The role of the tryptophan-metabolizing enzyme indoleamine 2,3-dioxygenase (IDO) in down-regulating human alloresponses has recently been controversially debated. We here demonstrate that human monocyte-derived dendritic cells (mDCs) can be endowed with sustained IDO competence in vitro by 48-hour activation with lipopolysaccharide (LPS) and interferon-gamma (IFN-␥). IFN-␥ also amplified proinflammatory cytokine secretion during activation. Yet, on reculture after activation cytokine production ceased, whereas IDO enzymatic activity IntroductionIndoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in tryptophan catabolism, has attracted attention for its proposed role in tolerance induction. 1,2 IDO, when expressed in antigen presenting cells (APCs), such as dendritic cells (DCs), establishes a microenvironment that at the DC/T-cell interface is depleted of tryptophan and enriched with tryptophan metabolites. Because of this alteration of the intercellular microenvironment, IDO activity has been suggested to impair T-cell responses. 3,4 The mechanisms of IDO-mediated inhibition include that T cells stimulated under tryptophan-depleted conditions are impaired to undergo full cell cycle progression 3,5 and are susceptible to apoptotic cell death. 6,7 Furthermore, it has been reported that IDO-expressing DCs can expand naturally occurring regulatory T cells. 8 In a murine model Fallarino et al 9 have shown that IDO activity supported the generation of adaptive regulatory T cells. Likewise, human IDOexpressing tumor cells have been reported to induce CD4 ϩ CD25 ϩ regulatory T cells. 10 Most recently, the previously recognized immunoregulatory activity of human plasmacytoid DCs has been related to IDO activity. 11 Thus, IDO-mediated down-regulation of T-cell responses has been suggested to be involved in a multitude of immunoregulatory processes, for example, pregnancy, 12 tumor growth, 13 and the induction of tolerance in transplantation (reviewed in Hainz et al 14 ).IDO expression is not a constitutive feature of human DCs in homeostatic immunologic conditions but requires induction. Among the multiple mediators of IDO induction (reviewed in Puccetti 15 ), interferon-␥ (IFN-␥) plays a prominent role. 16 IFN-␥ has generally been considered a prototypic proinflammatory cytokine (reviewed in Schoenborn and Wilson 17 ); compelling evidence, however, supports the ability of IFN-␥ to promote anti-inflammatory responses. [18][19][20] The ability of IFN-␥ to induce IDO has been suggested as a critical factor linked to this anti-inflammatory activity. 21,22 In our previous studies addressing possible mechanisms of the immunodeficient state after hematopoietic stem cell transplantation, 23 we found that monocytes after hematopoietic stem cell transplantation were particularly sensitive to respond to an exposure to IFN-␥ with an accelerated release of tryptophan metabolite kynurenine, and, thus, to turn into suppressor cells. This finding suggested the possibility that an augmented IDO activity in recipients of a hemat...

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Treatment of Langerhans cell histiocytosis (LCH) remains problematic. To test the hypothesis that rapid initiation and long-term continuation of chemotherapy can improve survival and reduce recurrence and late consequences of disseminated LCH, we have completed a prospective clinical trial (DAL HX-83). One hundred six newly diagnosed patients were stratified into three risk groups (A: multifocal bone disease [n = 28]; B: soft tissue involvement without organ dysfunction [n = 57]; C: organ dysfunction [n = 21]). All patients received an identical initial 6-week treatment (etoposide [VP-16], prednisone, and vinblastine), and continuation treatment for 1 year, slightly adapted according to stratification at diagnosis. It included oral 6-mercaptopurine and eight pulses of vinblastine and prednisone for all patients, plus VP-16 in group B and VP-16 and methotrexate in group C. Eighty-nine percent and 91% of patients in groups A and B and 67% of the most severely affected group C, achieved complete resolution of disease. The speed of resolution was rapid (median 4 months) and independent of disease severity. The frequency of recurrence after initial resolution was low (12%, 23%, and 42% in groups A, B and C); overall fully 77% of patients have remained free of recurrence. Permanent consequences developed after diagnosis in 20% of the patients. Diabetes insipidus after initiation of treatment occurred in only 10% of patients. Mortality (9%) was limited to patients of groups B (two patients) and C (eight patients). Finally, among the 106 patients treated by DAL HX-83 none have developed a malignancy (median follow-up 6 years, 9 months). The shorter duration of active disease, low rate of recurrence and permanent consequences, and improved survival among patients with poor prognosis support the strategy of rapid initiation of a predefined prolonged treatment upon the diagnosis of disseminated LCH.

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