title: Superagonistic CD28 Protects against Renal Ischemic Injury by Expansion of Regulatory T-Cell.
abstract: BACKGROUND
  Regulatory T (Treg) cells are a highly suppressive subset of CD4+ lymphocytes and have recently been proved to be crucial to suppress the inflammatory responses of ischemic kidney injury. CD28 superagonists (CD28sa) are monoclonal antibodies that preferentially expand Treg cells without a T-cell receptor and a costimulatory signal. This study aims to test the protection and discover the mechanisms of CD28sa treatment against renal ischemia-reperfusion (IR) injury (IRI).
  
  
  METHODS
  Male C57BL/6N mice were treated with CD28sa via peritoneal injection (0.1 mg) 6 days before the induction of IRI, or with 18-min ischemic precondition (IPC). IRI was induced by bilateral clamping of renal pedicles for 35 min followed by reperfusion. The role of Treg expansion in renal protection conferred by CD28sa treatment was examined using anti-CD25 antibody.
  
  
  RESULTS
  CD28sa treatment alone significantly increased the percentage of Treg cells in the spleen (18.10 ± 2.00 vs. 6.64 ± 0.86%, p < 0.01), peripheral blood (16.43 ± 5.94 vs. 2.57 ± 1.09%, p < 0.01), and kidney (2.69 ± 0.90 vs. 0.53 ± 0.14%, p < 0.01) of C57BL/6N mice 6 days after the administration. Mice pretreated with CD28sa or IPC had less renal injury at 24 h after IRI with attenuation of renal tubular damage and lower serum creatinine compared with the mice that underwent renal IRI alone. The number of infiltrating macrophages in the kidney and IFN-γ secreting CD4+ T cells in peripheral blood were diminished in the CD28sa-IR group and the IPC-IR group. The renal protection bestowed by CD28sa or IPC was abolished by anti-CD25 antibody administration.
  
  
  CONCLUSIONS
  Treg expansion induced by CD28sa ameliorated renal IRI.
authors.affiliation: Department of Nephrology, Zhongshan Hospital, Shanghai, China.
authors.forename: Yiran
authors.initials: Y
authors.lastname: Liang
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Qing
authors.initials: Q
authors.lastname: Kuang
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Ding
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wei
authors.forename: Yi
authors.initials: Y
authors.lastname: Fang
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D018106:CD28 Antigens / Q000037:antagonists & inhibitors*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D056747:Immunomodulation; D007371:Interferon-gamma / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors; D007668:Kidney / Q000276:immunology*; D018655:Lymphocyte Count; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; C000611649:IFNG protein, mouse; C508018:Il2ra protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D007371:Interferon-gamma
keywords: CD28 superagonists; Inflammation; Ischemic preconditioning; Regulatory T cell; Renal ischemia-reperfusion injury