Human Gingiva-Derived Mesenchymal Stromal Cells Inhibit Graft-Versus-Host Disease Through CD39 and IDO

Song Guo Zheng¹, Maogeng Chen¹, Dong Dong Chen², Jian Gu³ and Yi Shen⁴, ¹Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, ²Medicine, Zhoushan Hospital at Zhejiang Province, Zhoushan, China, ³Medcine, University of Southern California Keck School of Medicine, Los Angeles, CA, ⁴Medicine, Shanghai East Hospital at Tongji University, Shanghai, China

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Animal models, Rheumatic disease, stem cells and therapy

Session Information

Title: Cytokines, Mediators, Cell-cell Adhesion, Cell Trafficking and Angiogenesis II

Session Type: Abstract Submissions (ACR)

Background/Purpose: We recently have reported that human-derived gingival mesenchymal stem cells (GMSC) have strong capacity to suppress immune responses and T cell-mediated collagen-induced arthritis, however, it is unclear whether these cells can suppress human T cell-mediated diseases. In this project, we have developed a humanized animal model to investigate the interventional role of human GMSC in xeno-GVHD model, which is a best animal model to study human cell therapy prior to clinical trial.

Methods: Human gingival tissues were gained from discard samples from the patients who underwent dental operation. GMSC were isolated and grown from gingival tissues and cultured in α-MEM with 10%FBS for 3-6 generations. GMSC were harvested and added to human CD25 depleted CD3+ T cells for the co-culture with 0.025ng/ml anti-human CD3 antibody for in vitro suppression test. To determine the relative molecular mechanisms, various inhibitors and antagonists were added to the cultures. In vivo, sub-lethally irradiated NOD mice were given 2 × 10⁷ peripheral blood mononuclear cell (PBMC) intravenously (IV) without (PBMC group) or with 2 × 10⁶ GMSC (PBMC + GMSC group), while other NOD mice received 2 × 10⁶ nTreg (PBMC + nTreg group) or 2×10⁶ human fibroblast cell (PBMC + Fibroblast) for the controls. The levels of cytokines and IgG in mouse serum were measured by ELISA. Mice weight was measured twice a week and survival was monitored.

Results: We showed that GMSCs potently suppress the proliferation of human PBMC in vitro independent of cell contact. GMSC also suppress Th1, Th2 and Th17 cell differentiation. Co-transfer of human PBMC and GMSC significantly suppress IFN and IgG production, maintained weight and prolonged the mouse survival. In contrast, the adoptive transfer of human fibroblast cells did not suppress xeno-GVHD. Moreover, we demonstrated that GMSCs suppress xenogenic response of human PBMCs via CD39 and IDO signals.

Conclusion: Human GMSCs can suppress human immune responses and immune system-mediated diseases, offering a pre-clinical option to be used for modulating GVHD and other autoimmune diseases.

Disclosure:

S. G. Zheng,
None;

M. Chen,
None;

D. D. Chen,
None;

J. Gu,
None;

Y. Shen,
None.

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