Abstract
The pathogenesis of human autoimmune disorders is incompletely understood. This has led to the development of numerous murine models in which the pathogenesis of autoimmunity can be probed and the efficacy of novel therapies can be tested. One of the most widely-used murine models of autoimmunity is experimental autoimmune encephalomyelitis (EAE). To induce autoimmune pathology, mice are often immunized with an autoantigen alongside an adjuvant, typically complete Freund's adjuvant (CFA). Unfortunately, CFA causes significant inflammation at the site of administration. Despite the well-recognized complication of injection site inflammation, CFA with autoantigen immunization is widely used to induce central nervous system autoimmunity. We performed a literature review which allowed us to estimate that over 10,000 mice were immunized with CFA in published EAE studies in 2013. In this study, we demonstrated that subcutaneously administered myelin basic protein (MBP)-pulsed CD11c+ bone marrow-derived dendritic cells (BMDC) were as effective at inducing EAE as subcutaneously administered MBP plus CFA. Importantly, we also discovered that the CD11c+ BMDC caused significantly less injection site inflammation than MBP plus CFA immunization. This study demonstrated that the use of CD11c+ BMDC can enable the development of autopathogenic T-cells to be studied in vivo without the unwanted side-effects of long-lasting injection site inflammation. This model represents a significant refinement to existing EAE models and may lead to the improvement of the welfare of experimental mice used to study the development of autoimmunity in vivo.
Highlights
The pathogenesis of human autoimmune disorders is incompletely understood
We have recently addressed these shortcomings by developing a novel dendritic cells (DC)-driven EAE model in which host mice, seeded with myelin basic protein (MBP) reactive T-cell receptor (TCR) transgenic CD4þ T-cells, develop a monophasic ascending paralysis following the subcutaneous administration of lipopolysaccharide (LPS)-activated, MBP-loaded bone marrow-derived DC (BMDC).[20]
These findings demonstrate that the autopathogenic inflammatory infiltrate in the central nervous system (CNS) of mice which develop EAE post MBP-loaded CD11cþ bone marrow-derived dendritic cells (BMDC) immunization is very similar to the infiltrate which has been previously reported to occur in the CNS of mice immunized with complete Freund’s adjuvant (CFA) plus MBP
Summary
The pathogenesis of human autoimmune disorders is incompletely understood. This has led to the development of numerous murine models in which the pathogenesis of autoimmunity can be probed and the efficacy of novel therapies can be tested. This study demonstrated that the use of CD11cþ BMDC can enable the development of autopathogenic T-cells to be studied in vivo without the unwanted side-effects of long-lasting injection site inflammation This model represents a significant refinement to existing EAE models and may lead to the improvement of the welfare of experimental mice used to study the development of autoimmunity in vivo. Over 60 years ago, it was demonstrated that administration of complete Freund’s adjuvant (CFA) and central nervous system (CNS) tissue could induce inflammatory lesions, which are similar to human demyelinating lesions as is typically observed in patients with MS.[7,8] Subsequently, EAE models have played a major role in advancing understanding of immune-mediated injury and have been instrumental in the development of novel MS therapies.[7]. A recent review entitled ‘Reducing suffering in EAE’ highlighted the need for careful consideration during adjuvant selection while taking into account animal welfare considerations.[15]
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