title: Pharmacologic recruitment of regulatory T cells as a therapy for ischemic acute kidney injury.
abstract: Regulatory T cells (Tregs) are key components of the peripheral tolerance system and have become an immunotherapeutic agent for treating inflammatory processes. This therapeutic option, however, is hampered by problems arising from isolating and expanding desirable Tregs. Here we used an alternative approach with a pharmacologic agent to stimulate Tregs to achieve immunosuppressive effects. Pretreatment of mice with the naturally occurring sphingosine N,N-dimethylsphingosine (DMS) was found to increase both tissue-infiltrating T effectors (Teffs, CD4(+)Foxp3(-)) and Tregs (CD4(+)Foxp3(+)) in the early phase of bilateral renal ischemia/reperfusion injury. DMS itself had no effects on renal function or histopathology, but rapidly and transiently increased both Teffs and Tregs and increased the expression of chemokines CXCL9, CCL5, and CXCL10 in non-ischemic kidneys (sham operation). This renoprotection was abolished by administration of the Treg suppressing agents, anti-CTLA-4 or anti-CD25 monoclonal antibodies, suggesting that Tregs play a key role in DMS-induced renoprotection. Thus, Tregs recruited to the kidney by DMS ameliorate acute kidney injury and provide a new approach to control inflammatory diseases.
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona, USA. Electronic address: liwen7@gmail.com.
authors.forename: Li-Wen
authors.initials: LW
authors.lastname: Lai
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona, USA.
authors.forename: Kim-Chong
authors.initials: KC
authors.lastname: Yong
authors.affiliation: Department of Medicine, University of Arizona, Tucson, Arizona, USA; Arizona Kidney Disease and Hypertension Center, Tucson, Arizona, USA.
authors.forename: Yeong-Hau H
authors.initials: YH
authors.lastname: Lien
mesh_terms: D058186:Acute Kidney Injury / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D060908:CTLA-4 Antigen / Q000276:immunology; D018946:Chemokine CCL5 / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D019610:Cytoprotection; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007155:Immunologic Factors / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D007511:Ischemia / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism; D015427:Reperfusion Injury / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D004791:Enzyme Inhibitors; D051858:Forkhead Transcription Factors; D007155:Immunologic Factors; D053645:Interleukin-2 Receptor alpha Subunit; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D014409:Tumor Necrosis Factor-alpha; D000099157:Sphingosine Kinase; C503460:Ccl5 protein, mouse; C556707:Ctla4 protein, mouse; C485433:Cxcl10 protein, mouse; C485969:Cxcl9 protein, mouse; C498833:Foxp3 protein, mouse; C508018:Il2ra protein, mouse; C061800:N,N-dimethylsphingosine