Regulatory T cells (Tregs) are a key population in immune tolerance and their potential use in the treatment of chronic inflammatory diseases has been increasingly and they are gaining wider acceptance for their potential in the treatment of chronic inflammatory diseases. Adoptive immunotherapy with donor Treg has been reported to successfully prevent graft vs host disease after allogeneic hematopoietic stem cell transplantation. Nevertheless, this therapy in humans still presents many challenges, particularly the difficulty in obtaining sufficient numbers of clinical grade Treg due to the very few numbers of Treg in the peripheral blood. The expansion of these cells in vitro to increase Treg yield by induction of Treg from conventional CD4 T cells is particularly appealing due to the abundance of this population. However, the stability and functional ability of induced Treg need to be thoroughly ensured prior to clinical application.
Mesenchymal stromal cells (MSCs) also constitute an important immunoregulatory population almost like Treg. Multipotent progenitor MSCs play a suppressive role by inhibiting both innate and adaptive immune responses. Previously MSC‐mediated immunomodulation was suggested to be partly driven by Treg induction and/or expansion. However the resulting Treg‐like cells populations was not assessed in absolute counts nor fully characterized. Thus far, the potential of MSCs to recruit Treg has been poorly understood.
A study released in Stem Cells demonstrates for the first time that MSCs are able to induce functional Treg through epigenetic modification of human Tcon in vitro. Led by Rita I. Azevedo, Ph.D., at the Instituto de Medicina Molecular in Lisbon, Portugal, these data suggest that MSC‐induced Treg have a potential application as a cellular therapy in clinical settings where immune tolerance is compromised that includes everything from cancer and asthma to inflammatory bowel disease, rheumatoid arthritis and more.
To conduct the study, researchers cocultured peripheral blood mononuclear cells from healthy donors with allogeneic bone marrow‐derived MSCs expanded under xenogeneic‐free conditions. The data show an increase in the counts and frequency of Treg cells (4‐ and 6‐fold, respectively) after a 14‐day coculture. These MSC‐induced Treg‐like cells also resemble Treg functionally, since they suppress autologous Tcon proliferation. Importantly, the DNA methylation profile of MSC‐induced Treg‐like cells more closely resembles that of natural Treg than of Tcon, indicating that this population is stable. Overall, the study suggests that Treg enrichment by MSCs results from Tcon conversion into Treg‐like cells, rather than to expansion of natural Treg. This MSC‐induced Treg population closely resembles natural Treg in terms of phenotype, suppressive ability, and methylation profile.
"Our data sheds new light into the origin, functional potential and stability of MSC-induced Treg-like cells, which are key features for their potential applicability in the clinical setting." Dr. Azevedo concluded. "The co-administration of MSC and Treg might have the potential to constitute a more effective cellular therapy approach by harnessing the suppressive capacity of both these immunomodulatory populations."*
"This is an exciting advance", said Dr. Jan Nolta, Editor-in-Chief of Stem Cells. "Dr. Azevedo and her team have defined important MSC-based mechanisms to induce and enrich Treg cells, which could have important future implications for the treatment of chronic diseases."*