Published ahead of print on December 30, 2005, doi:10.1164/rccm.200503-468OC Am. J. Respir. Crit. Care Med., Volume 173, Number 6, March 2006, 599-606 A more recent version of this article appeared on March 15, 2006
Submitted on March 24, 2005 A Novel Low Molecular Weight Inhibitor of Dendritic Cells and B-cells Blocks Allergic InflammationPeter Ettmayer1,1 Department of Autoimmunity and Transplantation, Novartis Institutes for Biomedical Research, Vienna, Austria, 2 Department of Dermatology, Medical University of Vienna, Basel, Switzerland, 3 Department of Autoimmunity and Transplantation, Novartis Institutes for Biomedical Research, Basel, Switzerland * To whom correspondence should be addressed. E-mail: maximilian.woisetschlaeger{at}novartis.com.
Rationale and Objective: During allergic lung inflammation dendritic cells (DC) direct the generation and function of effector T-helper type 2 (Th2) cells. Th2 cells not only orchestrate the inflammatory processes in the tissue by inducing the accumulation and activation of pro-inflammatory cells but also induce IgE production by B-cells. Thus, inhibitors of DC function should have therapeutic benefits in allergic patients. Methods, Measurements: VAF347, a novel low molecular weight immuno-modulator is described which acts as anti-inflammatory compound due to a dual mode of action. Results: VAF347 inhibited the function of human monocyte derived dendritic cells (DC) to induce T-cell proliferation and cytokine production. Mechanistically, this effect may be due to reduced expression of CD86, HLA-DR and IL-6 by DC. In addition, the compound inhibited IgE synthesis in an isotype specific fashion by human B-lymphocytes. In a mouse model of antigen-induced eosinophilic inflammation, VAF347 blocked lung eosinophilia, mucus hyperplasia and serum IgE levels, representing the hallmarks of allergic lung inflammation. The biological effects in vivo are most likely mediated by the immuno-regulatory role of VAF347 on DC since allergic lung inflammation was also inhibited in B-cell deficient mice. Conclusion: Thus, VAF347 represents a novel type of immuno-modulator by affecting two major pathways in allergic airway pathogenesis: dendritic cell mediated Th cell activation and induction of IgE production by human B-lymphocytes. Key words: asthma, immunobiology, pharmacology
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