Efficacy and safety of a new intravenous immunoglobulin (Panzyga® ) in chronic immune thrombocytopenia.

OBJECTIVES: To assess the efficacy and safety of intravenous immunoglobulin (IVIG) 10% (Panzyga® ), a novel human normal IVIG 10%, in patients with chronic immune thrombocytopenia (ITP). BACKGROUND: First-line treatment options in ITP include IVIGs. METHODS: In this prospective, open-label, non-controlled, multicentre, phase III study, patients received a daily dose of IVIG 10% (1 g kg-1 body weight) for two consecutive days. The primary end point was clinical response rate; secondary end points included alternate response definitions, time to response, response duration, platelet counts, regression of bleeding and safety. RESULTS: Forty patients were enrolled (57·5% male, mean age 36·7 years); the full analysis set comprised 36 patients. A clinical response was seen for 29 of 36 patients (80·6%). Median time to response and response duration was 2 days and 14 days, respectively. IVIG 10% was well tolerated at a maximum infusion rate of 8 mg (kg min)-1 in all but one patient; adverse events were mainly mild to moderate in severity, and the most frequent was headache (42·5%). CONCLUSION: IVIG 10% is well tolerated even at a high infusion speed and induces a rapid platelet count increase, thus decreasing the bleeding rate and the severity of bleeding events. TRIAL REGISTRY: ClinicalTrials.gov record: NCT01349790.

Experimental regulation of STAT gene expression reveals an involvement of STAT5 in interleukin-4-driven cell proliferation.

The precise roles of signal transducers and activators of transcription (STATs) in cytokine-triggered control of cell physiology are not sufficiently well understood. We have established cell lines in which the individual functional contributions of STAT6 and STAT5a/b to interleukin-(IL-) 3 and -4-dependent processes can be readily studied. Mutants of STAT6, STAT5a and 5b lacking the transcriptional transactivation domain were fused to the green fluorescent protein (GFP) and expressed in the murine pro-B cell line Ba/F3 in a regulatable fashion. The expression of these truncated STAT variants could be tightly controlled over a wide range by doxycycline in the medium. They specifically bound to cognate DNA elements upon cytokine stimulation and acted dominant-negatively on the transcription of respective reporter genes in response to IL-3 and -4. The system was applied to the question of STAT contributions to cytokine-dependent cell proliferation. Expression of dominant-negative STAT6 had no significant effect on cell growth in response to both IL-3 and IL-4. In contrast, truncated STAT5 interfered with cell proliferation in response to IL-3, and, interestingly, also to IL-4. The results support our earlier findings on a role of STAT5 in IL-4-induced intracellular signaling and indicate that STAT5b in particular is involved in IL-4 receptor-triggered control of cell proliferation.

A two-step selection approach for the identification of ligand-binding determinants in cytokine receptors.

We have developed a novel cell-based method for the isolation and selection of mutant cytokine receptors with defects in ligand binding and applied it to the human interleukin-4 receptor. The experimental procedure is based upon the functional heterologous expression of receptor mutants in eukaryotic cells followed by a two-step selection procedure. Positive selection for cells that express receptor variants is achieved by means of an agonistic antibody that mediates cell survival through receptor dimerization. An IL-4-coupled toxin is subsequently used to select against cells expressing wild-type receptors. Cells expressing mutant receptors that are unable to bind the cytotoxic ligand survive and can be amplified. The procedure allows the isolation of rare receptor variants from cell pools containing predominantly wild-type cells. This method, which should be equally applicable to similar receptor systems, was used to demonstrate the importance of a critical charged amino acid residue in the human IL-4 receptor alpha-subunit for IL-4-induced receptor activation.