Mesenchymal stem cells administered after liver transplantation prevent acute graft-versus-host disease in rats

Abstract

Acute graft-versus-host disease is a serious and life-threatening complication of liver transplantation (LT) that occurs in 1% to 2% of liver allograft recipients. It is associated with a high mortality rate, and effective therapies are lacking. In our established rat model, a relative decrease in regulatory T cells (Tregs) was previously shown to be associated with acute graft-versus-host disease after liver transplantation (LT-aGVHD). Mesenchymal stem cells (MSCs) have been used to treat graft-versus-host disease after allogeneic hematopoietic stem cell transplantation, and they have been shown to induce Tregs, which have immunomodulatory effects. In this study, when a treatment with donor-or recipient-derived MSCs was administered from day 8 to day 14 after the typical symptoms of LT-aGVHD started, the recipients were not cured, and their survival time was not prolonged. However, when MSCs of different origins were administered from day 0 to day 6 after LT, the recipients survived significantly longer than the control group, and the surviving MSC-treated rats did not show typical LT-aGVHD symptoms. In vivo tracings of carboxyfluorescein diacetate succinimidyl ester-stained MSCs did not show significant accumulations in the target organs after administration. Flow cytometry analysis showed that the Treg ratios in peripheral blood were more higher for the MSC-treated groups versus the control group. More immunohistochemically stained forkhead box P3-positive cells were also found in the intestines of the MSC-treated groups versus the control group. Further investigations of the function of MSCs showed that they could increase the Treg ratio in a mixed lymphocyte reaction (MLR) and lead to a greater reduction in MLR proliferation in vitro. In conclusion, the post-LT administration of MSCs of either donor or recipient origin could prevent the onset of LT-aGVHD in our rat model. Liver Transpl 18:696-706, 2012. V C 2012 AASLD.

Immunological effect induced by mesenchymal stem cells in a rat liver transplantation model

“…These effects may be due to a number of reasons. Firstly, MSCs may immunoregulate the functions of host T cells (28)(29)(30) by direct regulation (31,32), where the MSCs change the immune function through direct contact between cells to regulate the ratio changes of T cell subsets, or indirect regulation (33)(34)(35), where MSCs may inhibit the growth and activation of T cells to cause relative changes to the T cell subsets in order to induce a lower T cell response, through the secretion of immune cytokines, including TGF-β 1 , hepatocyte growth factor, and metabolic products, such as prostaglandin E2 or indole-2,3-dioxygenase. Beyth et al (9) indicated that MSCs affected the maturation of normal APCs indirectly to cause T cells to become unresponsive, through the secretion of IL-10 and the inhibition of monocyte IL-12 secretion, ultimately inhibiting immune rejection.…”

Mesenchymal stem cells in tumor development

“…[9][10][11][12][13][14] They display a number of remarkable properties, such as the tendency to home to sites of injury, the capacity to suppress immune reactions and the ability to aid in the repair and regeneration of damaged tissues. [15][16][17] Accordingly, MSCs have been explored widely for their applications in regenerative medicine and as delivery vehicles for use in gene therapy. 18 In the context of cancer, MSCs are becoming increasingly recognized as important stromal facilitators of tumor development.…”

The use of mesenchymal stromal cells in solid organ transplantation

“…Rats that received donor-or recipient-derived BM-MSCs from day 0 to day 6 after LT (5 × 10 6 MSCs/day) had a significantly longer survival and no typical LT-associated GVHD symptoms, while administration of MSCs after the onset of symptoms was ineffective for treating GVHD. The efficacy of MSC therapy was associated with higher Treg ratios in the peripheral blood [54].…”