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.

CD20+ B Cell Depletion Alters T Cell Homing

“…According to our recently reported observations, this may be the lymphocryptovirus (LCV)-infected B cell. We found that LCV + B cells were more profoundly depleted by anti-CD20 mAb than with anti-BLyS mAb or anti-APRIL mAb (42). LCVs are a family of g-herpesviruses that infect B cells.…”

Lymphocryptovirus Infection of Nonhuman Primate B Cells Converts Destructive into Productive Processing of the Pathogenic CD8 T Cell Epitope in Myelin Oligodendrocyte Glycoprotein

“…Under nonpathogenic conditions, B cells cannot exert this function in vivo. However, we (15,18) found that infusion of autologous LCV-infected B cells, prepulsed in vitro with MOG34-56, into healthy rhesus monkeys or marmosets elicited CD8 + T cell activation in vivo. Therefore, the hypothesis tested in the current study is that LCV infection of B cells leads to limited processing of the exogenous encephalitogenic peptide MOG34-56 in such a way that the MOG40-48 epitope remains available for loading on MHC-E molecules and presentation to core pathogenic CD8 + T cells in the primate EAE model.…”

“…We observed that the opposite clinical effect in relapsingremitting MS of an anti-CD20 Ab (ofatumumab) and atacicept, a soluble antagonist of the B cell cytokines BAFF and APRIL (not effective), could be replicated in marmoset EAE (13,14). The paradoxical clinical effects could be correlated with differential depletion of CalHV3-infected B cells (15).…”

The common marmoset (<i>Callithrix jacchus</i>): a relevant preclinical model of human (auto)immune-mediated inflammatory disease of the brain

“…A possible explanation was found in the marmoset EAE model. We observed that in monkeys treated with anti-CD20 mAb the copy number of CalHV3 DNA in lymph nodes and spleen was strongly reduced while the copy number was increased in monkeys treated with anti-BlyS or anti-APRIL mAb (Jagessar et al, 2013b). Our interpretation of this finding is that B cells immortalized by the EBV-related γ -herpesvirus CalHV3 may not need BAFF or APRIL for their survival and thus ignore inactivation of the cytokines, while they express CD20 and can thus still be depleted with anti-CD20 mAb.…”