Heat shock protein 60 as a novel therapeutic target for diabetes and rheumatoid arthritis (HSPFORTHERAPY)

Leistungen

We identified peptide epitopes of HSP60 that are recognised by antigen receptors of autoimmune T cells and by innate (TLR) receptors of macrophages and T cells in experimental models of type 1 diabetes and arthritis, and in the peripheral blood T cells and monocytes of human patients, including patients in hsp peptide clinical trials. As planned, ample attention has been given to the identification of HSP epitopes. Given the plethora of different HSP families and different sources of HSP molecules in nature, the biology of HSP immune reactivity s is dependent on the nature of and degree of conservation of the epitopes recognized. In the experimental models initial understanding of the mechanism of HSP induced regulation was largely determined by the analysis of epitopes in the Lewis rat. As newer models of experimental arthritis were developed in the mouse, such as the human PG induced model in Balb/c mice, further epitope mapping was carried out in these mice. Very similar to the original findings in the rat, again epitopes were found which included conserved epitopes. For the innate TLR receptors in vitro reporter systems have been developed which were used amongst others for the screening of TLR triggering by heat shock proteins. In these assays also sets of peptides spanning surface exposed areas of HSP molecules were analyzed. Interestingly, from these analyses it has become apparent that HSP have the capacity to directly interact with TLR receptors. In addition some peptides, such as the diabetes associated p277 peptide, had a direct stimulatory effect on TLRs. The analysis of HSP60 epitopes in patients with juvenile idiopathic arthritis has resulted in the production of a collection of epitopes, both conserved and non-conserved of both human and bacterial HSP60. The success of this epitope analysis in patients depended for a large part on the very successful development of algorithms to select for pan-DR binding peptides. Therefore the resulting collection of novel HSP epitopes has the capacity to trigger T cell responses in a very broad HLA (MHC) background, which would enable us to undertake clinical trials in larger proportion of HLA selected patients. The phenotypes of T cell responses induced by these peptides were of a regulatory nature which has turned these HSP peptides into excellent and very attractive candidates for immune intervention in chronic arthritis (Kamphuis, Lancet 2005).

Leistungen

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