Abstract
Regulatory T (Treg) cells play an important role in the resolution of crescentic glomerulonephritis, where a T helper 1 (Th1)-predominant immune response promotes crescent formation. Therefore, agents that increase Treg cells appear to be ideal for suppressing T-cell-mediated renal pathology. We hypothesized that a superagonistic monoclonal antibody for CD28 (JJ316), which has been known to preferentially expand Treg cells in vivo, could prevent nephrotoxic serum-induced nephritis in Wistar-Kyoto rats, one of the experimental models of crescentic glomerulonephritis. Administration of JJ316 attenuated crescent formation, proteinuria and glomerular accumulation of macrophages and CD8(+) T cells. These changes were accompanied by increased infiltration of Treg cells. Among glomerular macrophages, the CD163(+) subset was significantly increased after treatment, suggesting that Treg cells may modulate the phenotype of macrophages leading to resolution of glomerulonephritis. In an adoptive transfer experiment, two T-cell subsets (CD4(+)CD25(+) and CD4(+)CD25(-) T cells) purified from spleens and lymph nodes of donor rats primed with JJ316 3 d before were inoculated into nephritic recipient rats, which recapitulated the beneficial effects of in vivo administration of JJ316. Furthermore, a single injection of JJ316 administered 3 d after disease induction completely protected nephritic rats from death for 2 months. In conclusion, we demonstrated that treatment with JJ316 has a dramatic therapeutic effect on an experimental crescentic glomerulonephritis, possibly due to expansion and activation of Treg cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Animals
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Antibodies, Monoclonal / immunology*
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Antibodies, Monoclonal / pharmacology
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Antigens, CD / immunology
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Antigens, CD / metabolism
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Antigens, Differentiation, Myelomonocytic / immunology
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Antigens, Differentiation, Myelomonocytic / metabolism
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CD28 Antigens / agonists
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CD28 Antigens / immunology*
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Cytokines / genetics
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Cytokines / immunology
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Dose-Response Relationship, Drug
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Flow Cytometry
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Gene Expression / drug effects
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Glomerulonephritis / immunology*
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Glomerulonephritis / metabolism
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Glomerulonephritis / prevention & control
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Humans
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Interleukin-2 Receptor alpha Subunit / immunology
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Interleukin-2 Receptor alpha Subunit / metabolism
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Kidney Glomerulus / drug effects
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Kidney Glomerulus / immunology*
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Kidney Glomerulus / pathology
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Lymph Nodes / drug effects
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Lymph Nodes / immunology
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Lymph Nodes / metabolism
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / immunology
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Macrophages / immunology
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Macrophages / metabolism
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Proteinuria / immunology
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Proteinuria / metabolism
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Proteinuria / prevention & control
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Rats
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Rats, Inbred WKY
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Receptors, Cell Surface / immunology
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Receptors, Cell Surface / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / metabolism
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Time Factors
Substances
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Antibodies, Monoclonal
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Antigens, CD
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Antigens, Differentiation, Myelomonocytic
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CD163 antigen
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CD28 Antigens
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Cytokines
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Interleukin-2 Receptor alpha Subunit
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JJ 316
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Receptors, Cell Surface