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IMMUNOLOGY Priming Cellular Pathway May Lead To New AIDS and Cancer Vaccines Dendritic Cells Could Be Turned Toward Smarter T Cell Activation In their quest to develop vaccines against two scourges of the 21st century, AIDS and cancer, researchers have been turning to a once obscure immune population, the dendritic cells. These octopus-shaped cells, which lurk in blood and tissue, are among the hardest working in the immune system. Equipped with pseudopodia, they not only root out pathogenic material but also travel to the lymph nodes, where they recruit and educate immature T cells to attack the antigens they have nabbed. Using its diaphanous pseudopodia, a dendritic cell makes contact with a T cell (inset, lower right). This event, and many of the steps that lead to it, are made possible by the activation of the CD2 receptor. (Image courtesy of Keith Crawford) Now HMS researchers have made a discovery that could turn these multi-tasking immune cells into even more effective vaccine agents against AIDS and cancer. Keith Crawford, Chester Alper, and their colleagues have found a set of signals that activates dendritic cells to perform their antigen- and T cell-scouting duties. By priming this pathway, it may be possible to create a set of dendritic cells that when introduced into patients could more effectively rouse their T cells to attack disease agents such as HIV or cancer cells. The findings appear in the April 24 online Blood and in an upcoming print version of the journal. "We could take dendritic cells out of a patient, give them the appropriate antigen, put them back in, and they will know where to go." --Keith Crawford "So we could take dendritic cells out of a patient, give them the appropriate antigen, put them back in, and they will know where to go," said Crawford, HMS research fellow in pediatrics at the Center for Blood Research. Alper is an HMS professor of pediatrics at the CBR. "We could tweak them a bit, activate them so they have the appropriate receptors on their surface, and they are on their way to the regional lymph tissue, where they would be ready to activate T cells efficiently," Crawford explained. The key to the pathway is the CD2 receptor. The researchers found that activating the receptor resulted in increased expression of molecules for most aspects of the dendritic cell's search-and-recruit mission. "The immune system is incredibly complex, but I try to keep it simple," said Crawford, a surgeon by training. "So I ask myself, 'What would I do if I were a dendritic cell?' Dendritic cells internalize antigen, process it, present it on their surface, and produce pseudopodia that come in contact with T cells." Having created a checklist of dendritic-cell activities, he and colleagues activated the CD2 receptor and looked for expression of molecules known to carry out those activities. Activation of CD2 resulted in expression of the antigen-presenting MHC class II molecules, as well as costimulatory and adhesion molecules. "T cells are continuously moving so dendritic cells need something to slow them down a tad. That's where the adhesion molecules come in," said Crawford. Dendritic cell-based vaccines would be used in combination with chemotherapy and radiation to prevent recurrence of diseases, such as cancer. "We are not trying to compete with chemotherapy. Everything works in concert," said Keith Crawford, right, with Chester Alper. (Photo by Steve Gilbert) There was one more requirement. To find T cells, dendritic cells must leave tissue and blood and travel to the lymph nodes, a task carried out by means of chemokine receptors. "I asked myself, 'Is there a key chemokine receptor that is upregulated?'" As it turned out, the chemokine receptor CCR7 was somewhat upregulated with CD2 activation. The findings are timely. Dendritic cell vaccines are being developed against cancer and are even in clinical trials at the Dana-Farber Cancer Institute and elsewhere. Though preliminary results appear promising, many vaccine attempts have been hampered by two problems. Dendritic cells are relatively rare and, indeed, researchers have had to resort to an artificial method for increasing their ranks, essentially using chemicals to prod them to develop from a pool of monocytes. The result can be a mixed bag of dendritic cells and their monocyte precursors, which makes for a much less effective reagent. In fact, patients must be given a cocktail of chemokines that prime the T cells to respond to the dendritic cell vaccine, which can often produce widespread inflammation in the body. The discovery that the CD2 pathway is responsible for many of a dendritic cell's activities helps get around these problems. To begin, the CD2 receptor could be used to distinguish dendritic cells from monocytes, which express only low levels of the molecule. In fact, Crawford, Alper, and their colleagues have developed such a method for isolating dendritic cells, which has been patented by the CBR. Second, by activating CD2 on dendritic cells before reintroducing them into patients, researchers could create more effective vaccines without the need for inflammation-producing chemokines. "So you get a pure population in an activated state, with the added advantage that it does not require total body exposure to a chemical compound," said Crawford. --Misia Landau