title: Differential Effects of Tacrolimus versus Sirolimus on the Proliferation, Activation and Differentiation of Human B Cells.
abstract: The direct effect of immunosuppressive drugs calcineurin inhibitor (Tacrolimus, TAC) and mTOR inhibitor (Sirolimus, SRL) on B cell activation, differentiation and proliferation is not well documented. Purified human B cells from healthy volunteers were stimulated through the B Cell Receptor with Anti-IgM + anti-CD40 + IL21 in the absence / presence of TAC or SRL. A variety of parameters of B cell activity including activation, differentiation, cytokine productions and proliferation were monitored by flow cytometry. SRL at clinically relevant concentrations (6 ng/ml) profoundly inhibited CD19(+ )B cell proliferation compared to controls whereas TAC at similar concentrations had a minimal effect. CD27(+) memory B cells were affected more by SRL than naïve CD27- B cells. SRL effectively blocked B cell differentiation into plasma cells (CD19(+)CD138(+) and Blimp1(+)/Pax5(low) cells) even at low dose (2 ng/ml), and totally eliminated them at 6 ng/ml. SRL decreased absolute B cell counts, but the residual responding cells acquired an activated phenotype (CD25(+)/CD69(+)) and increased the expression of HLA-DR. SRL-treated stimulated B cells on a per cell basis were able to enhance the proliferation of allogeneic CD4(+)CD25(-) T cells and induce a shift toward the Th1 phenotype. Thus, SRL and TAC have different effects on B lymphocytes. These data may provide insights into the clinical use of these two agents in recipients of solid organ transplants.
authors.affiliation: Department of Medicine-Nephrology, Northwestern University, Chicago, IL, United States of America; Comprehensive Transplant Center, Northwestern University, Chicago, IL, United States of America; Department of Medicine-Nephrology, Thammasart University Hospital, Pathumthani, Thailand.
authors.forename: Opas
authors.initials: O
authors.lastname: Traitanon
authors.affiliation: Comprehensive Transplant Center, Northwestern University, Chicago, IL, United States of America; Department of Surgery, Northwestern University, Chicago, IL, United States of America; Department of Microbiology-Immunology, Northwestern University, Chicago, IL, United States of America.
authors.forename: James M
authors.initials: JM
authors.lastname: Mathew
authors.affiliation: Department of Medicine-Nephrology, Northwestern University, Chicago, IL, United States of America; Comprehensive Transplant Center, Northwestern University, Chicago, IL, United States of America.
authors.forename: Giovanna
authors.initials: G
authors.lastname: La Monica
authors.affiliation: Department of Medicine-Nephrology, Northwestern University, Chicago, IL, United States of America; Comprehensive Transplant Center, Northwestern University, Chicago, IL, United States of America.
authors.forename: Luting
authors.initials: L
authors.lastname: Xu
authors.affiliation: University of Virginia, Department of Surgery, Charlottesville, VA, United States of America.
authors.forename: Valeria
authors.initials: V
authors.lastname: Mas
authors.affiliation: Department of Medicine-Nephrology, Northwestern University, Chicago, IL, United States of America; Comprehensive Transplant Center, Northwestern University, Chicago, IL, United States of America.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Gallon
mesh_terms: D018941:Antigens, CD19 / Q000032:analysis / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D016207:Cytokines / Q000032:analysis / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology*; D016559:Tacrolimus / Q000494:pharmacology*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000032:analysis / Q000276:immunology
chemical_list: D018941:Antigens, CD19; D016207:Cytokines; D007166:Immunosuppressive Agents; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D020123:Sirolimus; D016559:Tacrolimus