Vascularized composite allograft rejection is delayed by infusion of IFN-γ-conditioned BMSCs through upregulating PD-L1
Mesenchymal stromal cells (MSCs) have been applied in prevention from allograft rejection based on their immunomodulatory effects. However, conflicting results have been presented among recent studies, for which one possibility being acknowledged is that the exact effect is determined by the microenvironment when MSCs are applied in vivo. Using a hind limb composite tissue allograft model, we investigate the influence of IFN-γ-preconditioning on the immunomodulatory effects of MSCs and the subsequent allograft survival. Firstly, different doses of IFN-γ were respectively used to incubate with bone marrow–derived MSCs (BMSCs). We found that IFN-γ altered the expression of PD-L1, a major suppressor gene in the immune system during allograft rejection, in a strictly dose-dependent manner in BMSCs. Ten nanograms per milliliter IFN-γ-incubated BMSCs significantly stimulated PD-L1 expression and suppressed T cell proliferation and differentiation, while 50 ng/mL IFN-γ-incubated BMSCs sharply reduced PD-L1 expression. Moreover, we observed that, in contrast to the naive BMSC transplantation group, BMSCs pre-conditioned with 10 ng/mL IFN-γ (BMSCs-IFN-γ) significantly delayed the allograft rejection in vivo. In vitro mixed lymphocyte reaction (MLR) indicated that BMSCs-IFN-γ inhibited T lymphocyte proliferation and activation via PD-L1. Moreover, BMSCs-IFN-γ did not influence the proliferation and activation of T lymphocytes when PD-L1 protein was neutralized by the PD-L1 antibody. These data collectively reveal a role of recipient ongoing immune microenviroment in BMSC-based immunesuppressive therapy.
KeywordsAllograft rejection IFN-γ BMSC PD-L1 T cell proliferation and activation
This study was supported by National Natural Science Foundation Youth Program of China (No.81401593).
- Broekman W, Amatngalim GD, Mooijeijk YD, Oostendorp J, Roelofs H, Taube C, Stolk J, Hiemstra PS (2016) TNF-α and IL-1β-activated human mesenchymal stromal cells increase airway epithelial wound healing in vitro via activation of the epidermal growth factor receptor. Respir Res 17:3CrossRefGoogle Scholar
- Calkoen FG, Vervat C, van Halteren AG, Welters MJ, Veltrop-Duits LA, Lankester AC, Egeler RM, Ball LM, van Tol MJ (2014) Mesenchymal stromal cell therapy is associated with increased adenovirus-associated but not cytomegalovirus-associated mortality in children with severe acute graft-versus-host disease. Stem Cells Transl Med 3:899–910CrossRefGoogle Scholar
- Mielcarek M, Storb R, Georges GE, Golubev L, Nikitine A, Hwang B, Nash RA, Torokstorb B (2011) Mesenchymal stromal cells fail to prevent acute graft-versus-host disease and graft rejection after dog-leukocyte-antigen haploidentical bone marrow transplantation. Biol Blood Marrow Transplant 17:214–225CrossRefGoogle Scholar
- Obermajer N, Popp FC, Soeder Y, Haarer J, Geissler EK, Schlitt HJ, Dahlke MH (2014) Conversion of Th17 into IL-17Aneg regulatory T cells: a novel mechanism in prolonged allograft survival promoted by mesenchymal stem cell-supported minimized immunosuppressive therapy. J Immunol 193:4988CrossRefGoogle Scholar
- Pourgholaminejad A (2016) The effect of pro-inflammatory cytokines on immunophenotype, differentiation capacity and immunomodulatory functions of human mesenchymal stem cells. Cytokine 85:51–60Google Scholar
- Singh A, Mohan A, Dey AB, Mitra DK (2013) Inhibiting the programmed death 1 pathway rescues Mycobacterium tuberculosis-specific interferon γ-producing T cells from apoptosis in patients with pulmonary tuberculosis. J Infect Dis 208:603–615Google Scholar
- Tolar J, Blanc KL, Blazar BR (2013) MSCs for graft-versus-host disease. In: Hematti P, Keating A (eds) Mesenchymal stromal cells. Stem cell biology and regenerative medicine. Humana Press, New YorkGoogle Scholar