Infection

MIS416 innate immune induction

Innate immunity is the first line of defense against infection and exploits pathogen molecular pattern recognition receptors common to many micro-organisms to rapidly induce pro-inflammatory and anti-viral cytokines. Specific activators of these pathways are of potential therapeutic benefit against viral infections in both healthy and immunologically-compromised hosts. Several innate immune responses are considered to contribute towards the control of viral infections. These effector mechanisms are multi-faceted and include direct anti-viral activities as well as immunomodulatory effects on infected host immune cells that contribute towards elimination of these cells. Direct anti-viral activity may comprise soluble factors, such as CD8 anti-viral factor (CAF) and IFN-alpha, which have the capacity to directly affect viral transcription. Immunomodulatory/pro-inflammatory cytokines secreted by macrophage and dendritic innate immune cells, such as TNF (in concert with IFN-alpha) can act on virus infected cells, which exhibit increased sensitivity to cell lysis mediated by TNF. Further, cellular mechanisms such as natural killer (NK) cell-mediated killing of virus infected cells comprise another important aspect of innate anti-viral immunity.

MIS416 anti-infective activity

MIS416 has been designed to induce both high levels of IFN-alpha as well as other key pro-inflammatory cytokines that are clinically relevant to the induction of broad spectrum innate anti-viral immunity. Importantly, the simultaneous production of regulatory cytokines such as IL-10, means that MIS416 is able to induce a regulated immune response thereby avoiding hyper-immune stimulation that can be associated with immune-based mono-therapies. All this has been achieved by exploiting the immunostimulatory properties of certain pattern recognition receptor ligands that induce the desired breadth and magnitude of immune responses in a microparticle formulation. This restricts MIS416 uptake to key innate immune cell subsets thus avoiding clinically unacceptable side effects mediated by irrelevant cell types.

In vitro and in vivo data have established the following key anti-infective characteristics of MIS416:

• Induction of a broad range of pro-inflammatory and regulatory cytokines by PBMC
• Direct MIS416 uptake by NK and plasmocytoid dendritic cells
• Potent induction of plasmocytoid dendritic cell IFN-? secretion
• Potent induction of NK IFN-alpha and pro-inflammatory cytokine production following MIS416 uptake
• Induction of NK cytotoxicity
• Induction of soluble factors that inhibit viral (HIV-1) replication
• A substantial depot of MIS416 is formed in the liver following single IV delivery supporting the potential use of MIS416 as a standalone agent for treating Hepatitis via stimulation of liver-associated immune cells such as pDC
• Proof of concept animal study demonstrates MIS416 has anti-viral activity in an Influenza A model

Informational Links:

Innate Immunity Immune Defense against Bacterial Pathogens, from Todar's Online textbook, 2008