title: The different clinical effects of anti-BLyS, anti-APRIL and anti-CD20 antibodies point at a critical pathogenic role of γ-herpesvirus infected B cells in the marmoset EAE model.
abstract: The robust and rapid clinical effect of depleting anti-CD20 monoclonal antibodies (mAb) in multiple sclerosis (MS) demonstrates a critical pathogenic contribution of B cells. The clinical effect of anti-CD20 mAb has been replicated in a relevant preclinical MS model, experimental autoimmune encephalomyelitis (EAE) in marmoset monkeys (Callithrix jacchus). By contrast, treatment with mAbs against two essential cytokines in B cell activation growth and survival, i.e. BlyS/BAFF and APRIL, was only partially effective. All three mAbs induced depletion of CD20+ B cells from the circulation, albeit with different kinetics and based on distinct mechanisms of action. In the current study we analyzed whether the different clinical effect of anti-CD20 mAb or the anti-BLyS and anti-APRIL mAbs is due to different depletion of B cells infected with the EBV of marmosets, CalHV3. Employing a novel PCR-based assay, half of the colony of group-housed marmosets was tested positive for CalHV3 DNA in secondary lymphoid organs. The same prevalence was observed in placebo-treated monkeys. In marmosets treated with anti-CD20 mAb the load of CalHV3 DNA in lymphoid organs was substantially reduced, while this was not observed in the monkeys treated with anti-BLyS or anti-APRIL mAbs. To examine the pathogenic role of virus-transformed B cells, we infused EBV-transformed B lymphoblastic cell (BLC) lines presenting the immunodominant MOG34-56 peptide. We observed in the recipients of MOG34-56 pulsed BLC, but not in their fraternal siblings infused with non-pulsed BLC, activation of anti-MOG34-56 T cells and meningeal inflammation. Collectively, the data show that among CD20+ B cells, the herpesvirus-transformed subset has a particularly important pathogenic role in the marmoset EAE model.
authors.affiliation: Department Immunobiology, Biomedical Primate Research Centre, PO Box 3306, 2280 GH Rijswijk, The Netherlands. jagessar@bprc.nl
authors.forename: S
authors.initials: S
authors.lastname: Anwar Jagessar
authors.forename: Zahra
authors.initials: Z
authors.lastname: Fagrouch
authors.forename: Nicole
authors.initials: N
authors.lastname: Heijmans
authors.forename: Jan
authors.initials: J
authors.lastname: Bauer
authors.forename: Jon D
authors.initials: JD
authors.lastname: Laman
authors.forename: Luke
authors.initials: L
authors.lastname: Oh
authors.forename: Thi
authors.initials: T
authors.lastname: Migone
authors.forename: Ernst J
authors.initials: EJ
authors.lastname: Verschoor
authors.forename: Bert A
authors.initials: BA
authors.lastname: 't Hart
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D018951:Antigens, CD20 / Q000276:immunology*; D053264:B-Cell Activating Factor / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000821:virology*; D002144:Callithrix; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000628:therapy*; D005260:Female; D018142:Gammaherpesvirinae / Q000472:pathogenicity; D006801:Humans; D008297:Male; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D053264:B-Cell Activating Factor; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13