As an infection progresses, the body's arsenal for fighting it changes.

The body's first batter up is the innate immune system, which is fast but fairly nonspecific. The adaptive immune system, which is more specific but takes time to gear up, comes later in the game.

But while the body's response team changes during the course of an infection, some of the players don't. One cell type involved in both the innate and the adaptive immune response is the plasmacytoid dendritic cell. And in the July 24, 2006, issue of Journal of Experimental Medicine, scientists from Berkeley, Calif.-based Dynavax Inc. and the University of Michigan at Ann Arbor have published a study teasing apart the factors that control whether a plasmacytoid dendritic cell precursor will take part in the innate immune response, producing interferon alpha, or mature into a dendritic cell and activate T cells as part of adaptive immunity.

The research team used a group of oligonucleotides, known as CpGs, that contain immunostimulatory sequences and can be used to boost the immune response in infectious diseases, as well as cancer.

CpGs come in three groups, but to date "the most advanced clinical CpGs are class B," senior author Franck Barrat, associate director, inflammation and autoimmunity at Dynavax, told BioWorld Today. This is more of a practical issue than anything else - "Class A might be useful, but they form these large aggregates, which is a manufacturing challenge," he said.

Class Cs, in turn, are a recent discovery that may well be headed for the clinic; they are double-stranded molecules with a palindromic sequence that can induce both interferon production and dendritic cell precursor maturation.

CpGs activate TLR-9, the Toll-like receptor which is responsible for much of the immune system response to viral DNA. Toll-like receptors currently are something like the prom queens of drug development, being hotly pursued by Dynavax as well as a number of other biotechs in various indications. Dynavax has CpGs in clinical trials for hepatitis B, allergies, cancer and asthma. With more than $100 million, its competitor Coley Pharmaceutical Group Inc., of Wellesley, Mass., pulled off the second-biggest biotech IPO of 2005. (See BioWorld Today, Aug. 11, 2005, and Sept. 16, 2005.)

Unlike most other Toll-like receptors, TLR-9 is not found on the surface of cells; instead, it is located in endosomes, the cellular transport system that can be abused by some viruses to gain entry. The reason TLR-9, as well as three other Toll-like receptors, is inside endosomes rather than on the cell surface is to prevent autoimmune reactions.

"A lipid is a lipid, and a little piece of DNA is a little piece of DNA," Barrat explained. "So how does the system know whether it's coming from a virus or from a dying cell in your own body? TLRs trapped inside endosomes cannot see your own DNA."

Using cell cultures, the scientists tested all three classes of CpGs and found that the fate of precursor cells depended on where in the endosome the CpG interacted with TLR-9. The aggregate forming class A CpGs were found mainly in the early endosome; activation of TLR-9 in those endosomes led mainly to production of interferon-alpha. CpG-B usually progressed further along the endosomal pathway and promoted the maturation of the precursor cells into potent dendritic cells.

However, anatomy played a greater role in which response was induced, rather than technical membership in class A or B. When Barrat and his colleagues induced class B CpGs to form aggregates, they, too, tended to stay in the early endosome, and when they did, they stimulated the production of interferon-alpha. CpG-C sequences, which induce both IFN-alpha and cell maturation, are distributed in both types of endosomes.

The researchers concluded that the endosomal localization of CpGs, and hence their biological effects, "are a function of the physical form of the molecule, not directly a function of the sequence motifs or backbone chemistry of the molecule. Sequence and backbone are important, however, as both factors influence the equilibrium between simple and higher-order structures."