Epitopes hold the key to autoimmune disease therapy
Heat shock proteins (HSPs) or stress proteins, as their name suggests, are produced when cells are subjected to a range of environmental stresses such as heat and toxins. One of their functions was pertinent to the research by the members of the HSPFORTHERAPY project. They can act as antigens in immune responses involved in autoimmune diseases like diabetes and arthritis. There is a huge range of HSPs and there are six major families yielding vast potential for identification of conserved epitopes. These antigenic determinants react with immune cells including macrophage toll-like receptors (TLRs), peripheral blood T cells and monocytes. The researchers used experimental models for arthritis and diabetes type 1 and human patients in clinical HSP trials to isolate potential therapeutic candidates. The team at the Institute of Infectious Diseases and Immunology in the Netherlands directed their focus on HSP60 epitopes in both the innate and adaptive sectors of the immune system. The T cells that react against HSP60 inhibit immune responses. This mechanism serves as a feedback loop to suppress those inflammatory reactions that are hallmarks of autoimmune diseases. Computer algorithms were developed to identify, by score allocation for ability to interconnect, the most effective pan-DR binding peptides. These epitopes could then stimulate the proliferation of the T cells. The major strand to this research involved research into juvenile idiopathic arthritis. The scientists isolated a collection of conserved and non-conserved epitopes from both human and bacterial HSP60. Due to the screening algorithms, the novel HSP epitopes have the ability to trigger T cell responses in a wide Major histocompatability complex (MHC) background thus expanding the scope of future trials. Type 1 diabetes is also a candidate for therapy based on epitope peptides. As part of the innate immune system, TLRs are pathogen sensors. Heat shock proteins were screened using reporter systems for their ability to trigger TLR activity. In particular, p227, an HSP60 peptide, was found to directly stimulate the action of TLRs. The protein p227 plays a role in the pathology of type I diabetes and signalling through TLRs could therefore contribute to the treatment of this disease.
