title: Comparison of the effect of standard and novel immunosuppressive drugs on CMV-specific T-cell cytokine profiling.
abstract: BACKGROUND
  Data on how different immunosuppressive drugs affect cytomegalovirus (CMV)-specific T-cell responses may help guide more rational modification of immunosuppression in patients with CMV replication. We assessed the in vitro effects of individual standard and novel immunosuppressive drugs on a broad range of CMV-specific T-cell responses.
  
  
  METHODS
  Peripheral blood mononuclear cells from healthy CMV-seropositive donors were preincubated with serial dilutions of tacrolimus, mycophenolate (MPA), sirolimus, tofacitinib, and belatacept. CMV-pp65 or CMV-pp72 peptide pools were used for stimulation. CMV-specific cytokine (Th1 and Th2) and chemokine responses were determined (a total of 5400 measurements). P<0.01 was set as significant.
  
  
  RESULTS
  After CMV stimulation, dose-dependent suppression of Th1, Th2, and chemokines was seen, but significant differences between drugs were present. For example, tacrolimus was more potent in inhibiting CMV-specific Th1 cytokines versus Th2, whereas MPA preferentially inhibited Th2 cytokines. In a comparison of the relative potency of each drug at different dosing ranges, tacrolimus had the strongest Th1 inhibitory effect (median inhibition of interferon-γ at 97.5%; P=0.004-0.008) followed by sirolimus (median inhibition at 82.4%). The remaining agents (MPA, belatacept, and tofacitinib) had less apparent dose-dependent effects on interferon-γ (belatacept median inhibition at 21.5%; P=0.004 vs. tacrolimus).
  
  
  CONCLUSIONS
  Immunosuppression-specific and dose-dependent reductions in CMV-specific cytokine release were observed with significant differences in Th1 versus Th2 profiles and in relative potency of the drugs.
authors.affiliation: Alberta Transplant Institute, University of Alberta, Edmonton, Alberta, Canada. aegli@ualberta.ca
authors.forename: Adrian
authors.initials: A
authors.lastname: Egli
authors.forename: Deepali
authors.initials: D
authors.lastname: Kumar
authors.forename: Chris
authors.initials: C
authors.lastname: Broscheit
authors.forename: Daire
authors.initials: D
authors.lastname: O'Shea
authors.forename: Atul
authors.initials: A
authors.lastname: Humar
mesh_terms: D000069594:Abatacept; D000328:Adult; D016207:Cytokines / Q000378:metabolism*; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016559:Tacrolimus / Q000494:pharmacology; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D059467:Transcriptome / Q000187:drug effects*
chemical_list: D016207:Cytokines; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D000069594:Abatacept; C479163:tofacitinib; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus