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Current therapies for autoimmune diseases and allergy involve general immune suppression. However, the ideal therapy should specifically eliminate or modulate the (auto)pathogenic immune response or, alternatively, it should reinforce the regulatory response, without affecting the overall function of the immune system. This could be achieved by antigen-specific immunotherapy. Antigen-specific immunotherapy has received ample attention in the last years, and several clinical trials attempting to treat autoimmune diseases or allergy through the induction of antigen-specific tolerance or immune deviation have been conducted, albeit with varying success. Recent advances in our understanding of peripheral tolerance, regulatory T cells, and routes of antigen administration have resulted in better insight into the different working mechanisms and potential target molecules of antigen-specific immunotherapy. The experimental animal models and new technological developments force the pace in the development of these immunotherapies. The current review addresses several aspects of antigen-specific immunotherapies and focuses on the mechanisms of the different approaches in experimental autoimmune and allergy models.

In this contribution three examples are discussed of ongoing research where liposomes are used as carrier systems for immunotherapy and inflammation detection in autoimmune diseases. Liposomes can be used as carrier systems of antigenic peptides to peripheral blood mononuclear cells. The second example deals with their use as carrier systems for MHC-peptide complexes for multivalent Ag-presentation to autoreactive T lymphocytes to specifically modulate the activity of these T lymphocytes. The third example relates to our work on long circulating liposomes which are currently being tested in man for their potential to image inflammation sites.

The Lewis rat, an inbred rat strain susceptible to several well-characterized experimental autoimmune diseases, provides a good model to study peptide-mediated immunotherapy. Peptide immunotherapy focussing on the modulation of T cell responses by interfering with TCR-peptide-MHC complex formation requires the elucidation of the molecular basis of TCR-peptide-MHC interactions for an efficient design of modulatory peptides. In the Lewis rat most autoimmune-associated CD4+ T cell responses are MHC class II RT1.BL restricted. In this study, the characteristics of RT1.BL-peptide interactions were explored. A series of substitution analogs of two Lewis rat T cell epitopes was examined in a direct peptide-MHC binding assay on isolated RT1.BL molecules. Furthermore, other autoimmune-related as well as non-disease-related T cell epitopes were tested in the binding assay. This has led to the definition of an extended RT1.BL-peptide binding motif. The RT1.BL-peptide binding motif established in this study is the first described rat MHC-peptide binding motif based on direct MHC-peptide binding experiments. To predict good or intermediate RT1.BL binding peptides, T cell epitope search profiles were deduced from this motif. The motif and search profiles will greatly facilitate the prediction of modulatory peptides based on autoimmune-associated T cell epitopes and the identification of target structures in experimental autoimmune diseases in Lewis rats.

New strategies applied in the treatment of experimental autoimmune disease models involve blocking or modulation of MHC-peptide-TCR interactions either at the level of peptide-MHC interaction or, alternatively, at the level of T cell recognition. In order to identify useful competitor peptides one must be able to assess peptide-MHC interactions. Several well described autoimmune disease models exist in the Lewis rat and thus this particular rat strain provides a good model system to study the effect of competitor peptides. So far no information has been available on the peptide binding characteristics of the Lewis rat MHC class II RT1.B1 molecule. We have now developed a biochemical binding assay which enables competition studies in which the relative MHC binding affinity of a set of non-labelled peptides can be assessed while employing detection of biotinylated marker peptides by chemiluminescence. The assay is sensitive and specific. We have used this assay to determine the binding characteristics of several disease associated T cell determinants and their sequence analogues in the Lewis rat. Notably, most of the autoimmune disease associated peptide sequences tested were found to be intermediate to poor binders. Single amino acid substitutions at defined positions were sufficient to turn certain peptides into good binders. These results are relevant to the design of competitor peptides in the treatment of experimental autoimmune diseases.