Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Cell & Tissue Engineering, Cell Biology, MultiStem, Clinical-grade human multipotent adult progenitor cells, Cytotoxic T cells, Stem cell-based immune modulation, T cell-mediated cytotoxicity, MESENCHYMAL STEM-CELLS, MARROW STROMAL CELLS, INHIBIT, PROLIFERATION, DIFFERENTIATION, CD69, EXPRESSION, RESPONSES, THERAPY, Adult, Adult Stem Cells, Antigens, CD, Antigens, Differentiation, T-Lymphocyte, Biomarkers, Cell Communication, Cell Proliferation, Cytotoxicity, Immunologic, Galectin 1, Humans, Isoantigens, Lectins, C-Type, Lymphocyte Activation, Multipotent Stem Cells, Perforin, T-Lymphocytes, Cytotoxic, 0601 Biochemistry and Cell Biology, 1004 Medical Biotechnology, 1103 Clinical Sciences, 3206 Medical biotechnology, 4003 Biomedical engineering

Abstract:

: MultiStem cells are clinical-grade multipotent adult bone marrow-derived progenitor cells (MAPCs), with extensive replication potential and broader differentiation capacity compared with mesenchymal stem cells. Human MAPCs suppress T-cell proliferation induced by alloantigens and mutually interact with allogeneic natural killer cells. In this study, the interaction between MultiStem and CD8(+) cytotoxic T lymphocytes (CTLs) was addressed for the first time. In an in vitro setting, the immunogenicity of MultiStem, the susceptibility of MultiStem toward CTL-mediated lysis, and its effects on CTL function were investigated. MultiStem was nonimmunogenic for alloreactive CTL induction and was-even after major histocompatibility complex class I upregulation-insensitive to alloantigen-specific CTL-mediated lysis. Furthermore, MultiStem reduced CTL proliferation and significantly decreased perforin expression during the T-cell activation phase. As a consequence, MultiStem dose-dependently impaired the induction of CTL function. These effects of MultiStem were mediated predominantly through contact-dependent mechanisms. Moreover, MultiStem cells considerably influenced the expression of T-cell activation markers CD25, CD69, and human leukocyte antigen-DR. The MultiStem-induced CD8(-)CD69(+) T-cell population displayed a suppressive effect on the induction of CTL function during a subsequent mixed-lymphocyte culture. Finally, the killer activity of activated antigen-specific CTLs during their cytolytic effector phase was also diminished in the presence of MultiStem. This study confirms that these clinical-grade MAPCs are an immune-modulating population that inhibits CTL activation and effector responses and are, consequently, a highly valuable cell population for adoptive immunosuppressive therapy in diseases where damage is induced by CTLs.