The phagocyte NAPDH-oxidase complex consists of several phagocyte oxidase (phox) proteins, generating reactive oxygen species (ROS) upon activation. ROS are involved in the defense against microorganisms and also in immune regulation. Defective ROS formation leads to chronic granulomatous disease (CGD) with increased incidence of autoimmunity and disturbed resolution of inflammation. Because regulatory T cells (Tregs) suppress autoimmune T-cell responses and are crucial in down-regulating immune responses, we hypothesized that ROS deficiency may lead to decreased Treg induction. Previously, we showed that in p47 phox -mutated mice, reconstitution of macrophages (Mph) with ROSproducing capacity was sufficient to protect the mice from arthritis. Now, we present evidence that Mph-derived ROS induce Tregs. In vitro, we showed that Mph ROS-dependently induce Treg, using an NADPH-oxidase inhibitor. This finding was confirmed genetically: rat or human CGD Mph with mutated p47 phox or gp91 phox displayed hampered Treg induction and T-cell suppression. However, basal Treg numbers in these subjects were comparable to those in controls, indicating a role for ROS in induction of peripheral Tregs. Induction of allogeneic delayed-type hypersensitivity with p47 phox -mutated Mph confirmed the importance of Mph-derived ROS in Treg induction in vivo. We conclude that NAPDH oxidase activity in Mph is important for the induction of Tregs to regulate T cell-mediated inflammation.chronic granulomatous disease | NADPH oxidase | neutrophil cytosolic oxidase 1 | redox

The authors' data constitute the first direct demonstration that DC alternatively matured in the presence of glucocorticoid hormones can be exploited for the specific suppression of the alloreactive Th1 response, resulting in a delayed skin graft rejection in a complete major histocompatibility complex-incompatible strain combination.

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Monitoring of T cells involved in the alloimmune response after transplantation requires the availability of reliable in vitro assays for the detection of T cells with both direct and indirect allospecificity. While generally accepted assays exist to measure helper and cytotoxic T cells involved in direct allorecognition, consensus about an assay for monitoring indirect T-cell allorecognition in clinical transplantation is lacking. Many studies claim a relationship between the reactivity of T cells with indirect allospecificity and graft rejection, but different protocols are used and essential controls are often lacking. In this review, the disadvantages and pitfalls of the current approaches are discussed, in some cases supported by the results of our own in vitro experiments. We conclude that an international workshop is necessary to establish and validate a uniform, robust and reliable assay for the monitoring of transplant recipients and to study the actual role of indirect allorecognition in acute and chronic rejection.