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T cells activated to fight HIV basis for dendritic cell therapeutic vaccine
August 14, 2006Having their immune system cells go through a laboratory version of boot camp may help patients win their battle against HIV, believe University of Pittsburgh researchers. In essence, that's the concept behind the development of a novel therapeutic vaccine loaded with a patient's own souped up dendritic cells, which have been galvanized to rally other cells of the immune system in fighting the virus unique to that individual.
At the XVI International AIDS Conference (AIDS 2006), University of Pittsburgh researchers will describe one of the steps that is key to the approach's success - modifying the dendritic cells in such a way that they will get the attention of killer T cells. Results of these studies will be incorporated into the protocol for a clinical trial of the vaccine, which is expected to begin later this year.
"The goal of the approach is to teach killer T cells to more efficiently find, detect and destroy HIV infected cells. Our vaccine, as an immunotherapy, is custom-designed to target the unique virus that has evolved in each individual being treated. A patient's own dendritic cells together with their unique viral antigens comprise the main elements of the vaccine," said Charles R. Rinaldo, Jr., Ph.D., professor and chairman of the department of infectious diseases and microbiology at Pitt's Graduate School of Public Health (GSPH) and the study's senior author.
In particular, the approach aims to activate a type of T cell called a CD8, or cytotoxic, T cell, also known as a killer T cell. In a typical immune response, CD8 cells are called to action by dendritic cells. Persons infected with HIV and being treated with antiretroviral drugs can control but not eliminate HIV infection. If the drug therapy is discontinued, the virus comes roaring back. Dr. Rinaldo and others have hypothesized that this is because the drug therapy does not completely restore CD8 cell immunity to the virus. So, in trying to figure a way to activate the CD8 cells to more efficiently control HIV, the researchers focused on a molecule called interleuken-12 (IL-12). When dendritic cells recognize and capture viral antigens, they work together with CD4 T cells to release IL-12, which in turn triggers stimulation of killer CD8 cells that are specific to the virus.
Reporting at AIDS 2006, Xiao-Li Huang, M.D., research assistant professor of infectious diseases and microbiology at GSPH, said that IL-12 could be increased when CD40 ligand, a substance that binds to certain immune cells, and interferon gamma were added to dendritic cells.
In the study, white blood cells called monocytes were obtained from both HIV patients and individuals not infected with the virus. In the laboratory, the researchers coaxed them to differentiate into mature dendritic cells, and they were grown in culture with the addition of various substances to boost their potency. Separately, the researchers combined a small amount of the patient's HIV with their CD4 cells, in order to "super infect" them. In these now super-infected cells, the researchers inactivated the virus by promoting a process called apoptosis, or programmed cell death. In their dying state and with trace amounts of viral antigen still present, these CD4 cells were placed in culture with the beefed up dendritic cells. Recognizing the cells as foreign, the dendritic cells processed the antigen. Importantly, the dendritic cells presenting the HIV fragments were able to stimulate CD8 cells when the two cell types were combined.
"This model of T cell activation by dendritic cells provides a basis for immunotherapy trials of persons with HIV infection," said Dr. Huang.
The trial should be enrolling patients within the year, pending approval by the U.S. Food and Drug Administration. The researchers have already completed a similar trial in 18 patients that proved the approach is safe. In that trial, the vaccine was derived using a readily available HIV protein. Even with this somewhat generic approach, T cell immunity was enhanced.
"Quite likely, it will be a combination of anti-viral drugs and some sort of immunotherapy, such as a therapeutic vaccine, that will be the most effective weapon against HIV," noted Dr. Rinaldo.
University of Pittsburgh Medical Center
In particular, the approach aims to activate a type of T cell called a CD8, or cytotoxic, T cell, also known as a killer T cell. In a typical immune response, CD8 cells are called to action by dendritic cells. Persons infected with HIV and being treated with antiretroviral drugs can control but not eliminate HIV infection. If the drug therapy is discontinued, the virus comes roaring back. Dr. Rinaldo and others have hypothesized that this is because the drug therapy does not completely restore CD8 cell immunity to the virus. So, in trying to figure a way to activate the CD8 cells to more efficiently control HIV, the researchers focused on a molecule called interleuken-12 (IL-12). When dendritic cells recognize and capture viral antigens, they work together with CD4 T cells to release IL-12, which in turn triggers stimulation of killer CD8 cells that are specific to the virus.
Reporting at AIDS 2006, Xiao-Li Huang, M.D., research assistant professor of infectious diseases and microbiology at GSPH, said that IL-12 could be increased when CD40 ligand, a substance that binds to certain immune cells, and interferon gamma were added to dendritic cells.
In the study, white blood cells called monocytes were obtained from both HIV patients and individuals not infected with the virus. In the laboratory, the researchers coaxed them to differentiate into mature dendritic cells, and they were grown in culture with the addition of various substances to boost their potency. Separately, the researchers combined a small amount of the patient's HIV with their CD4 cells, in order to "super infect" them. In these now super-infected cells, the researchers inactivated the virus by promoting a process called apoptosis, or programmed cell death. In their dying state and with trace amounts of viral antigen still present, these CD4 cells were placed in culture with the beefed up dendritic cells. Recognizing the cells as foreign, the dendritic cells processed the antigen. Importantly, the dendritic cells presenting the HIV fragments were able to stimulate CD8 cells when the two cell types were combined.
"This model of T cell activation by dendritic cells provides a basis for immunotherapy trials of persons with HIV infection," said Dr. Huang.
The trial should be enrolling patients within the year, pending approval by the U.S. Food and Drug Administration. The researchers have already completed a similar trial in 18 patients that proved the approach is safe. In that trial, the vaccine was derived using a readily available HIV protein. Even with this somewhat generic approach, T cell immunity was enhanced.
"Quite likely, it will be a combination of anti-viral drugs and some sort of immunotherapy, such as a therapeutic vaccine, that will be the most effective weapon against HIV," noted Dr. Rinaldo.
University of Pittsburgh Medical Center
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