RRC ID 4775
Author Costa GL, Sandora MR, Nakajima A, Nguyen EV, Taylor-Edwards C, Slavin AJ, Contag CH, Fathman CG, Benson JM.
Title Adoptive immunotherapy of experimental autoimmune encephalomyelitis via T cell delivery of the IL-12 p40 subunit.
Journal J Immunol
Abstract CD4+ T cells are believed to play a central role in the initiation and perpetuation of autoimmune diseases such as multiple sclerosis. In the murine model for multiple sclerosis, experimental autoimmune encephalomyelitis, pathogenic T cells exhibit a Th1-like phenotype characterized by heightened expression of proinflammatory cytokines. Systemic administration of "regulatory" cytokines, which serve to counter Th1 effects, has been shown to ameliorate autoimmune responses. However, the inherent problems of nonspecific toxicity limit the usefulness of systemic cytokine delivery as a potential therapy. Therefore, we used the site-specific trafficking properties of autoantigen-reactive CD4+ T cells to develop an adoptive immunotherapy protocol that provided local delivery of a Th1 cytokine antagonist, the p40 subunit of IL-12. In vitro analysis demonstrated that IL-12 p40 suppressed IFN-gamma production in developing and effector Th1 populations, indicating its potential to modulate Th1-promoted inflammation. We have previously demonstrated that transduction of myelin basic protein-specific CD4+ T cells with pGC retroviral vectors can result in efficient and stable transgene expression. Therefore, we adoptively transferred myelin basic protein-specific CD4+ T cells transduced to express IL-12 p40 into mice immunized to develop experimental autoimmune encephalomyelitis and demonstrated a significant reduction in clinical disease. In vivo tracking of bioluminescent lymphocytes, transduced to express luciferase, using low-light imaging cameras demonstrated that transduced CD4+ T cells trafficked to the central nervous system, where histological analysis confirmed long-term transgene expression. These studies have demonstrated that retrovirally transduced autoantigen-specific CD4+ T cells inhibited inflammation and promoted immunotherapy of autoimmune disorders.
Volume 167(4)
Pages 2379-87
Published 2001-8-15
DOI 10.4049/jimmunol.167.4.2379
PMID 11490028
MeSH 3T3 Cells Animals Autoantigens / immunology CD4-Positive T-Lymphocytes / metabolism* CD4-Positive T-Lymphocytes / pathology CD4-Positive T-Lymphocytes / transplantation* Cell Differentiation / genetics Cell Differentiation / immunology Cell Line Cell Movement / genetics Cell Movement / immunology Cells, Cultured Encephalomyelitis, Autoimmune, Experimental / etiology Encephalomyelitis, Autoimmune, Experimental / immunology Encephalomyelitis, Autoimmune, Experimental / prevention & control Encephalomyelitis, Autoimmune, Experimental / therapy* Epitopes, T-Lymphocyte / administration & dosage Epitopes, T-Lymphocyte / genetics Gene Expression Regulation / immunology Guinea Pigs Humans Immunotherapy, Adoptive / methods* Interferon-gamma / antagonists & inhibitors Interferon-gamma / biosynthesis Interleukin-12 / administration & dosage* Interleukin-12 / biosynthesis Interleukin-12 / genetics Mice Mice, Inbred C57BL Mice, Transgenic Myelin Basic Protein / administration & dosage Myelin Basic Protein / genetics Myelin Basic Protein / immunology Peptide Fragments / administration & dosage Peptide Fragments / genetics Peptide Fragments / immunology Receptors, Antigen, T-Cell / biosynthesis Receptors, Antigen, T-Cell / genetics Retroviridae / genetics Spinal Cord / immunology Spinal Cord / pathology T-Lymphocyte Subsets / immunology T-Lymphocyte Subsets / pathology Transduction, Genetic Transfection Transgenes / immunology
IF 4.886
Times Cited 129
DNA material pCAmIL12p40 (RDB01415) Human ETB receptor cDNA (RDB01303)