A brief research history (eng text)
Characterization of autoaggressive and protective immunological mechanisms in mouse and rat EAE models
We have developed a novel experimental model of multiple sclerosis in the DBA/1 mouse, (MOG-induced Experimental Autoimmune Encephalomyelitis (MOG-EAE)) which is a severe disease model that exhibits the pathology most resembling human pathology of all mouse models (Link to Publication). We have dissected the immunological pathogenesis of MOG-EAE in this model by making use of various knockout mice (impossible to do in the rat models as yet). We have studied the relative contribution to pathogenesis of T cell subsets and determined that CD8+ T cells play a significant role through use of DBA/1 knockout mice lacking functional CD4+ or CD8+ T cells (Link to Publication). We have demonstrated the importance of B cells by using B cell deficient DBA/1 mice (Link to Publication), which led to further fine dissection using DBA/1 knockout mice lacking specific Fcgamma receptors (Link to Publication) and with consequent deficient B cell functions. These were the first studies to indicate that Fcgamma receptors are vital for MOG-EAE pathogenesis, and as these receptors are expressed on Antigen Presenting Cells (APCs) such as macrophages and microglia, they indicate that APC function may be equally important in pathogenesis as the T and B lymphocyte requirements we have already characterized. We additionally studied the role of FLIP in MOG-EAE in DBA/1 mice using retroviral-induced over-expression, which led to disease exacerbation (Link to Publication).
With respect to cells involved in pathogenesis or protection, we have characterized a difference in the proinflammatory activities of macrophages in susceptible and resistant rat strains (Link to Publication). Signaling pathways in macrophages from different rat strains differed after activation with a variety of stimuli, and this was associated with differential production of the pro-inflammatory mediators nitric oxide and IL-23. We continue this base characterization of APC functionality, including comparative studies of macrophages, dendritic cells and microglia in both mice and rats, with focus on the intracellular ion transporter Nramp1. We have also defined the respective roles of Th1 and Th17 encephalitogenic T cells in neuroinflammation during MOG-EAE (Link to Publication) and have more recently confirmed immune gene products in rat MOG-EAE to be the same as in human MS (Link to Publication), including more detailed analysis of the role of TNFa regulation (Link to Publication) and IL-22 (Link to Publication).
What makes an autoantigen a target for immune attack?
We study post-translational modification of autoantigens, as we believe that these inflammation-induced events are what changes a self protein from being unrecognized by the immune system to become an autoantigen capable of inducing autoimmune disease.
We have been able to demonstrate that when MOG is oxidised through aldehydation, it becomes more immunogenic and promotes a more severe disease when immunized into DBA/1 mice (Link to Publication). The structural alterations induced through this modification are subtle, but the resultant effects on immunogenicity are great.
Development of novel immunotherapies for treatment of autoimmune diseases
We design and test novel therapeutic interventions for modulation of rodent autoimmune models, with the intention of innovative technology transfer to treatment of patient groups.
Our efforts to date have yielded a vaccine formulation that completely protects against development of MOG-EAE, and the mechanism attributed to this effect is in part due to induction of Tr3 regulatory T cells (Link to Publication). In addition, we have been able to demonstrate that live parasite infections reduce development of autoimune disease (Link to Publication) and that adoptive transfer of specifically activated immunosuppressive macrophages can also reduce disease development in settings of both neuroinflammation (Link to Publication) and Type 1 Diabetes (Link to Publication).