Pluristem Therapeutics Inc., a leading developer of placenta-based cell therapy products, has announced the publication of a scientific study regarding PLacental eXpanded (PLX) cells in the prominent peer-reviewed journal Stem Cells. The paper, titled "Mesenchymal stromal cells prevent allostimulation in vivo and control checkpoints of Th1 priming: migration of human DC to lymph nodes and NK cell activation", describes the findings of a recent mechanism of action study conducted by independent scientists at the Berlin-Brandenburg Center for Regenerative Therapy at Charité - University Medicine Berlin. The paper was co-authored by scientists from the Charité and Pluristem.

The study demonstrated mechanisms by which PLX cells and other mesenchymal stromal cells (MSC) influence the immune system in order to modulate immune reactions and to prevent immune reactions against the cells when they are administered as an off-the-shelf product (unmatched). It was demonstrated in vitro that MSC, and in particular PLX cells, control the induction of an immune response at several points. The main target for MSC and PLX cells in this process are dendritic cells, which are the key player in inducing a T-cell immune response. Moreover, in vivo data from patients suffering from critical limb ischemia who were treated with PLX cells in a phase I/II study confirmed that HLA-unmatched PLX cells did not provoke an immune response in immunocompetent patients. These findings confirm the feasibility of using PLX cells in an off-the-shelf manner, and explain the mechanisms that make this possible.

"Our findings in this study provide novel evidence for the regulation of several checkpoints of T-cell priming by PLX cells and other MSC, via modulation of the crosstalk between myeloid dendritic cells and natural killer cells. While the complete mechanism of immunomodulation by PLX cells requires further investigation, this study demonstrates how PLX cells might inhibit the immune responses of Type 1 T helper cell," stated the study's Principal Investigator, Dr. Hans-Dieter Volk, Director of the Berlin-Brandenburg Center for Regenerative Therapy and head of the Institute of Medical Immunology at the Charité.

"The investigation of the interaction between unmatched PLX cells and patient immune systems is central to Pluristem's clinical research. This research may lead to a new understanding of how PLX cells influence, and potentially heal, the immune system, thereby possibly expanding the use of PLX cells for new indications," stated Pluristem CEO Zami Aberman. "By modulating a patient's immune response, PLX cells could potentially help treat severe diseases of the immune system such as aplastic anemia, which has been designated as an orphan indication, autoimmune diseases such as multiple sclerosis and lupus, as well as graft versus host disease (GVHD)," Aberman added.

Additional Findings from the Study

PLX cells, and other MSC, affected complex pathways in order to prevent the priming of Type 1 T helper cell (Th1) responses towards major histocompatibility complex mismatches. The study utilized both in vitro and ex vivo data from PLX cells and other MSC. In vivo evidence came from patients in a study of PLX cells for critical limb ischemia. Peripheral blood mononuclear cells (PBMC), collected from the patients at different time points after PLX injection, were re-stimulated with the corresponding PLX-PAD cells or unrelated third party donor PBMC. The in vivo induced memoryTh1 response was measured by using the IFN-g Elispot test. There was no,or only very marginal, Th1 priming specific for the MHC-mismatch even after application of high-dose allogeneic PLX cells. Collectively, the study data indicated that MSC, and in particular PLX cells, inhibit the priming of Th1-driven immune responses via modulation of myeloid dendritic cell (mDC). The maturation, migration to stimulatory chemokines, and the release of NK and T-cell stimulating cytokines of mDC are inhibited by PLX cells and some other MSC. For example, mDC exposed to PLX/MSC secreted reduced levels ofIL-12p70and IL-1b and increased levels of IL-10 and IL-1Ra, representing a cytokine profile typical for tolerogenic dendritic cells (TolDC), which are required for the development and maintenance of immunological tolerance.