The Authors’ Reply: Mesenchymal Stem Cells and Immunosuppressive Drug Interactions

Abstract

The findings by Buron et al. confirm our earlier results demonstrating that mesenchymal stem cells (MSCs) act synergistically with mycophenolic acid on peripheral blood mononuclear cell (PBMC) proliferation, but counteract the effect of calcineurin inhibitors (CNIs) and mammalian target of rapamycin inhibition (rapamycin) (1, 2). To explain these results, Buron et al. propose that the CNI inhibits the production of proinflammatory cytokines by immune cells, which are necessary to induce the immunosuppressive activity of MSC. CNI would thereby prevent an additive immunosuppressive effect of MSC. They support this hypothesis by showing that delayed addition of the CNI to alloactivated PBMC allows the MSC activation and thereby induce additive immunosuppression by MSC. An alternative approach to demonstrate the requirement for MSC activation would be to pre-expose MSC to proinflammatory cytokines and add them together with CNI to alloactivated PBMC and measure proliferation. We support the idea that prevention of MSC activation by CNI plays an important role in the lack of synergism between MSC and CNI. The decreased efficacy of the CNI in the presence of MSC, however, needs further explanation. Buron et al. and our group showed that the MSC increase the proliferation of alloactivated PBMC in the presence of CNI, which we think relates to the secretion of growth factors by the MSC under noninflammatory conditions. These factors include tumor necrosis factor-α, interleukin-6, and fibroblast growth factors, which stimulate the PBMC proliferation independently of calcineurin or mammalian target of rapamycin. Mycophenolic acid treatment is insensitive to the effects of trophic factors produced by the MSC, as it blocks the basis of cell proliferation, namely nucleotide synthesis. It would therefore seem that under inflammatory conditions, so in the absence of immunosuppressive drugs, the secretion of anti-inflammatory factors by MSC outweighs the secretion of growth factors, whereas under noninflammatory conditions, the balance shifts the other way. In conclusion, the recent studies on the interactions between MSC and immunosuppressive drugs demonstrate that the choice of drug will be of great importance for the outcome of clinical trials with the MSC. Martin J. Hoogduijn Meindert J. Crop Carla C. Baan Department of Internal Medicine Transplantation laboratory Erasmus University Medical Center Rotterdam, The Netherlands