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In adult patients, regulatory CD4+FOXP3+ T cells are suggested to have a role in the control of allo-reactive disease after hematopoietic SCT (HSCT). We compared CD4+FOXP3+ T-cell reconstitution after unrelated cord blood (UCB), matched unrelated donor (MUD) and matched sibling donor (MSD) HSCT in children, starting as early as 1 week after transplantation, and analyzed the association with allo-reactive disease. A total of 30 children were included who underwent a myeloablative-conditioning regimen followed by UCB (12/30), MUD (7/30) or MSD (11/30) HSCT. These three patient groups showed significant differences in FOXP3+ T-cell reconstitution pattern. Early after UCB and MSD, but not after MUD, HSCT a peak in FOXP3+ T cells was observed. There were significant differences in activation status and Ki67 expression of the FOXP3+ T cells after UCB and MSD, respectively. FOXP3+ T-cell proportions early after HSCT and in the graft were inversely correlated with allo-reactivity. This study indicates that FOXP3 reconstitution after HSCT is dependent on the type of graft used. Furthermore, in children evaluation of FOXP3+ T-cell numbers early after HSCT and in the graft may be used to judge the risk of developing allo-reactivity after HSCT.

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 [3]. 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 [4]. Heat shock proteins may be instrumental in restoring the immunological balance and thus contribute to a long-lasting disease remission.