Mesenchymal stem cells: immune evasive, not immune privileged

Abstract

The diverse immunomodulatory properties of mesenchymal stem/stromal cells (MSCs) may be exploited for treatment of a multitude of inflammatory conditions. MSCs have long been reported to be hypoimmunogenic or 'immune privileged'; this property is thought to enable MSC transplantation across major histocompatibility barriers and the creation of off-the-shelf therapies consisting of MSCs grown in culture. However, recent studies describing generation of antibodies against and immune rejection of allogeneic donor MSCs suggest that MSCs may not actually be immune privileged. Nevertheless, whether rejection of donor MSCs influences the efficacy of allogeneic MSC therapies is not known, and no definitive clinical advantage of autologous MSCs over allogeneic MSCs has been demonstrated to date. Although MSCs may exert therapeutic function through a brief 'hit and run' mechanism, protecting MSCs from immune detection and prolonging their persistence in vivo may improve clinical outcomes and prevent patient sensitization toward donor antigens.

Figure 1

The rise of MSC therapy. (a) The number of clinical trials in each phase using allogeneic or autologous MSCs. Trials in the registry that did not report a ‘phase’ are listed as “not reported.” (b) The cumulative total number of clinical trials that use allogeneic or autologous MSCs, plotted according to the year they were initiated. (c) Cumulative citations from early publications that support the ‘Universal Donor’ hypothesis (purple) and from work that highlights MSC immunogenicity (green), plotted from 2000–2012. Shades represent contributions of individual papers (references denoted on right). Contributions of papers are stacked upon one another with the most influential papers, as measured by citations, on the bottom and the least influential papers on the top. (d) Timeline of milestones that have marked the progress of MSC therapy. Data in a and b were collected from clinicaltrials.gov registry on December 15, 2013. Searches for “Mesenchymal Stem Cells,” “Mesenchymal Stromal Cells,” “Multipotent stromal cells,” “bone marrow stromal cells,” “Stem cells for Spinal Fusion,” “Prochymal” and “connective tissue progenitor” returned 347 unique MSC trials. Nine trials did not indicate the source (auto vs. allo) of the MSCs, and two reported using both allogeneic and autologous MSCs. Citation data for c was collected from Web of Knowledge (searched December 15, 2013).

Figure 2

Immune suppression enables immune evasion. (a) MSC immunosuppressive potential and immunogenicity are influenced by levels of systemic or local inflammatory cytokines (secreted by T cells and other cell types). High immunosuppressive potential permits MSCs to suppress inflammation and delay or evade allo-rejection through suppression of T-cell activation and inhibition of antigen-presenting cell (APC) maturation. However, MSCs that do not tip the balance toward immunosuppression are prone to immune detection and destruction through multiple modes of rejection, as debris from dead MSCs are processed by APCs in the context of danger signals. (b) The rate of immune detection and elimination of allogeneic MSCs is dictated by the balance between a given cell’s relative expression of immunogenic and immunosuppressive factors. IFN-γ, interferon gamma; TNF-α, tumor necrosis factor alpha; MHC, major histocompatibility complex; TCR, T-cell receptor; IDO, indoleamine 2;3 dioxygenase; TGF-β, transforming growth factor beta; TSG-6; TNF-stimulated gene 6 protein; sHLA-G5, soluble human leukocyte antigen-g5; PGE2, prostaglandin E2.

Figure 3

Strategies to facilitate MSC immune evasion. (a–c) A variety of engineering strategies can be applied to induce MSC expression of immunosuppressive and immunoevasive factors including forced expression through viral and nonviral modification (a), direct cell surface modification (b), and treatment with small molecules and/or biological agents directly or through controlled release biomaterials approaches (c). (c) The timing of MSC expression can potentially be extended by use of agent-doped, cell-internalized degradable microparticles or nanoparticles, or by use of agent-doped scaffolds that cells are seeded before in vivo implantation. (d) Decoy or inhibitory receptors can be directly engineered onto the cell surface through several techniques including chemical modification via covalent conjugation chemistry^,, engineered vesicles, or through insertion of antibody fusion proteins into the cell membrane via palmitated protein G (PPG) (b). (e,f) Increased persistence can also be achieved through reducing immunogenicity by the use of immunoevasins (e) or sustained release of immunosuppressive factors (f).