Adoptive Transfer of Treg Cells Combined with Mesenchymal Stem Cells Facilitates Repopulation of Endogenous Treg Cells in a Murine Acute GVHD Model

• Published in: PloS one 2015-09, Vol.10 (9), p.e0138846-e0138846
• Main Authors: Lee, Eun-Sol, Lim, Jung-Yeon, Im, Keon-Il, Kim, Nayoun, Nam, Young-Sun, Jeon, Young-Woo, Cho, Seok-Goo
• Format: Article
• Language: English
• Subjects: Acute Disease; Adoptive Transfer; Analysis; Animal models; Animals; Arthritis; Bone marrow; Bone marrow transplantation; Bone Marrow Transplantation - methods; Cell survival; Cells, Cultured; Combined Modality Therapy; Consortia; Disease Models, Animal; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Foxp3 protein; Gene Expression; Graft Survival; Graft vs Host Disease - genetics; Graft vs Host Disease - metabolism; Graft vs Host Disease - prevention & control; Graft-versus-host reaction; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Growth factors; Health aspects; Helper cells; Hematology; House mouse; Immunology; Immunoregulation; Inflammation; Interleukin 17; Laboratories; Lymphocytes; Lymphocytes T; Medicine; Mesenchymal Stem Cell Transplantation - methods; Mesenchymal stem cells; Mesenchyme; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Confocal; Organs; Repopulation; Reverse Transcriptase Polymerase Chain Reaction; Stem cell transplantation; Stem cells; Survival; T cell receptors; T cells; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - transplantation; Target detection; Therapy; Transplantation; Transplantation, Homologous; Treatment Outcome
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0138846

Therapeutic effects of combined cell therapy with mesenchymal stem cells (MSCs) and regulatory T cells (Treg cells) have recently been studied in acute graft-versus-host-disease (aGVHD) models. However, the underlying, seemingly synergistic mechanism behind combined cell therapy has not been determined. We investigated the origin of Foxp3+ Treg cells and interleukin 17 (IL-17+) cells in recipients following allogeneic bone marrow transplantation (allo-BMT) to identify the immunological effects of combined cell therapy. Treg cells were generated from eGFP-expressing C57BL/6 mice (Tregegfp cells) to distinguish the transferred Treg cells; recipients were then examined at different time points after BMT. Systemic infusion of MSCs and Treg cells improved survival and GVHD scores, effectively downregulating pro-inflammatory Th×and Th17 cells. These therapeutic effects of combined cell therapy resulted in an increased Foxp3+ Treg cell population. Compared to single cell therapy, adoptively transferred Tregegfp cells only showed prolonged survival in the combined cell therapy group on day 21 after allogeneic BMT. In addition, Foxp3+ Treg cells, generated endogenously from recipients, significantly increased. Significantly higher levels of Tregegfp cells were also detected in aGVHD target organs in the combined cell therapy group compared to the Treg cells group. Thus, our data indicate that MSCs may induce the long-term survival of transferred Treg cells, particularly in aGVHD target organs, and may increase the repopulation of endogenous Treg cells in recipients after BMT. Together, these results support the potential of combined cell therapy using MSCs and Treg cells for preventing aGVHD.