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Although most CD4CD25 regulatory T (Treg) cells develop in the thymus (i.e., natural Treg or nTreg), accumulating evidence suggests that they can also develop in the periphery (adaptive/induced Treg or iTreg). Both types of cells are functionally associated with the expression of Foxp3, a transcription factor that is constitutively expressed in nTreg cells and inducible during iTreg cell generation from CD4CD25- T lymphocytes. Multiple factors are involved in the generation and function of Treg cells, but a major role seems to be played by indoleamine 2,3-dioxygenase (IDO). IDO can both deplete tryptophan in local tissue microenvironments and generate immunoregulatory catabolites, known as kynurenines. Tryptophan starvation and presence of kynurenines can induce the conversion of naïve CD4CD25- T cells into highly suppressive CD4CD25Foxp3 Treg cells. In turn, Treg cells induce IDO in dendritic cells (DCs) and convert inflammatory into regulatory DCs, which can further expand the Treg cell compartment by tryptophan catabolism. Evidence suggests that the modulation of IDO activity favors the interconversion between Treg cells and T helper type 17 (TH17) inflammatory cells. Thus, in the periphery, tolerogenic immune responses mediated by Treg cells can be induced and amplified by IDO, a tryptophan catabolizing enzyme that also contributes to the plasticity of the Treg cell lineage.

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Plasmacytoid dendritic cells (pDCs) represent a specialized cell population that produces large amounts of type I interferons, the so-called natural interferon-producing cells. Recently, murine and human pDCs have been credited with a unique ability to express indoleamine 2,3-dioxygenase (IDO) and to mediate immunosuppression in specific settings. This suggests an important role for IDOexpressing pDCs in controlling the balance of inflammation and tolerance. Here we review recent advances in our understanding of how these cells may be critical at the interface of inflammation and tolerance and discuss the potential for therapeutic IDO modulation as an immunoregulatory maneuver targeting pDC function.

The role of cytokines in the pathogenesis of T cell-mediated diseases, and in particular autoimmune responses, has been the subject of intense investigation in the past few years. Transgenic strains of mice have been generated, each expressing individual cytokines in organs targeted by autoimmunity. These animal models provide the most advanced tool available for analyzing the relationship between cytokines and T-dependent autoimmune responses. On the one hand, these experiments confirm that the local expression of proinflammatory cytokines is pivotal in initiating and maintaining pathogenic responses to self. On the other hand, and somewhat unexpectedly, these models have also revealed that cytokine factors controlling autoimmunity can act both as potentiating and inhibitory agents, depending upon the site and timing of exposure. As a result, one major concept emerging from different experimental models, including those originally established in our laboratory, is that proinflammatory cytokines may ameliorate autoimmunity. In this review, we analyze the mechanisms whereby cytokines that are considered as proinflammatory may in contrast suppress immune responses to self antigens. Besides emphasizing that the proinflammatory / immunogenic properties of a given cytokine may not be an intrinsic property, we review evidence that the regulation imposed by the cytokine network on autoimmunity is a finely tuned balance between activation and downmodulation of an individual autoreactive T cell repertoire. By emphasizing that factors such as the duration of cytokine exposure and the type of cell population involved strongly influence that balance, we underline the potential therapeutic implications of cytokine-mediated modulation of autoimmunity.

We assessed the effect of rIL-12 on the expression of class II molecules and on the ratio between SDS-stable and unstable αβ dimers in dendritic cells. We found that in vitro exposure of the cells to IL-12 increased their surface expression of mature class II molecules, despite a marked decline in class II biosynthesis. This effect was accompanied by a striking increase in the overall proportion of SDS-stable heterodimers.

To determine the effect of interleukin 4 (IL-4) administration in a live sepsis model characterised by high-level production of tumour necrosis factor α (TNF-α), mice infected systemically with lethal or sublethal inocula of Pseudomonas aeruginosawere given the recombinant cytokine at different times before infection. Improved survival and decreased TNF-α production were observed in lethally infected mice treated with the cytokine 1 day before challenge. In contrast, increased mortality and overproduction of TNF-α were observed in sublethally infected mice given IL-4 at the time of infection.

AbstractFusion and gemination of permanent teeth are developmental anomalies of the dental hard tissues which may require endodontic and surgical treatment for functional, orthodontic or aesthetic reasons. Following a review of the dental literature on tooth fusion and gemination, a case of fusion of a maxillary central incisor and a supernumerary tooth and its endodontic and surgical treatment is presented.

An interleukin 4 (IL-4)-specific monoclonal antibody (mAb) was administered to mice infected systemically with the yeast Candida albicans, and the animals were monitored for mortality, development of delayed-type hypersensitivity, production of antibodies of different isotypes, release of IL-2, IL-4, IL-6, and interferon gamma (IFN-gamma) in vitro by splenic CD4+ lymphocytes, and levels of IL-4 and IFN-gamma mRNA in these cells. Neutralization of IL-4 by three weekly injections of mAb in several independent experiments resulted in an overall cure rate of 81% versus 0% of controls. Cure was associated with efficient clearance of the yeast from infected organs and histologic evidence of disease resolution, detection of strong T helper type 1 (Th1) responses, and establishment of long-lasting protective immunity. Soon after infection, and as a result of the first or second injection of mAb, there was a decrease in IL-4 mRNA in CD4+ cells, which was accompanied by an increase in the levels of IFN-gamma-specific transcripts. Our data thus indicate that the production of IL-4 by Th2 cells may limit Th1-associated protective immunity in murine candidiasis.

The in vivo and in vitro influence of lithium lactate on mouse natural killer activity was investigated. In vitro exposure of effector-target mixture to graded concentrations of lithium did not substantially modify the natural killer activity of mouse splenocytes, untreated or pretreated with cyclophosphamide. However in vitro treatment of effector splenocytes increased the frequency of NK-percursor cells.The in vivo treatment with lithium lactate greatly increased the natural killer activity in intact mice, whereas it did not improve this cytotoxic function in host immunodepressed by cyclophosphamide.These data suggest that lithium salts produce a modulation of natural killer activity of mouse spleen cells, probably through a mechanism involving the increase of the number of NK-precursors in hosts not subjected to cytotoxic chemotherapy.

A single injection of monoclonal antibody to gamma interferon administered in conjunction with a live Candida albicans yeast cell vaccine resulted in the detection of nonprotective Th2 rather than protective Th1 responses and altered the early expression of interleukin 4 and gamma interferon mRNA in CD4+ cells.