Abstract
Autoimmune encephalomyelitis may be ameliorated experimentally by enhancing NK cell-mediated elimination of activated autoreactive T cells through a mutation that interrupts the interaction between Qa-1(b) and CD94/NKG2A. Here we evaluate the ability of an anti-NKG2A F(ab')(2) Ab to enhance elimination of autoreactive T cells and reduce experimental autoimmune encephalomyelitis (EAE). Anti-NKG2A F(ab')(2) treatment diminishes progression of both myelin oligodendrocyte glycoprotein (MOG)-induced EAE in intact C57BL/6 mice and after adoptive transfer of disease-causing T cells. Analyses of the underlying mechanism revealed that administration of anti-NKG2A F(ab')(2) Ab reduces CD4(+) T recall responses to MOG and skews the proportion of IL-17- and IFNgamma-producing CD4(+) T cells toward the protective IL-4- and IL-10-secreting CD4(+) T cell subpopulations. CD94/NKG2A-dependent inhibition of inflammatory damage to spinal cord is associated with decreased infiltration of T cells and reduced microglia activation in the central nervous system. Because anti-NKG2A F(ab')(2) treatment had no detectable effect on the numbers or activity of T and B lymphocytes and NK cells in peripheral lymphoid tissues, this anti-NKG2A-based approach may represent a safe and effective therapy for this CNS disorder.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Amino Acid Sequence
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Animals
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Antibodies, Monoclonal / immunology
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Antibodies, Monoclonal / therapeutic use*
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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Central Nervous System / drug effects
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Central Nervous System / immunology
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Central Nervous System / pathology
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / therapy*
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Flow Cytometry
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Interferon-gamma / metabolism
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Interleukin-10 / metabolism
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Interleukin-17 / metabolism
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Interleukin-4 / metabolism
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Killer Cells, Natural / drug effects
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Killer Cells, Natural / immunology
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Killer Cells, Natural / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Molecular Sequence Data
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Myelin Proteins
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Myelin-Associated Glycoprotein / chemistry
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Myelin-Associated Glycoprotein / immunology
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Myelin-Oligodendrocyte Glycoprotein
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NK Cell Lectin-Like Receptor Subfamily C / immunology*
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NK Cell Lectin-Like Receptor Subfamily C / metabolism
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Peptide Fragments / immunology
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T-Lymphocytes / drug effects*
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
Substances
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Antibodies, Monoclonal
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Interleukin-17
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Mog protein, mouse
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Myelin Proteins
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Myelin-Associated Glycoprotein
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Myelin-Oligodendrocyte Glycoprotein
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NK Cell Lectin-Like Receptor Subfamily C
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Peptide Fragments
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Interleukin-10
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Interleukin-4
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Interferon-gamma