title: Cladribine Exposure Results in a Sustained Modulation of the Cytokine Response in Human Peripheral Blood Mononuclear Cells.
abstract: OBJECTIVE
  Cladribine is a cytotoxic drug which ameliorates the clinical course of relapsing-remitting multiple sclerosis. In addition to cytotoxicity, the mode of action may include immunomodulatory mechanisms. This in vitro study was designed to investigate cladribine's effects on cell function after the removal of cladribine to distinguish cytotoxic versus immunomodulatory effects.
  
  
  METHODS
  Cells were incubated in the absence or presence of cladribine (1 × 10(-8) M to 1 × 10(-5) M) for 72 h. Cladribine was removed from the cell culture and surviving peripheral blood mononuclear cells were cultured up to 58 days to determine the immunomodulatory effects of cladribine on cell function (e.g., proliferation and cytokine release).
  
  
  RESULTS
  In the long-term, brief cladribine exposure did not impair the proliferation of surviving peripheral blood mononuclear cells. However, it induced an anti-inflammatory shift in the cytokine milieu with significantly enhanced release of IL-4 (Days 9 and 44, p<0.01; Day 58, p<0.05) and IL-5 (Day 9, p<0.01), resulting in an increased IL-4/INF-gamma ratio (Days 9 and 44, p<0.01; Day 58, p<0.05). Additionally, a trend towards an increased IL-10 production was observed. No changes were found in the production of IFN-gamma, TNF-alpha, IL-6, IL-8, IL-17A, IL-23 or NGF-beta.
  
  
  CONCLUSIONS
  In vitro cladribine exposure induces a sustained anti-inflammatory shift in the cytokine profile of surviving peripheral blood mononuclear cells. This immunomodulatory action might contribute to cladribine's beneficial effects in the treatment of multiple sclerosis.
authors.affiliation: Section of Neuroimmunology, Department of Neurology, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Korsen
authors.affiliation: Center for Regenerative Therapies, DFG-Research Center and Cluster of Excellence Dresden, Dresden, Germany.
authors.forename: Sara
authors.initials: S
authors.lastname: Bragado Alonso
authors.affiliation: Department of Inflammation and Tissue Repair, Centre for Respiratory Research, University College London, London, United Kingdom.
authors.forename: Lizzy
authors.initials: L
authors.lastname: Peix
authors.affiliation: Department of Immunology, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Bröker
authors.affiliation: Section of Neuroimmunology, Department of Neurology, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dressel
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects*; D017338:Cladribine / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008297:Male
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D017338:Cladribine