Background Regulatory T cells (Treg) are a promising tool for the suppression of pathogenic immune responses against self-antigens, which are detrimental in autoimmune diseases such as systemic lupus erythematosus (SLE). Dendritic cells (DC) in the steady state are important for the maintenance of peripheral self-tolerance by inducing or expanding T cell subsets with regulatory properties upon tolerogenic antigen-presentation.
Objectives To induce or restore antigen-specific tolerance in murine lupus by targeting steady state DC directly in vivo via anti-DEC205/anti-33D1 antibodies coupled to a lupus-specific autoantigen.
Methods Antibodies against the DC antigen receptors DEC205 and 33D1 were coupled to SmD1(83-119), a key autoantigen in lupus, and to ovalbumin as control antigen in our facility according to published procedures (plasmids were a kind gift of M. Nussenzweig). The potential of both fusion constructs to expand Treg in vivo, induce antigen-specific tolerance and to influence the course of disease was evaluated in (NZBxNZW) F1 model with two different doses of the respective antibody-antigen fusion protein (1μg and 5μg/mouse). CD4 T cells from lymphoid organs and were analyzed by flowcytometry either ex vivo or after antigen specific restimulation in vitro.
Results Single injections of both antibody-antigen conjugates (aDEC205 and a33D1) induced an increase of CD4+Foxp3+ Treg in the lymphoid organs of lupus prone mice. However, the expansion of Treg was accompanied by an increase in conventional CD4+Foxp3- T cells with a CD44hi effector/memory phenotype and an increase in antigen-specific Th1 cells. Corresponding to this, monthly injections of both antibody-antigen conjugates in a preventive setting resulted in an earlier onset of disease and resulted in an earlier appearance of lupus-specific autoantibodies. In addition, treatment with neither antibody was capable to influence already established disease.
Conclusions Although promising results had been obtained in several autoimmune models in the past, targeting of steady state DC via DEC205 and 33D1 failed to be successful in the (NZBXNZW) F1 model for lupus. This may be in part explained by the abundance of proinflammatory signals present in lupus prone mice that could induce the rapid activation and maturation of steady state DC, leading to an immunogenic presentation of auto-antigens instead of a tolerogenic one.
Disclosure of Interest None Declared
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