Defining the boundaries of a healthy immune response

To define the boundaries of a healthy immune response we combined the use of the TruCulture whole blood culture system with the use of complex stimuli (i.e., whole microbes), or simple stimuli like agonists specific for defined host sensors, clinically employed cytokines and activators of T cell immunity. Our results provide an initial assessment of healthy donor reference values for induced cytokines and chemokines.

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From complex to simple stimuli

Individual heterogeneity in the immune response can have important medical consequences, such as the likelihood to respond to anti-infectious therapy, the efficiency of vaccine administration, or the development of side effects secondary to treatment. To define the boundaries of a “healthy immune response,” or its naturally occurring variability we have defined the protein signatures induced by medically relevant bacteria, fungi and viruses.

During the last two decades host pathways that are engaged by microbial components have been identified and characterized in detail. To tease apart the immune variability linked to single pathways involved in response to microbes, we further developed assay systems to study the response to purified or synthetic ligands (Microbe Associated Molecular Patterns, MAMPs) for the major innate host response pathways, including those triggered by the Toll-like receptors (TLRs), Nod-like receptors (NLRs) and C-type lectin-like receptors (CLRs). Cytokines, induced as part of the immune response, can in turn modulate inflammatory responses via positive and negative feedback loops. To directly evaluate the variable responses following cytokine receptor signaling, we also tested several clinically employed cytokines. Finally, we utilized direct T cell receptor cross-linking (i.e., anti-CD3 + anti-CD28), and super-antigen stimulation as two distinct mechanisms for eliciting T cell activation.