The development of effective vaccines for people with compromised immune systems may be feasible after all, according to a team of researchers, who demonstrated their approach could protect against pneumocystis pneumonia in mice lacking the same population of immune cells that HIV destroys in humans. The vaccine platform developed by Children's Hospital of Pittsburgh researchers, working in collaboration with researchers from the University of Pittsburgh and Louisiana State University, suggests that the immune system can be primed to ward off other infections as well, such as those caused by the flu, smallpox or exposure to anthrax, even in patients who have the highest risk for infection.
Reporting in the Journal of Clinical Investigation, Jay K. Kolls, MD, division chief of Pediatric Pulmonology, Laboratory of Lung Immunology and Host Defense at Children's Hospital of Pittsburgh, and professor of Pediatrics and Immunology at the University of Pittsburgh School of Medicine, and co-authors describe how their vaccine consisting of a specific antigen to pneumocystis and a molecule normally expressed on activated T-cells of the immune system offers protection from infection even in the absence of essential immune cells.
Pneumocystis is a common and very serious infection in people with deficient function of CD4+ T-cells, such as patients with transplanted organs, HIV and children with leukemia. Without normal reservoirs of these particular T-cells that are key to immune responses, these patients are unable to stave off an infection that in most people causes, at most, a bad cold.
The findings are being published in the December 1 issue of the journal. The manuscript will be available online after 5 p.m. Nov. 23, 2005, at www.jci.org.
"In addition to protection against pneumocystis, our vaccine platform may be effective in preventing viral illnesses such as influenza, in high-risk, immune-deficient individuals," Dr. Kolls said. "This new technology opens up the possibility that therapeutic vaccine response can be achieved in populations of patients who face the greatest risk -- children, the immunosuppressed and the elderly.
Although not discussed in the paper, Dr. Kolls says the vaccine approach is worth investigating its potential for offering protection against weaponized agents, such as anthrax.
In mice depleted of CD4+ T cells, which are essential for signaling other cells and for producing antigen-specific antibodies, the vaccine strategy provided protection against pneumocystis. Importantly, this vaccine strategy was able to bypass the need for T cells.
A series of experiments helped identify the two key components of the experimental DNA vaccine, so called because it has only the molecular signatures of these constructs: the molecule used by activated CD4+ T cells to signal production of antibodies, and importantly, the specific fragment of pneumocystis that receptors on these antibodies recognize.
The researchers first identified as key CD40L, a molecule expressed on activated CD4+ T cells that in turn signals other cells, including B cells, to produce antibodies against the pathogen. But antibodies rely on other cells, such as dendritic cells, to capture the antigen and advertise their bounty, which they do by displaying an antigen fragment on their cell surface. Antibodies see this antigen fragment as a mug shot of sorts, and when they recognize the same fragment expressed on the on the infecting organism the antibodies give phagocytic cells the OK to consume, or eliminate, the pathogen. Through their studies, the researchers discovered a particularly potent fragment of pneumocystis, the kexin molecule, which when isolated yielded greater antibody response than pneumocystis as a whole.
In perhaps the most significant experiments the researchers conducted, mice depleted of CD4+ T cells received the combination CD40L-kexin vaccine in three doses administered three weeks apart. Three weeks later, they were infected with pneumocystis. Upon examination, the vaccinated mice had significantly less organism in their lungs. According to the researchers, nearly 100 percent (999.999 percent) of the invading pneumocystis was thwarted by the vaccine-induced antibody-mediated process, compared to about 20 percent in animals that had not been vaccinated.
The number of people with compromised immune systems continues to rise, a population that cannot be protected against polio, the flu and other infectious agents with existing vaccines that depend on a normal T-cell response. As such, the researchers were motivated to develop CD4+ T-cell-independent therapeutic strategies to meet this growing need.
"While we'll need to replicate these findings in larger animal models, our studies indicate it may be feasible to develop vaccines for bioterrorism agents and transplant patients, as well as high-risk individuals who have defective CD4+ T-cell function," Dr. Kolls said. "We are excited about the results because they indicate that we can engineer a vaccine to create a new protection for those who are immunosuppressed."
In addition to Dr. Kolls, other authors include Mingquan Zheng, M.D.; Chad Steele, Ph.D., and Florencia McAllister, M.D., all of Children's Hospital and the department of pediatrics, University of Pittsburgh School of Medicine; Corrine Kliment, Christopher Crowe and Rekha R. Rapaka, University of Pittsburgh School of Medicine M.D.-Ph.D. students; Karen A. Norris, Ph.D., department of immunology, University of Pittsburgh School of Medicine; and Alistair J. Ramsey, Ph.D.; Myles B. Robichaux, M.S., Judd E. Shellito, M.D., and Paul Schwarzenberger, M.D., from Louisiana State University.
The National Heart, Lung, and Blood Institute of the National Institutes of Health supported the research.
For more information about Children's Hospital of Pittsburgh, Dr. Kolls or Children's Pulmonology program, please visit the Children's online press room at www.chp.edu.
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