Abstract
Technologies that enable induction of therapeutic tolerance may revolutionize the treatment of autoimmune diseases by their supposed potential to induce drug-free and lasting disease remission. In combination with diagnostic tests that screen for individuals at risk, these approaches may offer chances to halt disease before serious damage in the tissues can occur. In fact, for healthy individuals at risk, this could lead to a preventive form of vaccination. For therapeutic tolerance to re-instate natural self-tolerance it seems essential to induce tolerance for the critical autoantigens involved in disease. However, for most autoimmune diseases such antigens are poorly defined. This is the case for both disease inciting autoantigens and antigens that become involved through epitope spreading. A possible source of surrogate auto-antigens expressed in tissues during inflammation are heat shock proteins (HSP) or stress proteins. In this mini-review we discuss unique characteristics of HSP which provide them with the capacity to inhibit inflammatory processes. Various studies have shown that epitopes of HSP60 and HSP70 molecules can function as vaccines to downregulate a variety of autoimmune inflammatory diseases. Currently, several research groups are developing cell therapies with the intention to reach therapeutic tolerance. In this review, in which we are proposing to ex vivo load tolerant dendritic cells with a Treg inducing HSP70 derived peptide called B29, we are discussing the chances to develop this as an autologous tolDC therapeutic tolerance therapy for rheumatoid arthritis.
Highlights
Originally discovered by their enhanced expression following the rise of temperature, the enhanced expression of heat shock proteins (HSP) is known to depend on a multitude of factors which include the mediators associated with inflammation
Before introducing the possible mechanisms leading to the tolerance promoting activities of HSP peptides we describe in more detail our B29 peptide
In a different set of experiments carried out by others, mycobacterial HSP70 was shown to impair the maturation of bone marrow derived dendritic cells (DC), to induce IL-10 production and to inhibit T cell proliferation [17]
Summary
Originally discovered by their enhanced expression following the rise of temperature, the enhanced expression of HSP is known to depend on a multitude of factors which include the mediators associated with inflammation. Similar results were obtained more recently for HSP70 in a model of proteoglycan induced arthritis in mice In this model, the B29 peptides, of which mB29b was already mentioned here above to be present in the MHC-II elution profile of stressed cells, were found capable of inducing protective T cells based on microbial-mammalian cross-recognition [5]. In a different set of experiments carried out by others, mycobacterial HSP70 was shown to impair the maturation of bone marrow derived DC, to induce IL-10 production and to inhibit T cell proliferation [17] These findings, together with the reported disease inhibitory activities of HSP molecules, are pleading against HSP being DAMPs, but indicative of their immune DAMPing capacities instead. This is due to recent insights into the immunology of RA, coupled with advances in autoantibody identification and T and B-cell monitoring
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