MSC-NTF Cell Immunomodulation: Effects on T and B Regulatory Cells

Objective: We evaluated the immunomodulatory properties of MSC-NTF cells and their effects on T and B regulatory cells. Background: MSC-NTF cells (NurOwn®) are autologous, differentiated bone-marrow derived mesenchymal stem cells (MSC) that secrete neurotrophic factors (NTFs), regulatory miRNAs that demonstrate neuroprotection and immunomodulation in preclinical models and are currently under evaluation in phase 2 progressive MS and phase 3 ALS trials. Disordered T and B regulatory cell function has been implicated in the pathogenesis of ALS and MS. Furthermore, IL-10 production by regulatory B cells, may ‘regulate the regulators’, and has been viewed as a protective mechanism in ALS and MS animal models, possibly through effects on microglial networks. Design/Methods: MSC-NTF cells were generated from healthy controls and were co-cultured with human peripheral blood mononuclear Cells (PBMC) or isolated B cells. The effect of MSC-NTF cells on proliferation of T or B cells and on induction of regulatory T or B cells was evaluated using flow cytometry. ELISA was used to measure secretion of different cytokines and IgM. Results: MSC-NTF cells inhibited IFN-g and TNF-a secretion and CD4+/ CD8+ T cell proliferation when co-cultured with activated PBMCs, and induced CD4+CD25+FoxP3+ regulatory T cells. MSC-NTF cells did not affect B cells proliferation, however we observed that they induced CD24hiCD38hi regulatory B cells, stimulated IL-10 secretion, and inhibited B cell IgM secretion. Conclusions: Neuroinflammation is a prominent pathological feature of ALS and progressive MS. Reduced T and B regulatory function may contribute to disease progression, and lower IL-10 levels may be associated with reduced ALS function and with higher disability and MRI lesion load in secondary progressive MS. The immunomodulatory properties of MSC-NTF cells, including their effects on T and B regulatory cells, combined with neuroprotective and repair mechanisms may extend the potential therapeutic benefits of MSC-NTF cells. Disclosure: Dr. Aricha has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with BrainStorm Cell Therapeutics. Dr. Abramov has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with BrainStorm Cell Therapeutics. Dr. Semo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with BrainStorm Cell Therapeutics. Dr. Kaspi has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with BrainStorm Cell Therapeutics. Dr. Lebovits has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with BrainStorm Cell Therapeutics. Dr. Lebovits has received compensation for serving on the Board of Directors of BrainStorm Cell Therapeutics. Dr. Kern has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with BrainStorm Cell Therapeutics Ltd. BrainStorm Cell Therapeutics Ltd. employee