The Primate EAE Model Points at EBV-Infected B Cells as a Preferential Therapy Target in Multiple Sclerosis

Abstract

The remarkable clinical efficacy of anti-CD20 monoclonal antibodies (mAb) in relapsing-remitting multiple sclerosis points at the critical involvement of B cells in the disease. However, the exact pathogenic contribution of B cells is poorly understood. In this publication we review new data on the role of CD20+ B cells in a unique experimental autoimmune encephalomyelitis (EAE) model in common marmosets (Callithrix jacchus), a small-bodied neotropical primate. We will also discuss the relevance of these data for MS. Different from rodent EAE models, but similar to MS, disease progression in marmosets can develop independent of autoantibodies. Progressive disease is mediated by MHC class Ib (Caja-E) restricted cytotoxic T cells, which are activated by γ-herpesvirus-infected B cells and cause widespread demyelination of cortical gray matter. B-cell directed monoclonal antibody therapies (anti-CD20 versus anti-BLyS and anti-APRIL) have a variable effect on EAE progression, which we found associated with variable depletion of the Epstein Barr virus (EBV)-like γ-herpesvirus CalHV3 from lymphoid organs. These findings support an important pathogenic role of CD20+ B cell in MS, especially of the subset infected with EBV.

CD20+ B Cell Depletion Alters T Cell Homing

“…Best known is the human representative EBV, which is considered an important infectious risk factor for MS (43). Consistent with the strong association of EBV with MS, the important pathogenic role of B cells, and supported by results obtained in the marmoset EAE model, we have postulated that the LCV/EBV-infected B cell has an essential role in the presentation of autoantigen to core pathogenic T cells (44). The potent stimulation of adaptive and innate immune functions by LCV/EBV has been well established (45), and several of these features could be reproduced in marmosets or rhesus monkeys injected with LCV-infected autologous B lymphoblastoid cells (42,46).…”

Selective Blockade of CD28-Mediated T Cell Costimulation Protects Rhesus Monkeys against Acute Fatal Experimental Autoimmune Encephalomyelitis

“…More detailed analysis has been performed in another primate EAE model, i.e., in the common marmoset. In that model we found a dual role of B cells, which depended on the disease stage (37). B cells contribute to the early EAE initiation phase by producing antirhMOG Abs.…”

“…B cells contribute to the early EAE initiation phase by producing antirhMOG Abs. In late-stage disease, they act as APC for a pathogenic subset of cytotoxic T cells (37).…”

Reverse translation of failed treatments can help improving the validity of preclinical animal models

“…In non-human primates, which carry chronic latent infections with herpes-and polyomaviruses equivalent to those infecting humans, both compartments are functional. Data obtained in nonhuman primate models of MS suggests that autoreactive T cells causing chronic inflammation are recruited from the inward compartment (see reviews 't Hart et al (2011Hart et al ( , 2013). …”