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Therapies that Ag-specifically target pathologic T lymphocytes responsible for multiple sclerosis (MS) and other autoimmune diseases would be expected to have improved therapeutic indices compared with Ag-nonspecific therapies. We have developed a cellular immunotherapy that uses chimeric receptors to selectively redirect therapeutic T cells against myelin basic protein (MBP)-specific T lymphocytes implicated in MS. We generated two heterodimeric receptors that genetically link the human MBP84-102 epitope to HLA-DR2 and either incorporate or lack a TCRzeta signaling domain. The Ag-MHC domain serves as a bait, binding the TCR of MBP-specific target cells. The zeta signaling region stimulates the therapeutic cell after cognate T cell engagement. Both receptors were well expressed on primary T cells or T hybridomas using a tricistronic (alpha, beta, green fluorescent protein) retroviral expression system. MBP-DR2-zeta-, but not MBP-DR2, modified CTL were specifically stimulated by cognate MBP-specific T cells, proliferating, producing cytokine, and killing the MBP-specific target cells. The receptor-modified therapeutic cells were active in vivo as well, eliminating Ag-specific T cells in a humanized mouse model system. Finally, the chimeric receptor-modified CTL ameliorated or blocked experimental allergic encephalomyelitis (EAE) disease mediated by MBP84-102/DR2-specific T lymphocytes. These results provide support for the further development of redirected therapeutic T cells able to counteract pathologic, self-specific T lymphocytes, and specifically validate humanized MBP-DR2-zeta chimeric receptors as a potential therapeutic in MS.

Type

Journal article

Journal

J Immunol

Publication Date

01/03/2008

Volume

180

Pages

3601 - 3611

Keywords

Amino Acid Sequence, Animals, Base Sequence, Cell Line, Cell Line, Transformed, Cell Line, Tumor, Encephalomyelitis, Autoimmune, Experimental, Epitopes, T-Lymphocyte, HLA-DR2 Antigen, Humans, Immunotherapy, Adoptive, Mice, Mice, Inbred C57BL, Mice, Transgenic, Molecular Sequence Data, Myelin Basic Protein, Receptors, Antigen, T-Cell, Recombinant Fusion Proteins, T-Lymphocyte Subsets