Immunoregulatory properties of clinical grade mesenchymal stromal cells: evidence, uncertainties, and clinical application

Cédric Ménard,Karin Tarte

doi:10.1186/scrt214

Abstract

Mesenchymal stromal cell (MSC)-based therapy holds great promise for treating immune disorders and for regenerative medicine in agreement with their paracrine trophic and immunosuppressive activities. Various processes have been developed worldwide to produce clinical grade MSCs but, so far, it is not known if one given MSC is more efficient than another. In addition, while their broad activity on innate and adaptative immune cell subsets is now widely admitted, the precise mechanisms supporting their immunoregulatory capacities are still a matter of debate. Finally, quantitative immunological potency assays correlated to clinical efficacy and clinically relevant immunomonitoring approaches for MSC-treated patients are sorely needed. Multiple parameters could influence the immunomodulatory potential of therapeutic MSCs. The most important challenge is now to differentiate, within a high number of poorly comparable and even contradictory pre-clinical studies, the parameters that could have some clinical impact from those that are only due to uncontrolled experimental variability. Importantly, besides MSC-related differences, primarily linked to production processes, several important variables associated with immune assays themselves, including selection of effector immune cells, activation signals, and read-out techniques, should be carefully considered to obtain solid results with potential therapeutic application. In this review, we establish a core of common and reproducible immunological properties of MSCs, shed light on technical issues concerning immunomodulatory potential assessment, and put them into perspective when considering clinical application.

Highlights

Interest in adult mesenchymal stromal cells (MSC) as a promising tool in regenerative medicine and for treating severe immune-mediated diseases has increased over the past decade [1]
A combination of IFN-γ and TNF-α for 40 hours has been proposed as the standard MSC licensing protocol but Toll-like receptor (TLR) ligands are well known to variably modify MSC immune properties and should be considered depending on the specific clinical application [20]
In keeping with the multiple levels of regulation of IDO, we found no link between IDO mRNA level and T-cell inhibition but a good correlation exists between the capacity of MSCs to suppress T cells and to express IDO protein and enzymatic activity after inflammatory licensing [18,33]

Summary

Introduction

Interest in adult mesenchymal stromal cells (MSC) as a promising tool in regenerative medicine and for treating severe immune-mediated diseases has increased over the past decade [1]. A combination of IFN-γ and TNF-α for 40 hours has been proposed as the standard MSC licensing protocol but TLR ligands are well known to variably modify MSC immune properties and should be considered depending on the specific clinical application [20] Another crucial parameter is the cell culture expansion evaluated by the cumulative number of population doubling. The only parameter significantly correlated to T-cell inhibition is the capacity of MSCs to produce active IDO [18,33] but it remains to be firmly demonstrated in forthcoming clinical trials that in vitro quantification of IFN-γ-induced IDO activity is a good surrogate biological marker of in vivo clinical potency Another important issue is the design of relevant immunomonitoring approaches. Dissecting the molecular mechanisms behind MSC-mediated immune suppression could open innovative therapeutic avenues based on the use of these cellderived bioactive factors as a drug instead of MSC themselves, as recently suggested for TSG-6 [29]

Conclusion

Findings

40. Galipeau J