Dendritic cells are responsible for directing the body’s immune response, and they’re activated through receptors on their surfaces. Now, in research that may have implications for novel disease therapies, Rockefeller University scientists have shown that the balance of two different versions of these Fcγ receptors — activating versus inhibitory — appears to affect production of an important set of genes, called interferon-response genes, including one believed to play an important role in autoimmunity and cancer. The researchers believe that manipulating the ratio of these receptors could lead to new therapies for these disorders.
The researchers had previously shown that by blocking some of the inhibitory Fcγ receptors, they could increase the creation of antitumor immune cells. But they didn’t know why. So they compared these Fcγ dendritic cells with others, and found that what makes them different is increased activity of several interferon-response genes. “We know that interferons are very important for immune responses, and that the balance of downstream signaling can enhance immune responses generated by dendritic cells,” says Kavita Dhodapkar, assistant professor of clinical investigation in Ralph Steinman’s Laboratory of Cellular Physiology and Immunology and the study’s first author.
But despite the increased activity of the interferon-response genes, there didn’t appear to be any rise in the production of interferons themselves. Dhodapkar and her colleagues found that this surprising result could be directly attributed to the ratio of Fcγ activating to inhibitory receptors. The researchers believe that they may be able to take advantage of this pathway: downregulating the interferon-response genes in order to treat diseases, such as lupus, in which the immune system has turned on its own body, and upregulating them to enhance immunity against cancer. Ideally, Dhodapkar says, they’d like to create a cancer vaccine that would go straight to the activating Fcγ receptors on dendritic cells and program them to enhance the immune system’s ability to attack cancerous tumors. “We’ve done this in tissue culture,” she says, “but now we need to extend these studies to see if it works in patients.”
Journal reference: Journal of Experimental Medicine 204(6): 1359–1369 (June 2007)
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