CD20 antibody (C2B8)-induced apoptosis of lymphoma cells promotes phagocytosis by dendritic cells and cross-priming of CD8+ cytotoxic T cells.

C2B8 (Rituximab, MabThera) is a chimeric mouse/human monoclonal antibody (mAb) directed against the human B cell-restricted cell surface antigen CD20 which is used as an alternative medication in the treatment of B cell non-Hodgkin lymphomas (NHL). Treatment of CD20+ B cells with C2B8 triggers different cell damaging effects including complement-dependent lysis of tumor cells, antibody-dependent cellular cytotoxicity and induction of apoptosis. Dendritic cells (DC) have recently been shown to ingest cell debris and to present associated antigens even on MHC class I molecules, a mechanism called cross-presentation. In this study, we investigated whether C2B8 treatment of lymphoma promotes the induction of CD8+ T cell responses against lymphoma cell-associated antigens via, cross-presentation. We used Daudi lymphoma cells as a model system in our studies and could demonstrate, that C2B8-treated Daudi cells undergo apoptosis, are phagocytosed by DC and induce in DC typical features of maturation; among them, the induction of CD83 expression as well as the up-regulation of prominent accessory molecules (CD40, CD86) and MHC molecules. Importantly, upon co-culture of such lymphoma cell-pulsed DC with autologous T cells, we could induce efficient cytotoxic T cell (CTL) responses against Daudi cell-associated antigens. These findings suggest that antibody treatment of tumor cells can, in addition to its direct cell damaging effects, under certain conditions, contribute to an induction of potentially protective cytotoxic T cell responses.

Hemodynamic effects of continuous urodilatin infusion: a dose-finding study.

OBJECTIVE: To evaluate the effects of urodilatin (INN, ularitide) on systemic and renal hemodynamic parameters. METHODS: Twenty healthy male subjects were included in this double-blind, randomized placebo-controlled trial and assigned to receive either continuous intravenous infusion of different doses of 7.5, 15, or 22.5 ng/kg body weight/min urodilatin or placebo over 300 minutes. Cardiac performance, systolic time intervals, and airway function were measured noninvasively. The effects on renal hemodynamic values were assessed with para-aminohippurate and inulin clearance techniques. RESULTS: Urodilatin was well tolerated by all subjects at doses of 7.5 and 15 ng/kg/min. Infusion was stopped prematurely for the group that received 22.5 ng/kg/min urodilatin group because of systemic hypotensive responses with nausea and dizziness. Infusion of 15 ng/kg/min urodilatin significantly increased urine flow by a maximum of 165%, filtration fraction by 46%, renal resistance by 49%, and systemic vascular resistance by 45%. It decreased renal plasma flow by a maximum of 31% from baseline value. No change in cardiac inotropic function was detectable, but cardiac output decreased in all dose groups. Effects on glomerular filtration rate, forced expiratory volume, blood pressure, and pulse were not different from those with placebo. CONCLUSION: Continuous infusion of 7.5 ng/kg/min and 15 ng/kg/min urodilatin exerts a significant increase in systemic and renal vascular resistance. Results of our experiments suggested that the therapeutic window for continuous urodilatin infusion is small and that doses higher than approximately 20 ng/kg/min urodilatin carry high risk for adverse drug reactions.

Systemic and renal effects of an ET(A) receptor subtype-specific antagonist in healthy subjects.

1. Endothelins (ETs) might play a pathophysiological role in a variety of vascular diseases. The aim of the present study was to characterize the effects of BQ-123, a specific ET(A) receptor antagonist on systemic and renal haemodynamics in healthy subjects. This was done at baseline and during infusion of exogenous ET-1. 2. The study was performed in a balanced, randomized, placebo-controlled, double blind 4 way cross-over design in 10 healthy male subjects. Subjects received co-infusions of ET-1 (2.5 ng kg(-1) min(-1) for 120 min) or placebo and BQ-123 (15 microg min(-1) for 60 min and subsequently 60 microg min(-1) for 60 min) or placebo. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were assessed by the para-aminohippurate (PAH) and the inulin plasma clearance method, respectively. 3. BQ-123 alone had no renal or systemic haemodynamic effect. ET-1 significantly reduced RPF (-24%, P<0.001) and GFR (-12%, P=0.034). These effects were abolished by co-infusion of either dose of BQ-123 (RPF: P=0.0012; GFR: P=0.020). 4. BQ-123 reversed the renal haemodynamic effects induced by exogenous ET-1 in vivo. This indicates that vasoconstriction in the kidney provoked by ET-1 is predominantly mediated by the ET(A) receptor subtype.