Immunomodulation by mesenchymal stem cells: Lessons from vascularized composite allotransplantation

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.