft survival by MSC. The question is whether the support
of chimerism by MSC is specific for VCA or whether
this applies for other transplants as well.
Overall, the study by Plock et al adds to the accumulating
evidence that in accordance to their effects in graftversus-
host disease and solid-organ transplantation MSC
have a therapeutic future in VCA. The experimental details
contribute to better understanding of MSC treatment and
to the development of effective therapy.
Additional Metadata | |
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doi.org/10.1097/TP.0000000000001534, hdl.handle.net/1765/95625 | |
Transplantation | |
Organisation | Erasmus MC: University Medical Center Rotterdam |
Hoogduijn, M. (2017). Immunomodulation by mesenchymal stem cells: Lessons from vascularized composite allotransplantation. Transplantation (Vol. 101, pp. 30–31). doi:10.1097/TP.0000000000001534 |