Modelling clinical systemic lupus erythematosus: similarities, differences and success stories

Abstract

Mouse models of SLE have been indispensable tools to study disease pathogenesis, to identify genetic susceptibility loci and targets for drug development, and for preclinical testing of novel therapeutics. Recent insights into immunological mechanisms of disease progression have boosted a revival in SLE drug development. Despite promising results in mouse studies, many novel drugs have failed to meet clinical end points. This is probably because of the complexity of the disease, which is driven by polygenic predisposition and diverse environmental factors, resulting in a heterogeneous clinical presentation. Each mouse model recapitulates limited aspects of lupus, especially in terms of the mechanism underlying disease progression. The main mouse models have been fairly successful for the evaluation of broad-acting immunosuppressants. However, the advent of targeted therapeutics calls for a selection of the most appropriate model(s) for testing and, ultimately, identification of patients who will be most likely to respond.

Disease stage-specific pathogenicity of CD138 (syndecan 1)-expressing T cells in systemic lupus erythematosus

“…Second, we investigated a possible correlation between TCRβ+CD138+ cells and the progression of disease in MRL/Lpr mice and found that the frequency of TCRβ+CD138+ cells progressively increased with the age of mice (Figure 1B). Moreover, the increase in TCRβ+CD138+ cell population was also detected in pristine-injected Balb/c and C57BL/6 mice (Supplemental Figure 1C and D), which also develop lupus-like autoimmune symptoms [27]. It is important to note that in B6/lpr mice, TCRβ+CD138+ cells were previously reported to be confined to the lymph nodes [25], however, we found high percentage of these cells also in the thymus, spleen, lymph nodes and blood of MRL/Lpr mice (Figure 1C).…”

The Lupus Susceptibility Locus Sgp3 Encodes the Suppressor of Endogenous Retrovirus Expression SNERV

“…Generation of Snerv1/Snerv2-competent NZB and NZW will permit targeted approaches to manipulate the gp70 phenotype in vivo and can be used to conclusively test the requirement for dysregulated NEERV in the pathogenesis of lupus. Although Snerv1 and Snerv2 are in epistasis with additional susceptibility loci that enhance disease in models of spontaneous lupus (Celhar and Fairhurst, 2017;Crampton et al, 2014;Morel, 2010), such experiments will elucidate the connection between ERV mis-regulation and lupus pathogenesis. Using Snerv1/Snerv2-competent lupus-prone mice, it will be possible to rigorously test how tolerance is lost in the setting of high NEERV autoantigen production, how anti-NEERV autoantibodies are induced, and how NEERV dysregulation itself contributes to lupus severity.…”

The lupus susceptibility locus Sgp3 encodes the suppressor of endogenous retrovirus expression SNERV

“…Generation of Snerv1/2-competent NZB and NZW will permit targeted approaches to manipulate the gp70 phenotype in vivo, and can be used to conclusively test the requirement for dysregulated NEERV in the pathogenesis of lupus. While Snerv1 and Snerv2 are in epistasis with additional susceptibility loci that enhance disease in models of spontaneous lupus (Celhar and Fairhurst, 2017;Crampton et al, 2014;Morel, 2010), such experiments will elucidate the connection between ERV misregulation and lupus pathogenesis. Using Snerv1/2-competent lupus-prone mice, it will be possible to rigorously test how tolerance is lost in the setting of high NEERV autoantigen production, how anti-NEERV autoantibodies are induced, and how NEERV dysregulation itself contributes to lupus severity.…”

“…NZB-and NZW-based lupus models are widely used in pre-clinical drug efficacy trials, as they recapitulate more clinical features of human SLE than other mouse strains (Celhar and Fairhurst, 2017;Li et al, 2017). Of the few drugs approved for treatment of SLE by the FDA, essentially all-systemic immunosuppressants, antimalarials, anti-BAFF, anti-CD20, anti-CTLA-4, interferon-alpha blockade, and toll-like receptor agonists-were tested pre-clinically in NZB/W models (Celhar and Fairhurst, 2017). Clarifying the role of NEERV in disease progression will shape how pre-clinical testing for lupus nephritis proceeds and whether it may be feasible to pursue the development of therapeutics that target ERV.…”