Antibodies Against Human BLyS and APRIL Attenuate EAE Development in Marmoset Monkeys

B lymphocyte stimulator (BLyS, also indicated as BAFF (B-cell activating factor) and CD257), and A Proliferation Inducing Ligand (APRIL, CD256) are two members of the TNF superfamily with a central role in B cell survival. Antibodies against these factors have potential therapeutic relevance in autoimmune inflammatory disorders with a proven pathogenic contribution of B cells, such as multiple sclerosis (MS). In the current study we performed a multi-parameter efficacy comparison of monoclonal antibodies against human anti-BLyS and anti-APRIL in a common marmoset (Callithrix jacchus) model of experimental autoimmune encephalomyelitis (EAE). A MS-like disease was induced by immunization with recombinant human myelin/oligodendrocyte glycoprotein (rhMOG) in complete Freund's adjuvant. The results show that the anti-BLyS and anti-APRIL antibody cause significant depletion of circulating CD20+ B cells, but a small subset of CD20 + CD40highB cells was not depleted. Induction of CD20+ B cell depletion from lymph nodes was only observed in the anti-BLyS treated monkeys. Both antibodies had a significant inhibitory effect on disease development, but all monkeys developed clinically evident EAE. Anti-BLyS treated monkeys were sacrificed with the same clinical signs as saline-treated monkeys, but nevertheless displayed significantly reduced spinal cord demyelination. This effect was not observed in the anti-APRIL treated monkeys. The two antibodies had a different effect on T cell subset activation and the profiles of ex vivo released cytokines. In conclusion, treatment with anti-BLyS and anti-APRIL delays the development of neurological disease in a relevant preclinical model of MS. The two mAbs achieve this effect via different mechanisms

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

Non-human primate models of human disease have an important role in the translation of a new scientific finding in lower species into an effective treatment. In this study, we tested a new therapeutic antibody against the IL-7 receptor alpha chain (CD127), which in a C57BL/6 mouse model of experimental autoimmune encephalomyelitis (EAE) ameliorates disease, demonstrating an important pathogenic function of IL-7. We observed that while the treatment was effective in 100 % of the mice, it was only partially effective in the EAE model in common marmosets (Callithrix jacchus), a small-bodied Neotropical primate. EAE was induced in seven female marmoset twins and treatment with the anti-CD127 mAb or PBS as control was started 21 days after immunization followed by weekly intravenous administration. The anti-CD127 mAb caused functional blockade of IL-7 signaling through its receptor as shown by reduced phosphorylation of STAT5 in lymphocytes upon stimulation with IL-7. Group-wise analysis showed no significant effects on the clinical course and neuropathology. However, paired twin analysis revealed a delayed disease onset in three twins, which were high responders to the immunization. In addition, we observed markedly opposite effects of the antibody on pathological changes in the spinal cord in high versus low responder twins. In conclusion, promising clinical effect of CD127 blockade observed in a standard inbred/SPF mouse EAE model could only be partially replicated in an outbred/non-SPF non-human primate EAE model. Only in high responders to the immunization we found a positive response to the treatment. The mechanism underpinning this dichotomous response will be discussed

Analysis of the cross-talk of Epstein-Barr virus-infected B cells with T cells in the marmoset

Despite the well-known association of Epstein-Barr virus (EBV), a lymphocryptovirus (LCV), with multiple sclerosis, a clear pathogenic role for disease progression has not been established. The translationally relevant experimental autoimmune encephalomyelitis (EAE) model in marmoset monkeys revealed that LCV-infected B cells have a central pathogenic role in the activation of T cells that drive EAE progression. We hypothesized that LCV-infected B cells induce T-cell functions relevant for EAE progression. In the current study, we examined the ex vivo cross-talk between lymph node mononuclear cells (MNCs) from EAE marmosets and (semi-) autologous EBV-infected B-lymphoblastoid cell lines (B-LCLs). Results presented here demonstrate that infection with EBV B95-8 has a strong impact on gene expression profile of marmoset B cells, particularly those involved with antigen processing and presentation or co-stimulation to T cells. At the cellular level, we observed that MNC co-culture with B-LCLs induced decrease of CCR7 expression on T cells from EAE responder marmosets, but not in EAE monkeys without clinically evident disease. B-LCL interaction with T cells also resulted in significant loss of CD27 expression and reduced expression of IL-23R and CCR6, which coincided with enhanced IL-17A production. These results highlight the profound impact that EBV-infected B-LCL cells can have on second and third co-stimulatory signals involved in (autoreactive) T-cell activation