Combined activation of innate and T cell immunity for recognizing immunomodulatory properties of therapeutic agents

Complex syndromes such as atherosclerosis and type 2 diabetes are disorders that are associated with inflammatory processes involving innate and adaptive immunity. Emerging knowledge about the pathological consequences of immune imbalances in a wide range of disease settings is expected to help to identify novel therapeutic targets. However, current test systems for immunomodulatory drugs tend to be too simplistic, as they rely only on cells of the innate- or the adaptive-immune system, or they are complex, in vivo models, which are not suitable for screening purposes. Using a modified mixed lymphocyte culture (MMLC) assay for combined analysis of innate and adaptive immunity, we show that this assay is very sensitive for the presence of low concentrations of immunomodulatory agents. Low-dose lipopolysaccharide stimulation of cells from two unrelated donors yields a strong cytokine response including interleukin (IL)-12 and IL-18, which induce interferon-gamma as a potential analysis parameter. As the MMLC assay is based on the mutual interaction of cells of the innate and adaptive immunity, it enables the monitoring of cytokine release under almost physiological conditions and might be of interest for the characterization of known and novel drugs concerning their immunomodulatory potency.