title: 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.affiliation: Department of Geriatric Medicine and Nephrology (B6), Osaka University Graduate School of Medicine, Suita, Japan. takaba@kid.med.osaka-u.ac.jp
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Takabatake
authors.forename: Xiao-Kang
authors.initials: XK
authors.lastname: Li
authors.forename: Masayuki
authors.initials: M
authors.lastname: Mizui
authors.forename: Kenro
authors.initials: K
authors.lastname: Miyasato
authors.forename: Isao
authors.initials: I
authors.lastname: Matsui
authors.forename: Noritaka
authors.initials: N
authors.lastname: Kawada
authors.forename: Enyu
authors.initials: E
authors.lastname: Imai
authors.forename: Thomas
authors.initials: T
authors.lastname: Hünig
authors.forename: Shiro
authors.initials: S
authors.lastname: Takahara
authors.forename: Takashi
authors.initials: T
authors.lastname: Wada
authors.forename: Kengo
authors.initials: K
authors.lastname: Furuichi
authors.forename: Hiromi
authors.initials: H
authors.lastname: Rakugi
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Isaka
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology / Q000378:metabolism; D018106:CD28 Antigens / Q000819:agonists / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D005921:Glomerulonephritis / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D007678:Kidney Glomerulus / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D011507:Proteinuria / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D051381:Rats; D011921:Rats, Inbred WKY; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D000098902:CD163 Antigen
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D018106:CD28 Antigens; D016207:Cytokines; D053645:Interleukin-2 Receptor alpha Subunit; C568777:JJ 316; D011956:Receptors, Cell Surface