title: Diminazene aceturate (Berenil) modulates the host cellular and inflammatory responses to Trypanosoma congolense infection.
abstract: BACKGROUND
  Trypanosoma congolense are extracellular and intravascular blood parasites that cause debilitating acute or chronic disease in cattle and other domestic animals. Diminazene aceturate (Berenil) has been widely used as a chemotherapeutic agent for trypanosomiasis in livestock since 1955. As in livestock, treatment of infected highly susceptible BALB/c mice with Berenil leads to rapid control of parasitemia and survival from an otherwise lethal infection. The molecular and biochemical mechanisms of action of Berenil are still not very well defined and its effect on the host immune system has remained relatively unstudied. Here, we investigated whether Berenil has, in addition to its trypanolytic effect, a modulatory effect on the host immune response to Trypanosoma congolense.
  
  
  RESULTS
  BALB/c and C57BL/6 mice were infected intraperitoneally with T. congolense, treated with Berenil and the expression of CD25 and FoxP3 on splenic cells was assessed directly ex vivo. In addition, serum levels and spontaneous and LPS-induced production of pro-inflammatory cytokines by splenic and hepatic CD11b⁺ cells were determined by ELISA. Berenil treatment significantly reduced the percentages of CD25⁺ cells, a concomitant reduction in the percentage of regulatory (CD4⁺Foxp3⁺) T cells and a striking reduction in serum levels of disease exacerbating pro-inflammatory cytokines including IL-6, IL-12, TNF and IFN-γ. Furthermore, Berenil treatment significantly suppressed spontaneous and LPS-induced production of inflammatory cytokines by splenic and liver macrophages and significantly ameliorated LPS-induced septic shock and the associated cytokine storm.
  
  
  CONCLUSIONS
  Collectively, these results provide evidence that in addition to its direct trypanolytic effect, Berenil also modulates the host immune response to the parasite in a manner that dampen excessive immune activation and production of pathology-promoting pro-inflammatory cytokines, suggesting that this drug may also be beneficial for treatment of disease conditions caused by excessive production of inflammatory cytokines.
authors.affiliation: Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Shiby
authors.initials: S
authors.lastname: Kuriakose
authors.forename: Helen M
authors.initials: HM
authors.lastname: Muleme
authors.forename: Chukwunonso
authors.initials: C
authors.lastname: Onyilagha
authors.forename: Rani
authors.initials: R
authors.lastname: Singh
authors.forename: Ping
authors.initials: P
authors.lastname: Jia
authors.forename: Jude E
authors.initials: JE
authors.lastname: Uzonna
mesh_terms: D000818:Animals; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004133:Diminazene / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007111:Immunity, Cellular / Q000187:drug effects*; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007728:Kupffer Cells / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014348:Trypanosoma congolense; D014353:Trypanosomiasis, African / Q000150:complications / Q000188:drug therapy*
chemical_list: D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; C003915:diminazene aceturate; D004133:Diminazene