Mesenchymal Stem Cell and Immunosuppressive Drug Interactions

Abstract

Mesenchymal stem cells (MSCs) are an interesting new therapeutic approach in solid organ transplantation owing to their immunomodulatory properties demonstrated in vitro and in vivo (1, 2). However, when they are used in transplant patients, it will probably be with immunosuppressive drugs and little was known about these interactions until a recent work of Hoogduijn et al. (3). They first evaluated the direct effect of immunosuppressants (IS) on MSC, expanded from human heart tissue. Clinical doses of tacrolimus, mycophenolic acid (MPA), or rapamycin did not induce any toxicity or apoptosis of MSC. The two antiproliferative IS, rapamycin and MPA, inhibited the proliferation of MSC, which have their own molecular targets. Then, they assessed MSC and IS interactions on the inhibition of lymphocyte proliferation by adding them at the beginning of mixed lymphocyte reactions. MSC reduced the immunosuppressive effect of tacrolimus and rapamycin, whereas they enhanced the effect of MPA. Our work on human bone marrow-derived MSC showed similar results: we found an antagonistic effect on lymphocyte proliferation between MSC and rapamycin, tacrolimus and cyclosporine A (CsA), and a synergistic effect with MPA. To explain these results, Hoogduijn et al. remind us that tacrolimus and rapamycin strongly reduce lymphocyte activity and that MSC support lymphocytes that are in a quiescent state (4). We propose another hypothesis: calcineurin inhibitors (CNI) inhibit lymphocyte activation and the production of interferon-γ and other proinflammatory cytokines necessary for MSC to exert their immunosuppressive effects (5, 6). Then, CNI could antagonize the immunomodulatory effect of MSC by inhibiting the proinflammatory microenvironment required for their activation. We tested our hypothesis in mixed lymphocyte reaction experiments. Introduction of CsA was delayed for 24 and 48 hr to allow MSC activation by the inflammatory microenvironment. As shown in Figure 1, MSC and CsA alone inhibited lymphocyte proliferation. When added together on day 0, their effects were antagonistic to lymphocyte proliferation. However, when CsA was introduced on day 1 or 2, this antagonistic effect between MSC and CsA disappeared. Conversely, delayed introduction of MPA did not modify its synergistic effect with MSC (data not shown). This was expected because both MPA and MSC inhibit lymphocyte proliferation.FIGURE 1.: Interactions between mesenchymal stem cells (MSC) and cyclosporine A (CsA) on allogenic lymphocyte proliferation. Mitomycin C-treated MSC at a ratio of 1 MSC to 10 responder cells were added at the beginning of a mixed lymphocyte reaction (MLR) (105 peripheral blood mononuclear cells [PBMC] stimulated with 105 allogenic mitomycin C-treated PBMC). CsA 100 ng/mL was added on day 0, 1, or 2 of the MLR. Proliferation was assessed by 3H-thymidine incorporation during the last 16 hr of a 6-day culture. Results are expressed as a percentage of mean±standard deviation of triplicates of one of two representative experiments. *shows statistically significant differences (P<0.05).In vivo studies are in concordance with the Hoogduijn results and our results, showing an antagonistic effect between CsA and MSC in several models of solid organ allografts in rat (7, 8). Moreover, Popp et al. (9) found synergy between MSC and low doses of mycophenolate to induce long-term acceptance in rat heart allografts. To conclude, according to their mechanisms of action, IS could promote (MPA) or antagonize (CNI, rapamycin) the immunomodulatory effects of MSC. These interactions have to be taken into consideration to optimize MSC use in transplantation. Fanny Buron Emmanuel Morelon INSERM, U851 21 Avenue Tony Garnier Lyon, France Service de Néphrologie et Transplantation Pavillon P, Hospices Civils de Lyon Hôpital Edouard Herriot Lyon, France Hélène Perrin INSERM, U851 21 Avenue Tony Garnier Lyon, France Christophe Malcus Françoise Touraine Moulin Laboratoire d’ Immunologie Pavillon E, Hospices Civils de Lyon Hôpital Edouard Herriot Lyon, France Olivier Héquet INSERM, U851 21 Avenue Tony Garnier Lyon, France Banque de tissus et de cellules Pavillon I, Hospices Civils de Lyon Hôpital Edouard Herriot Lyon, France