title: Calcineurin inhibitors dampen humoral immunity by acting directly on naive B cells.
abstract: Calcineurin inhibitors (CNI), used frequently in solid organ transplant patients, are known to inhibit T cell proliferation, but their effect on humoral immunity is far less studied. Total and naive B cells from healthy adult donors were cultured in immunoglobulin (Ig)A- or IgG/IgE-promoting conditions with increasing doses of cyclosporin, tacrolimus, rapamycin or methylprednisolone. The effect on cell number, cell division, plasmablast differentiation and class-switching was tested. To examine the effect on T follicular helper (Tfh) cell differentiation, naive CD4(+) T cells were cultured with interleukin (IL)-12 and titrated immunosuppressive drug (IS) concentrations. Total B cell function was not affected by CNI. However, naive B cell proliferation was inhibited by cyclosporin and both CNI decreased plasmablast differentiation. Both CNI suppressed IgA, whereas only cyclosporin inhibited IgE class-switching. Rapamycin had a strong inhibitory effect on B cell function. Strikingly, methylprednisolone, increased plasmablast differentiation and IgE class-switching from naive B cells. Differentiation of Tfh cells decreased with increasing IS doses. CNI affected humoral immunity directly by suppressing naive B cells. CNI, as well as rapamycin and methylprednisolone, inhibited the in-vitro differentiation of Tfh from naive CD4(+) T cells. In view of its potent suppressive effect on B cell function and Tfh cell differentiation, rapamycin might be an interesting candidate in the management of B cell mediated complications post solid organ transplantation.
authors: Department of Pediatric Gastroenterology, Hepatology and Nutrition, Princess Elisabeth Children's Hospital.
authors: R
authors: R
authors: De Bruyne
authors: Department of Pediatrics, Princess Elisabeth Children's Hospital.|Clinical Immunology Research Laboratory, Department of Respiratory Medicine.
authors: D
authors: D
authors: Bogaert
authors: Upper Airways Research Laboratory, Department of Otorhinolaryngology.
authors: N
authors: N
authors: De Ruyck
authors: Laboratory of Immunoregulation, VIB Inflammation Research Center, Ghent, Belgium, Clinical Immunology Research Laboratory, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium, Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands.
authors: B N
authors: BN
authors: Lambrecht
authors: Department of Pediatric Gastroenterology, Hepatology and Nutrition, Princess Elisabeth Children's Hospital.
authors: M
authors: M
authors: Van Winckel
authors: Upper Airways Research Laboratory, Department of Otorhinolaryngology.
authors: P
authors: P
authors: Gevaert
authors: Clinical Immunology Research Laboratory, Department of Respiratory Medicine.
authors: M
authors: M
authors: Dullaers
mesh_terms: D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D065095:Calcineurin Inhibitors / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D056724:Immunity, Humoral / Q000187:drug effects*; D017578:Immunoglobulin Class Switching / Q000187:drug effects / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007378:Interleukins / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D007378:Interleukins; D000098546:Interleukin-21
keywords: B cells; T follicular helper cells; calcineurin inhibitors; immunoglobulins; immunosuppression