CD20+ B Cell Depletion Alters T Cell Homing

Abstract

Depleting mAbs against the pan B cell marker CD20 are remarkably effective in the treatment of autoimmune-mediated inflammatory disorders, but the underlying mechanisms are poorly defined. The primary objective of this study was to find a mechanistic explanation for the remarkable clinical effect of the anti-CD20 mAbs in a representative nonhuman primate autoimmune-mediated inflammatory disorder model, experimental autoimmune encephalomyelitis (EAE) in common marmosets, allowing detailed analysis of secondary lymphoid organs (SLO). We observed that the depletion of CD20+ B cells creates a less immunostimulatory environment in the SLO reflected by reduced expression of MHC class II, CD40, CD83, and CD80/CD86. APCs isolated from SLO of B cell–depleted EAE monkeys were also less responsive to mitogenic stimulation. The depleted B cell areas were replenished by T cells, of which the majority expressed CD127 (IL-7R) and CCR7. Such effects were not detected in EAE marmosets treated with mAb against BLyS or APRIL, where B cell depletion via withdrawal of essential survival cytokines was not associated with a marked clinical effect. We propose that at least part of the efficacy of anti-CD20 mAb therapy is attributable to the sustained CCR7 expression on T cells within SLO, limiting their release into the circulation.

B Cell Reconstitution after Rituximab Treatment in Idiopathic Nephrotic Syndrome

“…19,[45][46][47] RTX-induced B cell depletion could actually modify antigen presentation and cytokine production 45 as well as alteration of T cell homeostasis and homing. 48 Our results showed that total T cells were not affected by RTX, and whereas CD4 + /CD8 + T cell ratio increased after RTX treatment, there was no difference between relapsers and nonrelapsers in the T cell subsets.…”

Blockade of CD127 Exerts a Dichotomous Clinical Effect in Marmoset Experimental Autoimmune Encephalomyelitis

“…Previous findings hint at a role for the IL-7 signaling pathway in EAE developing in marmosets immunized with recombinant human myelin oligodendrocyte glycoprotein (rhMOG)/CFA. Depletion of CD20 + B cells in the marmoset EAE model inhibits the activation and lymph node emigration of T cells and consequently prevents the development of clinical symptoms and pathology (Jagessar et al 2012;Kap et al 2010;Kap et al 2014). In B-cell depleted marmosets, CD127 expression on T cells was not down-regulated, but IL-7 mRNA levels were profoundly suppressed (Kap et al 2014).…”

“…Depletion of CD20 + B cells in the marmoset EAE model inhibits the activation and lymph node emigration of T cells and consequently prevents the development of clinical symptoms and pathology (Jagessar et al 2012;Kap et al 2010;Kap et al 2014). In B-cell depleted marmosets, CD127 expression on T cells was not down-regulated, but IL-7 mRNA levels were profoundly suppressed (Kap et al 2014). In addition, in B-cell depleted marmosets the viral load of CalHV3, which is the marmoset lymphocryptovirus equivalent of EpsteinBarr virus (EBV), was reduced (Jagessar et al 2013a).…”

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

“…We observed that the space left inside lymph nodes by the depletion of CD20+ ve B cells is replenished by activated T cells expressing the lymph node homing receptor CCR7. This was not observed in monkeys treated with anti-BlyS or anti-APRIL mAb (Kap et al, 2014). This finding may suggest that the anti-CD20 treatment may interfere with the licensing of activated autoreactive T cells to egress the lymph nodes.…”