Uptake of Leishmania major by dendritic cells is mediated by Fcgamma receptors and facilitates acquisition of protective immunity.

Uptake of Leishmania major by dendritic cells (DCs) results in activation and interleukin (IL)-12 release. Infected DCs efficiently stimulate CD4- and CD8- T cells and vaccinate against leishmaniasis. In contrast, complement receptor 3-dependent phagocytosis of L. major by macrophages (MPhi) leads exclusively to MHC class II-restricted antigen presentation to primed, but not naive, T cells, and no IL-12 production. Herein, we demonstrate that uptake of L. major by DCs required parasite-reactive immunoglobulin (Ig)G and involved FcgammaRI and FcgammaRIII. In vivo, DC infiltration of L. major-infected skin lesions coincided with the appearance of antibodies in sera. Skin of infected B cell-deficient mice and Fcgamma-/- mice contained fewer parasite-infected DCs in vivo. Infected B cell-deficient mice as well as Fcgamma-/- mice (all on the C57BL/6 background) showed similarly increased disease susceptibility as assessed by lesion volumes and parasite burdens. The B cell-deficient mice displayed impaired T cell priming and dramatically reduced IFN-gamma production, and these deficits were normalized by infection with IgG-opsonized parasites. These data demonstrate that DC and MPhi use different receptors to recognize and ingest L. major with different outcomes, and indicate that B cell-derived, parasite-reactive IgG and DC FcgammaRI and FcgammaRIII are essential for optimal development of protective immunity.

Critical role of IL-10 in the induction of low zone tolerance to contact allergens.

The development and mechanisms of tolerance to allergens are poorly understood. Using the murine low zone tolerance (LZT) model, where contact hypersensitivity (CHS) is prevented by repeated topical low-dose applications of contact allergens, we show that LZT induction is IL-10 dependent. IL-10 is required for the generation of LZT effector cells, that is, CD8+ regulatory T cells. Only T cells from tolerized IL-10+/+ mice or IL-10-/- mice reconstituted with IL-10 during LZT induction adoptively transferred LZT to naive mice and prevented CHS, whereas T cells from IL-10-/- mice failed to do so. The IL-10 required for normal LZT development is derived from lymph node CD4+ T cells, the only skin or lymph node cell population found to produce relevant amounts of IL-10 after tolerization. CD4+ T cells derived from IL-10+/+ mice, but not from IL-10-/- mice, allowed the induction of LZT in adoptively transferred T cell-deficient mice. Interestingly, IL-10 injections during tolerization greatly enhanced LZT responses in normal mice. Thus, the generation of CD8+ LZT effector T cells by CD4+ regulatory T cells via IL-10 may be a promising target of strategies aimed at preventing contact allergies and other harmful immune responses.

Activation of MAP kinase p38 is critical for the cell-cycle-controlled suppressor function of regulatory T cells.

Regulatory T cells play an essential role in the control of self-tolerance and processes of adaptive immunity. Tolerogenic IL-10-modulated human dendritic cells (IL-10DCs) induce anergic T cells with strong suppressive properties (iTregs) that inhibit the activation of effector T cells. In this study, we evaluated the interaction between cell-cycle regulation and intracellular signaling in these iTregs. Analysis of signal transduction events revealed a down-regulation of the mitogen-activated protein kinases (MAPKs) Jun N-terminal kinase (JNK) and a nonactivation of extracellular-signal-regulated kinase (ERK) in contrast to a marked activation of p38 MAPK and the p38 effector MAPK-activated protein kinases 2/3 (MAPKAP2/3). The elevated activation of p38 is critical for the induction and maintenance of anergy controlled by an increased expression of the cell-cycle inhibitor p27(Kip1). Moreover, blocking experiments with the specific inhibitor SB203580 demonstrated that the regulatory function of iTregs is associated with an enhanced p38 MAPK activity. In contrast to other Treg populations, the suppressor function of iTregs is independent of IL-10. In conclusion, our data indicate that a cross-talk of cell-cycle regulation and p38-dependent signal transduction is required for the suppressor function of iTregs.

Endovenous laser treatment of the lesser saphenous vein with a 940-nm diode laser: early results.

BACKGROUND: Until now, endovenous laser treatment (ELT) of the lesser saphenous vein (LSV) has not been reported. OBJECTIVE: To evaluate efficacy and side effects for ELT of the LSV. METHOD: Otherwise unselected patients with an incompetent LSV were included. After perivenous infiltration of tumescent local anesthesia, laser energy (940 nm) was administered endovenously, either in a pulsed fashion or continuously during constant backpull of the laser fiber. Patients were scheduled for duplex follow-up at Day 1 and also at 1, 3, 6 and 12 months, postoperatively. RESULTS: Forty-one LSVs were targeted in 33 patients with a median age of 66 years (range, 35 to 93). Seventy-three percent of patients had skin changes (C4). Thirty-six percent had an open or healed venous ulcer (C5,6) and 15% a postthrombotic syndrome (ES AS,D PR). Thirty-nine LSVs (95%) completed ELT successfully. During a median follow-up interval of 6 months (range, 3 to 12 months), no recanalization event could be observed. Apart from one thrombosis of the popliteal vein in a patient with polycythemia vera, only minor side effects, particularly no permanent paresthesia, could be observed. CONCLUSION: ELT of the LSV under tumescent local anesthesia is feasible and effective. Caution is warranted with ELT of thrombophilic patients.

Nonocclusion and early reopening of the great saphenous vein after endovenous laser treatment is fluence dependent.

BACKGROUND: Parameters influencing failure and recanalization rates of endovenous laser treatment (ELT) of the great saphenous vein (GSV) are still to be determined. OBJECTIVE: To evaluate treatment-related parameters of ELT with respect to early failure of occlusion or recanalization of GSVs. METHODS: A series of 77 consecutive patients received ELT of 106 GSVs with continuous pullback of the laser fiber. Duplex examination was performed at 1 day, 4 weeks, and 3 months after the procedure. Clinical patient and vessel characteristics as well as technical parameters of the ELT procedure were evaluated via multiple logistic regression analysis. RESULTS: A median vein length of 60 cm (range of 18 to 90) was treated with a median pullback velocity of 0.6 cm/sec (range of 0.4 to 1.3), resulting in a median energy delivery of 23.4 J/cm (range of 11.8 to 35.5) and a median laser fluence of 11.8 J/cm2 (range of 2.8 to 37.3). At day 1 after ELT, 6 GSVs (6%) were not occluded. At 1 and 3 months after ELT, 9 GSVs (9%) and 11 GSVs (10%), respectively, were found open by color duplex examination. Risk factors for nonocclusion 3 months after ELT, by univariate analysis, were laser fluence, laser energy per centimeter of vein length, diameter of the vein before treatment, and distance of the thrombus to the sapheno-femoral junction at day 1 after treatment. Finally, multiple regression analysis selected laser fluence (p=0.004, odds ratio=0.40 J/cm2) as the relevant risk factor for ELT failure or recanalization. CONCLUSION: ELT failure seems to be related to the administration of low laser fluences.

Induction of tolerogenic DCs: 'you are what you eat'.

Dendritic cells (DCs) take up antigens using antigen receptors that can be divided into three major classes: C-type lectins, integrins and Fc receptors. These receptors facilitate effective presentation of MHC-peptide complexes to T cells, resulting in the induction of immune responses. However, we discuss recent evidence that some receptors also cause induction of tolerance. Signaling motifs within the receptors either block maturation of DCs or induce signals that render DCs tolerogenic. These DCs then either induce regulatory T cells or cause deletion of effector T cells, resulting in the induction of tolerance. Antigen receptors expressed by DCs might therefore have an important role in the induction and maintenance of peripheral tolerance.