title: Anti-fibrotic characteristics of Vγ9+ γδ T cells in systemic sclerosis.
abstract: OBJECTIVE
  γδ T cells of the Vγ9Vδ2 subtype secrete anti-fibrotic cytokines upon isopentenyl pyrophosphate (IPP) stimulation. In this study, we sought to compare IPP and Zoledronate, an up-regulator of IPP, effects on proliferation and cytokine secretion of Vγ9+ T cells from systemic sclerosis (SSc) patients and healthy controls (HCs). We also examined the effect of IPP-triggered peripheral blood mononuclear cells (PBMC) on fibroblast procolla- gen secretion.
  
  
  METHODS
  PBMC from SSc patients and HCs were stimulated by increasing concentrations of Zoledronate, with or without IPP, and Vγ9+ T cell percentages were calculated using FACScan analysis. Subsequently, PBMC were cultured with IPP or toxic shock syndrome toxin-1 (TSST-1), and contents of the anti-fibrotic cytokines tumour necrosis factor (TNF)-α and interferon (IFN)-γ were measured by ELISA kits. Finally, supernatants of IPP-triggered Vγ9+ T cells from SSc patients were added to fibroblast cultures, and relative intensities of procollagen α1 chains were determined by densinometry.
  
  
  RESULTS
  Higher concentrations of Zoledronate were required for maximal proliferation of Vγ9+ T cells in 9 SSc patients compared to 9 HCs, irrespective of exogenous IPP. When compared to stimulation by TSST-1, a non-Vγ9+ selective reagent, secretion of the anti-fibrotic cytokines TNF-α and IFN-γ in response to IPP was relatively diminished in SSc but not in HCs. Reduction of procollagen secretion by fibroblasts cultured with supernatants of IPP-stimulated PBMC was observed only in some SSc patients.
  
  
  CONCLUSIONS
  Activated Vγ9+ T cells could act as anti-fibrotic mediators in SSc, although decreased responsiveness to IPP may play a role in the pathological fibrosis of this disease.
authors.affiliation: Department of Medicine A, Chaim Sheba Medical Center, Tel Hashomer; and Institute of Clinical Pharmacology, Sheba Medical Center, Tel Hashomer, Israel. noamarkovits@gmail.com.
authors.forename: Noa
authors.initials: N
authors.lastname: Markovits
authors.affiliation: Laboratory for Immunoregulation, Chaim Sheba Medical Center, Tel Hashomer; and Sackler School of Medicine, Tel Aviv University, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Bendersky
authors.affiliation: Institute of Clinical Pharmacology, Sheba Medical Center, Tel Hashomer; and Sackler School of Medicine, Tel Aviv University, Israel.
authors.forename: Ronen
authors.initials: R
authors.lastname: Loebstein
authors.affiliation: Sackler School of Medicine, Tel Aviv University; and Maurice & Gabriela Goldschleger Eye Research Institute, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Marina
authors.initials: M
authors.lastname: Brusel
authors.affiliation: Sackler School of Medicine, Tel Aviv University; and Maurice & Gabriela Goldschleger Eye Research Institute, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Efrat
authors.initials: E
authors.lastname: Kessler
authors.affiliation: Laboratory for Immunoregulation, Chaim Sheba Medical Center, Tel Hashomer; Department of Medicine F, Chaim Sheba Medical Center, Tel Hashomer; and Sackler School of Medicine, Tel Aviv University, Israel. ibank@post.tau.ac.il.
authors.forename: Ilan
authors.initials: I
authors.lastname: Bank
mesh_terms: D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D005355:Fibrosis; D045782:Hemiterpenes / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010641:Phenotype; D011347:Procollagen / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology* / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D000077211:Zoledronic Acid
chemical_list: D024042:Collagen Type I; D004164:Diphosphonates; D045782:Hemiterpenes; C573415:IFNG protein, human; D007093:Imidazoles; D009943:Organophosphorus Compounds; D011347:Procollagen; D016692:Receptors, Antigen, T-Cell, gamma-delta; C521522:T-cell receptor Vgamma9, human; D014409:Tumor Necrosis Factor-alpha; C004809:isopentenyl pyrophosphate; D000077211:Zoledronic Acid; D007371:Interferon-gamma