A superagonistic monoclonal antibody for CD28 ameliorates crescentic glomerulonephritis in wistar-kyoto rats.

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.

• Authors: Yoshitsugu Takabatake, Xiao-Kang Li, Masayuki Mizui, Kenro Miyasato, Isao Matsui, Noritaka Kawada, Enyu Imai, Thomas Hünig, Shiro Takahara, Takashi Wada, Kengo Furuichi, Hiromi Rakugi, Yoshitaka Isaka
• Journal: Molecular medicine (Cambridge, Mass.) (Mol Med) Vol. 17 Issue 7-8 Pg. 686-96 ( 2011) ISSN: 1528-3658 [Electronic] England
• PMID: 21487638 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antigens, CD
• Antigens, Differentiation, Myelomonocytic
• CD163 antigen
• CD28 Antigens
• Cytokines
• Interleukin-2 Receptor alpha Subunit
• JJ 316
• Receptors, Cell Surface

Topics

• Adoptive Transfer
• Animals
• Antibodies, Monoclonal (immunology, pharmacology)
• Antigens, CD (immunology, metabolism)
• Antigens, Differentiation, Myelomonocytic (immunology, metabolism)
• CD28 Antigens (agonists, immunology)
• CD4-Positive T-Lymphocytes (immunology, metabolism)
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Cytokines (genetics, immunology)
• Dose-Response Relationship, Drug
• Flow Cytometry
• Gene Expression (drug effects)
• Glomerulonephritis (immunology, metabolism, prevention & control)
• Humans
• Interleukin-2 Receptor alpha Subunit (immunology, metabolism)
• Kidney Glomerulus (drug effects, immunology, pathology)
• Lymph Nodes (drug effects, immunology, metabolism)
• Lymphocyte Activation (drug effects, immunology)
• Macrophages (immunology, metabolism)
• Proteinuria (immunology, metabolism, prevention & control)
• Rats
• Rats, Inbred WKY
• Receptors, Cell Surface (immunology, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• T-Lymphocytes, Regulatory (immunology, metabolism)
• Time Factors