Stimulating Immune Responses

STIMULATING IMMUNE RESPONSES

Some differences in chemical structure between genetic information of pathogenic microorganisms and mammals form a recognition signal for immune activation. Specific receptors exist that recognize pathogenic DNA or RNA that subsequently activate a series of genetic programs. This broad pro-inflam-matory activation can have applications in antiviral, immune activating, vaccine adjuvant, and antitumor applications.

Prokaryotic DNA contains many CpG dinucleo-tide sequences, while mammalian DNA has very few, which are usually methylated. Synthetic ONs contain-ing CpG motifs can mimic prokaryotic DNA, and induce immune responses (Krieg, 2006). The CpG sequence is a strong recognition signal for mamma-lian cells through interaction with Toll-like receptor 9 in the endosomes leading to B-cell proliferation and activation of cells of myeloid lineage (Rothenfusser et al., 2003). CPG 7909 is currently in clinical trials for cancer, while CPG 10101 is developed for hepatitis C virus by Coley Pharmaceutical Group Inc. The difference between the two sequences, which essen-tially share the same mechanism of action is that CPG 10101 appears a more potent inducer of the interferon-a pathway, particularly important to fight viralinfections. The same firm also develops VaxImmune as a support for vaccination protocols, which is based on the same immunostimulatory principle.

In a similar manner, dsRNA can be a predictor of viral infection and Toll-like receptor 3 recognizes dsRNA in the endosomes. In particular, synthetic dsRNA composed of poly-inosinic and poly-cytidylic acids are strong activators (poly-IC). It is clinically tested as poly-ICLC (Hiltonol^TM) by Oncovir Inc., a poly-lysine complexed formulation of poly-IC, to protect the dsRNA from nuclease action. The system is being developed for the treatment of glioma patients with or without supportive chemotherapy.