Human autoimmune diseases are characterized by chronic, non-remitting inflammation. In the early phase of chronic arthritis auto-reactive T cells initiate a cascade of events that leads to chronic inflammation. Following the initial phase of the disease, other cells such as macrophages and monocytes mainly mediate the ongoing non-specific inflammation. At this later stage, auto reactive T cells presumably do not play an important role in sustaining the chronic inflammation. Mechanisms underlying the perpetuation of this cascade of non-specific inflammation are still poorly understood. As a consequence, treatment of the disease until now has been mainly focused on non-specific suppression of inflammation. In patients with chronic arthritis, such juvenile idiopathic arthritis (JIA) and rheumatoid arthritis (RA) blockade of the tumour necrosis factor alpha pathway has proven to be a very potent treatment option. On the other hand, such treatment is costly and fails to induce a long-lasting remission of the disease. As a consequence long-term treatment with immune suppressive agents is necessary, which increases not only the costs of the treatment but also harbours considerable risk for long-term side effects. Thus, the need for additive and/or alternative strategies is growing. Ideally such alternative treatment should be safe, not expensive and specifically modulate cells that are responsible for the inflammation and/or counter-regulation. Lately, a lot of attention has focused on the role of regulatory T cells for the control of autoimmunity. There are currently two well-characterized types of regulatory T cells, Tr1 cells and CD4+CD25+ T regulatory cells. The CD4+CD25+ T regulatory cells are a heterogeneous group of cells identified by the expression of CD25 and the transcription factor foxP3. We recently showed that these so-called naturally occurring T regulatory cells and regulatory T cells with specificity towards heat shock proteins may play a role in determining disease outcome in JIA [1,2]. Following autologous stem cell transplantation for arthritis T regulatory cell function is restored coinciding with a remission of the arthritis (de Kleer et al., submitted). Moreover, oral treatment with a peptide (dnaJP1), derived from heat shock protein dnaJ, restored T regulatory cells in peripheral blood mononuclear cells from patients with RA .
Thus, due to insufficient numbers of regulatory T cells, feedback mechanisms fail, resulting in an unrestrained proinflammatory immune response and severe tissue damage in RA and JIA. A lack of a counter-regulatory mechanism based by regulatory T cells is at least in part responsible for the perpetuation of inflammation . Heat shock proteins may be instrumental in restoring the immunological balance and thus contribute to a long-lasting disease remission.
de Kleer IM, Wedderburn LR, Taams LS, Patel A, Varsani H, Klein M, de Jager W, Pugayung G, Giannoni F, Rijkers G, et al.: CD4+CD25(bright) regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis.
de Kleer IM, Kamphuis SM, Rijkers GT, Scholtens L, Gordon G, de Jager W, Hafner R, Van De Zee, Van Eden W, Kuis W, Prakken BJ: The spontaneous remission of juvenile idiopathic arthritis is characterized by CD30+ T cells directed to human heat-shock protein 60 capable of producing the regulatory cytokine interleukin-10.
Prakken BJ, Samodal R, Le TD, Giannoni F, Yung GP, Scavulli J, Amox D, Roord S, de Kleer I, Bonnin D, Lanza P, et al.: Epitope-specific immunotherapy induces immune deviation of proinflammatory T cells in rheumatoid arthritis.