The ectopeptidases dipeptidyl peptidase IV (DP IV, CD26) and aminopeptidase N (APN, CD13) are known to regulate T cell activation. Since selective inhibitors of DP IV and APN suppress DNA synthesis and cytokine production of stimulated T cells in a TGF-beta1-dependent manner, we tested whether combined application of DP IV and APN inhibitors enhances this immunomodulatory effect. The results show that simultaneous application of DP IV and APN inhibitors significantly suppressed DNA synthesis in mitogen- or anti-CD3-stimulated human T cells in vitro when compared to the use of a single DP IV or APN inhibitor. Moreover, the combined action of DP IV and APN inhibitors markedly increased TGF-beta1 production associated with the observed immunosuppressive effects. In vivo, targeting both DP IV and APN led to a potent treatment of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS). This review summarizes the evidence for the role of both enzymes in T cell activation in vitro and in vivo and provides a rationale for using combined and dual peptidase inhibitors to treat autoimmune diseases like MS.
Transforming growth factor-beta (TGF-beta), a multifunctional, immunosuppressive cytokine, is shown to be present in substantial amounts in commercially available intravenous immunoglobulin (IVIG) preparations. To assess whether TGF-beta isoforms are changed in the plasma of paediatric patients with childhood autoimmune diseases after IVIG infusion, 17 patients who received over a period of 12 months overall 56 IVIG infusions (Endobulin) were enrolled in a study. High levels of TGF-beta1 (16.95 +/- 8.16 ng/ml) as well as TGF-beta2 (62.71 +/- 9.50 ng/ml) were detected in the used 56 IVIG probes. TGF-beta1 and TGF-beta2 plasma concentrations were measured prior and 120 min after IVIG infusions by specific TGF-beta ELISA. Interestingly, significant increased TGF-beta1 and TGF-beta2 plasma levels were found in patients after treatment with IVIG. This data suggest that a TGF-beta-mediated mechanism of action may accompany other molecular effects of IVIG therapy. The amount of the potent anti-inflammatory TGF-beta isoforms within the IVIG preparations may exert a differentiated view regarding the manifold indications of IVIG therapy.
RESSAS) durch Verwendung tensidhaltiger Lösungen schonend stabilisiert werden. Um den Einfluss relevanter Systemgrößen, wie Schaumschichthöhe und pH-Wert, auf die Abscheide-und Stabilisierungseffizienz zu ermitteln, wurde eine Modellblasensäule eingesetzt. Es zeigte sich, dass bereits bei geringen Bauhöhen die Kombination von Transportprozessen in den aufsteigenden Blasen und in der Schaumschicht zur effizienten Abscheidung von Nanopartikeln führt, die durch die zugegebenen Tenside gut stabilisiert werden. Der pH-Wert seinerseits beeinflusst die Eigenschaften des Schaums und darüber auch die Abscheideeffizienz.Organic drug nanoparticles may be stabilized in nanosupensions by Rapid Expansion of Supercritical Solutions into Aqueous Solutions (RESSAS) using surfactant solutions. A model bubble column was used in the present work in order to study the influence of relevant system parameters, such as foam height and pH value, on the deposition and stabilization efficiency. It turned out that, already at low heights, the combination of deposition processes in the rising bubbles and in the foam results in high separation efficiency for nanoparticles, which are well stabilized by the surfactants. The pH value influences the foam properties and consequently the separation efficiency.
Abbildung 4. Zeitliche Entwicklung der C-Konzentration in derFlüssigkeitssäule für verschiedene pH-Werte. Eingezeichnet sind auch der Beginn und das Ende der Partikelzugabe, bei dem nur der Funkengenerator ausgeschaltet wurde, der N 2 -Gasstrom aber weiterlief.Abbildung 5. Entwicklung des Mediandurchmessers der stabilisierten Partikeln in Flüssigkeit (gefüllte Symbole) und Schaum (offene Symbole) für verschiedene pH-Werte für eine Aufsatzhöhe von 10 cm. Eingezeichnet sind auch das Ende der Partikelzugabe sowie die Größe der Ausgangspartikel (Aerosol) und der Primärpartikeln.
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