Abstract
The clinical acute graft-versus-host disease (GvHD)-therapy of mesenchymal stem cells (MSCs) is not as satisfactory as expected. Secondary lymphoid organs (SLOs) are the major niches serve to initiate immune responses or induce tolerance. Our previous study showed that CCR7 guide murine MSC line C3H10T1/2 migrating to SLOs. In this study, CCR7 gene was engineered into murine MSCs by lentivirus transfection system (MSCs/CCR7). The immunomodulatory mechanism of MSCs/CCR7 was further investigated. Provoked by inflammatory cytokines, MSCs/CCR7 increased the secretion of nitric oxide and calmed down the T cell immune response in vitro. Immunofluorescent staining results showed that transfused MSCs/CCR7 can migrate to and relocate at the appropriate T cell-rich zones within SLOs in vivo. MSCs/CCR7 displayed enhanced effect in prolonging the survival and alleviating the clinical scores of the GvHD mice than normal MSCs. Owing to the critical relocation sites, MSCs/CCR7 co-infusion potently made the T cells in SLOs more naïve like, thus control T cells trafficking from SLOs to the target organs. Through spoiling the fourth supplemental Billingham’s tenet, MSCs/CCR7 potently inhibited the development of GvHD. The study here provides a novel therapeutic strategy of MSCs/CCR7 infusion at a low dosage to give potent immunomodulatory effect for clinical immune disease therapy.
Highlights
Graft-versus-host disease (GvHD), a representative of T cell-mediated immune responses, remains a significant cause of morbidity and mortality in patients undergoing bone marrow transplantation
CCR7 can be successfully detected only in mesenchymal stem cells (MSCs)/CCR7at mRNA level detected by Reverse transcription-polymerase chain reaction (RT-PCR) assay, and at cell surface protein level examined by Flow cytometry (FCM)
Comparing with the mice ofGvHD and GvHD+MSCs groups, mice of GvHD+MSCs/CCR7 group had considerable alleviated scores (Fig. 5B–C). These results demonstrated that MSCs/CCR7-eGFP were more efficient in immunomodulation, presumably due to the pivotal relocation site they hold in Secondary lymphoid organs (SLOs)
Summary
Graft-versus-host disease (GvHD), a representative of T cell-mediated immune responses, remains a significant cause of morbidity and mortality in patients undergoing bone marrow transplantation. Some investigations highlighted that the effector cells migrating to the target tissues is important for the development of GvHD. Corticosteroids, the first-line therapy of GvHD, make lymphocytes trafficking into bone marrow, but away from lymph nodes and inflammatory organs. All these proved the critical role of the lymphocyte homing requirement in the GvHD development, which was proposed as a corollary to Billingham’s criteria [5]. This provided chances to modulate GvHD by controlling lymphocyte trafficking [6, 7]
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