title: Mycophenolate mofetil modifies kidney tubular injury and Foxp3+ regulatory T cell trafficking during recovery from experimental ischemia-reperfusion.
abstract: Lymphocytes participate in the early pathogenesis of ischemia-reperfusion injury (IRI) in kidney; however, their role during repair is largely unknown. Recent data have shown that Foxp3(+) regulatory T cells (Tregs) traffic into kidney during healing from IRI and directly participate in repair. Since lymphocyte-targeting therapy is currently administered to prevent rejection during recovery from IRI in renal transplants, we hypothesized that mycophenolate mofetil (MMF) would alter Treg trafficking and kidney repair. C57BL/6J and T cell deficient mice underwent unilateral clamping of renal pedicle for 45 min, followed by reperfusion, and were sacrificed at day 10. Mice were treated with saline (C) or MMF (100mg/kg) i.p. daily starting at day 2 until sacrifice (n=5-12/group). MMF worsened kidney tubular damage compared to C at 10 days (cortex and outer medulla: p<0.05) in wild-type mice; tubular apoptotic index was increased in cortex in MMF group as well (p=0.01). MMF reduced the total number of kidney-infiltrating mononuclear cells (p<0.001 versus C) and the percentages of TCRbeta(+)CD4(+) and TCRbeta(+)CD8(+) T cells (p<0.01), but not natural killer (NK), NKT or B lymphocytes. MMF specifically reduced kidney Foxp3(+) Tregs (0.82+/-0.11% versus 1.75+/-0.17%, p<0.05). Tubular proliferative index and tissue levels of basic FGF were increased in MMF group (p<0.05), IL-10 and IL-6 were decreased (p<0.05). To evaluate if MMF effect occurred through non-lymphocytic cells, T cell deficient mice were treated with MMF. Tubular injury in T cell deficient mice was not affected by MMF treatment, though MMF-treated animals had increased VEGF and decreased PDGF-BB protein tissue levels compared to controls (p<0.05). Thus, MMF modifies the structural, epithelial proliferative and inflammatory response during healing, likely through effects on T cells and possibly Tregs. Kidney repair after IRI can be altered by agents that target lymphocytes.
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Gandolfo
authors.forename: Hye Ryoun
authors.initials: HR
authors.lastname: Jang
authors.forename: Serena M
authors.initials: SM
authors.lastname: Bagnasco
authors.forename: Gang-Jee
authors.initials: GJ
authors.lastname: Ko
authors.forename: Patricia
authors.initials: P
authors.lastname: Agreda
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Soloski
authors.forename: Michael T
authors.initials: MT
authors.lastname: Crow
authors.forename: Hamid
authors.initials: H
authors.lastname: Rabb
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D007683:Kidney Tubular Necrosis, Acute / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000628:therapy; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid