Adhesive interactions of leukocytes and endothelial cells initiate leukocyte migration to inflamed tissue and are important for immune surveillance. Acute and chronic inflammatory diseases show a dysregulated immune response and result in a massive efflux of leukocytes that contributes to further tissue damage. Therefore, targeting leukocyte trafficking may provide a potent form of antiinflammatory therapy. Leukocyte migration is initiated by interactions of the cell adhesion molecules E-, L-, and P-selectin and their corresponding carbohydrate ligands. Compounds that efficiently address these interactions are therefore of high therapeutic interest. Based on this rationale we investigated synthetic dendritic polyglycerol sulfates (dPGS) as macromolecular inhibitors that operate via a multivalent binding mechanism mimicking naturally occurring ligands. dPGS inhibited both leukocytic L-selectin and endothelial P-selectin with high efficacy. Size and degree of sulfation of the polymer core determined selectin binding affinity. Administration of dPGS in a contact dermatitis mouse model dampened leukocyte extravasation as effectively as glucocorticoids did and edema formation was significantly reduced. In addition, dPGS interacted with the complement factors C3 and C5 as was shown in vitro and reduced C5a levels in a mouse model of complement activation. Thus, dPGS represent an innovative class of a fully synthetic polymer therapeutics that may be used for the treatment of inflammatory diseases.anti-inflammatory drug | complement inhibition | multiple target binding | multivalent selectin inhibitor | synthetic polymer

Elevated IL-10 has been implicated in reactivation tuberculosis (TB). Since macrophages rather than T cells were reported to be the major source of IL-10 in TB, we analyzed the consequences of a macrophage-specific overexpression of IL-10 in transgenic mice (macIL-10-transgenic) after aerosol infection with Mycobacterium tuberculosis (Mtb). MacIL-10 transgenic mice were more susceptible to chronic Mtb infection than nontransgenic littermates, exhibiting higher bacterial loads in the lung after 12 wk of infection and dying significantly earlier than controls. The differentiation, recruitment, and activation of Th1 cells as well as the induction of IFN-γ-dependent effector genes against Mtb were not affected by macrophage-derived IL-10. However, microarray analysis of pulmonary gene expression revealed patterns characteristic of alternative macrophage activation that were overrepresented in Mtb-infected macIL-10 transgenic mice. Importantly, arginase-1 gene expression and activity were strikingly enhanced in transgenic mice accompanied by a reduced production of reactive nitrogen intermediates. Moreover, IL-10-dependent arginase-1 induction diminished antimycobacterial effector mechanisms in macrophages. Taken together, macrophage-derived IL-10 triggers aspects of alternative macrophage activation and promotes Mtb recrudescence independent of overt effects on anti-TB T cell immunity.

CD8 + T cells are involved in protection againstMycobacterium tuberculosis infection and represent a promising target for new vaccine strategies. Because IL-15 is important for the homeostasis of CD8 + T cells, we studied the immune response in IL-15-deficient mice during tuberculosis. In the absence of IL-15, CD8 + T cells failed to efficiently accumulate in draining lymph nodes and at the site of infection. The expression of antigen-specific effector functions, such as the production of interferon-c and cytotoxicity, were impaired in CD8 + T cells, but not CD4 + T cells, from IL-15-deficient mice. This defect was associated with an increased mortality of IL-15-deficient mice during the chronic phase of infection. The lectin-like stimulatory receptor natural killer group 2D (NKG2D) was up-regulated on CD8 + T cells only from wild-type mice, but not from IL-15-deficient mice. Mechanistically, blocking NKG2D function with an mAb inhibited M. tuberculosis-directed CD8 + T cell responses in vitro. We conclude that in addition to regulating the expansion of CD8 + T cells, IL-15 is also necessary for inducing effector mechanisms in CD8 + T cells that depend on NKG2D expression. Hence, our results implicate IL-15 and NKG2D as promising targets for modulating CD8 + T cellmediated protection against tuberculosis. IntroductionHuman tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is responsible for eight million new cases and two million deaths annually [1]. Improved vaccination strategies will need to target all mechanisms that contribute to restricting the growth of Mtb [2]. Although the cell-mediated immune response is known to be critical in host defense against infection with mycobacteria, the relative contribution of T cell subsets and the mechanisms by which T cells participate in the control of infection are still not completely defined. It is generally accepted that both, CD4 + and CD8 + T cells, are an essential component of protective immunity against TB [3]. CD4 + T cells are particularly critical during the early phase of infection, while CD8 + T cells appear to contribute mostly at later stages [4,5]. Both, CD4 + and CD8 + T cells, produce interferon-c (IFN-c) which in turn stimulates the anti-microbial activity of macrophages. Intracellular pathogens are then killed through reactive nitrogen intermediates produced by the inducible nitric oxide synthase [6] or through effector mechanisms mediated by the newly described member of the 47-kD guanosine triphosphatase family, . CD8 + T cells can also cause death of both target cells and their intracellular bacterial cargo, either through perforin-dependent cytolysis by the release of granzymes and granulysin, or by ligation of Fas ligand (FasL) on their surface with Fas on infected macrophages [5,[8][9][10]. Because CD8 + T cells are involved in protection during the chronic stage of TB [4,5,11], and participate in memory immune responses to Mtb infection [12], generating a more robust CD8 + T cell response may provide an effective vaccination strate...

T-cell-mediated processes play an essential role in the pathogenesis of several inflammatory skin diseases such as atopic dermatitis, allergic contact dermatitis and psoriasis. The aim of this study was to investigate the role of the IL-2-inducible tyrosine kinase (Itk), an enzyme acting downstream of the T-cell receptor (TCR), in T-cell-dependent skin inflammation using three approaches. Itk knockout mice display significantly reduced inflammatory symptoms in mouse models of acute and subacute contact hypersensitivity (CHS) reactions. Systemic administration of a novel small molecule Itk inhibitor, Compound 44, created by chemical optimization of an initial high-throughput screening hit, inhibited Itk's activity with an IC50 in the nanomolar range. Compound 44 substantially reduced proinflammatory immune responses in vitro and in vivo after systemic administration in two acute CHS models. In addition, our data reveal that human Itk, comparable to its murine homologue, is expressed mainly in T cells and is increased in lesional skin from patients with atopic dermatitis and allergic contact dermatitis. Finally, silencing of Itk by RNA interference in primary human T cells efficiently blocks TCR-induced lymphokine secretion. In conclusion, Itk represents an interesting new target for the therapy of T-cell-mediated inflammatory skin diseases.

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Einleitung ! Die Harninkontinenz ist eine Erkrankung, die mittlerweile 30 % der über 60-Jährigen betrifft [1]; von diesen wird in über 70% der Fälle eine Belastungsinkontinenz diagnostiziert. In der operativen Therapie hat insbesondere die Einlage von spannungsfreien suburethralen Schlingen an Popularität gewonnen und invasive Methoden wie die Kolposuspension verdrängt. So ist die Operation des Tension-free Vaginal Tape (TVT) nach Ulmsten [2] zu einer der weltweit häufigs-ten Inkontinenzoperationen geworden. Neben der retropubischen Bandeinlage wie bei dem klassischen TVT scheint sich ebenfalls der transobturatorische Zugang (TVT-O) nach Delorme [3] oder De Leval [4] mit möglicherweise komplikationsärmeren Verläufen zu bewähren [5 -8]. In diesem Fallbericht beschreiben wir nun die Kombination beider Verfahren in einer Patientin zur Einlage eines suburethralen Bandes bei besonders schwierigen anatomischen und klinischen Bedingungen. Fallbericht ! Eine 68-jährige multimorbide Patientin mit Adipositas per magna (BMI 42) und ausgedehntem Intertrigo submammär, inguinal und suprapubisch stellte sich bei rezidivierender Belastungsinkontinenz vor. Die urodynamischen Untersuchungen zeigten eine hyperkapazitive, hyposensible, normotone, normokontraktile Harnblase mit hypotoner Urethra und normalen Uroflow. Die Patientin hatte drei Monate zuvor eine Blasenhalsinjektion von 2 ml Tegress (Ethinylvinylalkohol) erhalten, wonach sich keine Verbesserung der Inkontinenz zeigte. Eine Therapie mit Duloxetin oder mittels eines Pessars lehnte die Zusammenfassung !Wir berichten über eine 68-jährige multimorbide Patientin, welche sich bei rezidivierender Belastungsinkontinenz zur Einlage eines suburethralen Bandes vorstellte. Aufgrund einer Adipositas per magna und einem suprapubisch stark ausgeprägten Intertrigo, entschloss man sich für den transobturatorischen Zugang. Hierbei konnte der linke Schenkel wie gewöhnlich implantiert werden; auf der anderen Seite allerdings verhinderte eine Exostose des Ramus inferior ossis pubis die reguläre Bandeinlage, sodass man das rechte Band suprasymphysär legen musste. Postoperativ zeigte sich die Patientin sowohl objektiv als auch subjektiv kontinent. Dieser Fall zeigt, dass eine kombinierte TVT-O mit TVT in klinisch schwierigen Situationen angewendet werden kann, um eine Belastungsinkontinenz erfolgreich zu therapieren. Abstract !We report a case of a 68-year-old multimorbid woman with recurrent urodynamic stress incontinence who was planned for a suburethral sling. Due to obesity and suprapubic intertrigo we chose to implant a TVT-O sling. Intraoperatively the left transobturator needle passed easily through the obturator foramen. The right needle, however, could not be rotated under the pubic ramus for reasons which were initially unclear. This forced us to position the right side of the sling retropubically. Postoperatively pelvic X-ray confirmed an exostosis and the patient was subjectively and objectively continent at six weeks' follow-up. In conclusion a combined TVT and TVT-O application ca...