| RRC ID |
4775
|
| 著者 |
Costa GL, Sandora MR, Nakajima A, Nguyen EV, Taylor-Edwards C, Slavin AJ, Contag CH, Fathman CG, Benson JM.
|
| タイトル |
Adoptive immunotherapy of experimental autoimmune encephalomyelitis via T cell delivery of the IL-12 p40 subunit.
|
| ジャーナル |
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.
|
| 巻・号 |
167(4)
|
| ページ |
2379-87
|
| 公開日 |
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
|
| 引用数 |
129
|
|
WOS 分野
|
IMMUNOLOGY
|
| リソース情報 |
| 遺伝子材料 |
pCAmIL12p40 (RDB01415) Human ETB receptor cDNA (RDB01303) |
