Bone Marrow-Derived Mesenchymal Stem Cells Ameliorate Autoimmune Enteropathy Independent of Regulatory T Cells

¹ Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospitals for Children, Boston, MA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA
² Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospitals for Children, Boston, MA

^* To whom correspondence should be addressed. E-mail: ireis{at}sbi.org.

	Abstract

Cell-based tolerogenic therapy has been a new approach for the treatment of autoimmune diseases. Mesenchymal stem cells (MSCs) have been shown to be potent immunomodulatory agents in a number of experimental and clinical scenarios, however their use in various autoimmune diseases has been undefined. Herein, we report the efficacy of MSC transplantation in a multi-organ autoimmunity model. Mice with defective peripheral tolerance caused by a deficiency in regulatory T cells (Tregs) were used as a testbed for therapy. After screening multiple target tissues of autoimmune attack, we observed a MSC-specific improvement in the histopathology of the distal ileum of treated mice. We then showed that MSCs can reduce mesenteric lymph node (MLN) cellularity in autoimmune mice during active disease, and decrease activated T cell populations in the MLN. Trafficking studies using enhanced green fluorescent protein (eGFP)-reporter MSCs revealed no appreciable engraftment in the intestine, but the presence of eGFP+ cells organized in clusters within the MLN as well as ancillary nodes. Semi-quantitative analysis showed no difference in the number of clusters, however eGFP+ cells in MLNs compared to ancillary nodes had distinct fibroblastoid morphology and formed a network with neighboring eGFP+ cells. Finally, we show evidence that transplantation of MSCs caused global immunosuppression as measured by increased CD4+CD8+ thymocyte production and serum interleukin-10 and decreased serum interferon-. These data implicate the intestine as a new site of MSC tolerance induction and should motivate further studies evaluating the use of MSCs as a treatment for autoimmune enteropathies.