Immunosuppressive blood cells and methods of producing the same
a technology of immunosuppression and blood cells, which is applied in the direction of immunological disorders, antibody medical ingredients, peptide/protein ingredients, etc., can solve the problems of difficult to use for therapeutic applications, difficult to define natural suppressive dcs, and failure of clinical trials attempting to treat an ongoing disease in humans
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examples 1
Experimental Procedures
[0080](a) Mice
[0081]B10.PL mice were obtained from Jackson Laboratories (Bar Harbor, Me.). TCR-transgenic Tg4 mice (I-Au background) express a TCR derived from an encephalitogenic CD4+ T cell clone specific for a MBP peptide (aa 1-9)(9).
[0082](b) Generation of Dendritic Cells
[0083]Murine DCs are generated from bone marrow cells of B10.PL mice according to the protocol of Lutz et al. (10). For activation, 0.5 μM CpG-ODN 1668 is added. 90 min later non-adherent BMDC's are obtained. MMC (50 μg / m1) is added for 30 min of culture and the cells (106 / ml) are extensively washed. N-terminal acetylated MBP1-10 peptide Ac-ASQKRPSQRS (Ac1-10) is added at a concentration of 5 μM in combination with CpG-ODN. Human DCs are generated according to a standard protocol as previously described (11). For MBP-specific T cell studies, 30 μg / ml MBP (Sigma-Aldrich) is added to immature DCs until maturation. MMC (10-100 μg / ml) is added to the DC culture medium; after 30 min of incubati...
example 2
Results
[0102]Myelin-specific T cells have been proposed to play a role in the pathogenesis of MS (1, 4). Therefore, MBP represents a candidate antigen for specific immunotherapy in MS. In the following experiments we studied the capacity of MMC-BCs loaded with MBP to control the activity of specific T cells derived from MS patients in cell cultures, and we tested their action in a mouse EAE model.
[0103](a) Myelin-Basic-Protein-Loaded MMC-BCs Inhibit Specific T Cells of Multiple Sclerosis Patients In Vitro
[0104]BCs derived from MS patients are loaded with MBP and co-incubated with autologous T cells. In a parallel experiment, the BCs are loaded with MBP and treated with MMC. Whereas untreated BCs induce strong T cell stimulation, MMC-BCs do not (FIG. 1A).
[0105]Therapy of patients with active MS should address already activated autoreactive T cells. In order to find out whether these lymphocytes can be controlled by inhibitory BCs, pre-activated MBP-specific T cells derived from a MS ...
example 3
Discussion
[0120]Attempts to generate regulatory blood cells, in particular dendritic cells (DCs) for control of autoimmune reactions have recently been described. Enk's group generated suppressive DCs by incubating the cells in vitro with IL-10 and inhibited ovalbumin-specific CD4 T-cell responses in naïve and sensitized mice (23). Huang et al. (24) observed that a subpopulation of immature bone marrow-derived DCs, if pulsed with MBP and injected into syngeneic rats, protected from clinical EAE. Others showed that, to the contrary, mature but not immature DCs injected into mice with EAE reduced the severity of clinical signs and inflammation in the CNS (25). These conflicting findings stress the functional plasticity, from immunostimulation to suppression, of DCs under various conditions. Clinical signs of disease could also be reduced if rats or mice with incipient EAE are injected with interferon-y-treated DCs (26). In neither of the latter two studies are antigen-specific DCs use...
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