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April 1, 2010

Research Notes

Treg may inhibit HIV vaccine response

Regulatory T cells (Treg) may be limiting the effectiveness of HIV vaccines by slowing the immune system response too soon, report Pitt health sciences researchers in the current issue of PLoS ONE.

Their study, which looks at the role of regulatory T cells in therapeutic HIV vaccines, may help researchers improve the efficacy of such vaccines by devising ways to circumvent the braking mechanism of these cells.

Treg prevents the immune system from turning against itself by suppressing the immune response. Without Treg’s action, autoimmune disease could flourish.

But what if these cells are shutting down the immune response before a therapeutic vaccine has had a chance to bolster immunity against HIV? Pitt researchers sought to answer this question as follow-up to a clinical trial of a therapeutic dendritic cell-based HIV vaccine they developed to activate the CD8, or killer T cell, response. First reported in 2008, their findings indicated only limited success of the vaccine in the 17 patients enrolled in the trial.

For the current study, the researchers went back to the freezer, removed Treg from the patients’ blood cell samples and found it was masking a two-fold increase in immune response to HIV induced by the vaccine.

Senior author Charles R. Rinaldo Jr., chair of the Department of Infectious Diseases and Microbiology in the Graduate School of Public Health, said: “When we removed Treg from blood cells, we found a much stronger immune response to the vaccine, giving us insight into how we can develop more effective HIV vaccines. Treg normally shuts down CD8 responses once the infection has been controlled, but in this case it appears to be putting on the brakes early and possibly limiting the vaccine’s ability to do its job effectively.”

One theory is that HIV-infection drives up Treg, which in turn shuts down the HIV-1-specific CD8 T cell response, he said.

Bernard J.C. Macatangay, assistant director of Pitt’s Immunology Specialty Laboratory and the study’s lead author, said, “We know how to treat HIV, but are still learning how to use immunotherapy strategies to completely flush it out of the body. Our findings show Treg plays an important role, but we need to figure out how to maintain the right balance by getting around these cells without blocking them completely.”

Other Pitt authors of the study included Marta E. Szajnik and Theresa Whiteside of the University of Pittsburgh Cancer Institute and Sharon Riddler of medicine. The research was supported by the National Institute of Allergy and Infectious Diseases. The paper can be found at

Vaccine for IBD tested

An experimental vaccine against an abnormal protein found in some tumors has the potential to delay the onset of inflammatory bowel disease (IBD) and in turn prevent progression to colon cancer, according to School of Medicine researchers. Their findings are reported in Cancer Prevention Research, a journal of the American Association for Cancer Research.

People with chronic inflammatory disorders such as IBD are at greater risk for developing cancer at the inflamed site, said senior author Olivera Finn, chair of the Department of Immunology.

In other cases, genes that develop cancerous changes can trigger inflammation. The vaccine made by Finn’s team is directed against an abnormal variant of a self-made cell protein called MUC1, which is altered and produced in excess both in IBD and colon cancer.

“Our experiments indicate that boosting the immune response against this protein early in the disease can delay IBD development, control inflammation and thereby reduce the risk of future cancers,” Finn said. “These findings suggest also that the early stages of chronic inflammation might be considered a premalignant condition.”

The researchers tested transgenic mice that spontaneously develop IBD and then progress to colitis-associated colon cancer, producing the human version of MUC1 in both disease states. They found that animals that received the vaccine showed the first signs of IBD significantly later than those in two control groups that did not get the vaccine.

Microscopic evaluation of the colon tissue showed less inflammation in the vaccinated mice  and no indication of cancerous changes. Nearly half of the animals in each of the control groups had evidence of abnormal tissue, and two had colon cancer.

“The MUC1 vaccine seems to change the local environment from one that promotes cancer development to one that inhibits it,” Finn said. “Certain immune cells that we usually see in the inflamed colon aren’t present, and that could make the surroundings less friendly for potentially cancerous cells that also are directly targeted by the vaccine for destruction.”

This study suggests that in the future the vaccine might be considered as part of the therapeutic regimen for IBD as well. The experimental vaccine has been studied in patients with colon and pancreatic cancer and currently is being tested as a prevention measure in patients who have a high risk for developing colon cancer.

Other Pitt authors of the paper included lead author Pamela L. Beatty of immunology and co-author Sarangarajan Ranganathan, a faculty member in the Department of Pathology and a Children’s Hospital clinician.

The study was funded by the National Cancer Institute and the Cancer Prevention Foundation.

BRCA1 impacts IP chemo success

Ovarian cancer patients with lower levels of BRCA1 protein expression are more likely to benefit from chemotherapy delivered directly into the abdomen, or intraperitoneal (IP) chemotherapy, than are patients with high levels of BRCA1 expression.

A study presented recently at the Society of Gynecologic Oncologists annual meeting analyzed 393 ovarian cancer patients who previously participated in a phase 3 clinical trial that compared the effectiveness of traditional chemotherapy delivery to IP chemotherapy.

According to the results, patients with low expression of the BRCA1 protein were more likely to respond well to IP chemotherapy than those with high expression.

BRCA1 is a gene associated with higher rates of breast and ovarian cancers in women, and other cancers for both genders.

The research was conducted by Jamie Lesnock, a fellow in the Division of Gynecologic Oncology at Magee-Womens Hospital, under the direction of Thomas C. Krivak of the Department of Obstetrics, Gynecology and Reproductive Sciences, in conjunction with the nonprofit Gynecologic Oncology Group.

“This is potentially another small step toward personalized treatment for ovarian cancer,” said Krivak.

Because IP chemotherapy can be so rigorous, identifying the patient population most likely to benefit from it is important, Lesnock said.

“Ovarian cancer has few symptoms in its early stages, and because of this patients often are diagnosed after the disease has already spread,” said Lesnock. “Currently, we know that patients respond in very different ways to chemotherapy. If we can know ahead of time whether or not a patient will benefit from IP chemotherapy, it could help us improve outcomes.”

3-D online ads may not raise sales

Consumers may be drawn in by 3-D ads online, but such animations don’t necessarily raise their intent to buy, reports Pitt-Bradford computer information systems faculty member Y. Ken Wang in a paper published in the conference proceedings of the Americas Conference on Information Systems.

“As more and more companies start to use 3-D animated ads to present and promote their products on the Internet, there is a need to understand how certain characteristics of 3-D interface influence consumers’ attitudes toward the product and the company,” Wang said.

“Our research provided evidence that 3-D rich media may effectively attract consumers’ attention, but may not necessarily increase consumers’ intention to make a purchase. Consumers are more willing to purchase if the online interface allows a certain level of interactions with the products.”

Women’s health research funded

The Schools of the Health Sciences recently announced two grant awards:

Anda Vlad received an Early Career Development Award funded by the Ovarian Cancer Academy of the Department of Defense. The five-year, $840,000 grant will fund Vlad’s investigation of tumor-promoting genetic mutations and testing of novel ovarian cancer therapies.

Jacob Larkin, a maternal fetal medicine fellow in the Department of Obstetrics, Gynecology and Reproductive Sciences, received a three-year, $300,000 award, jointly sponsored by the American Association of Obstetricians and Gynecologists Foundation and the Society for Maternal-Fetal Medicine, to support his research on placental response to injury.

Suicidal, depressed elderly studied

Being too focused on the present and not factoring experience into decisions could contribute to suicide attempts in elderly depressed adults, according to a study by School of Medicine and University of Cambridge researchers published recently in the American Journal of Psychiatry.

Using a computerized test of the ability to change behavior based on positive and negative feedback, researchers found that those who had attempted suicide performed poorly.

Study lead author Alexandre Y. Dombrovski, a faculty member in Pitt’s Department of Psychiatry, said, “This is an important step forward in understanding why some people with depression take their own lives while others do not.”

While two-thirds of older adults who attempt suicide suffer from depression, the severity of the depression alone does not explain suicidal behavior. Identifying factors that are specific to suicidal behavior could help predict which individuals are most at risk.

The researchers assessed 65 individuals, age 60 and older, using a computerized test that requires the individuals to make the best possible choices in an uncertain and changing environment.

The task is made difficult by including occasional misleading feedback, where the participants are told that they are wrong after a correct response, and by changing the rule midway through the task. The study included participants who had attempted suicide, as well as those who were depressed and had contemplated suicide but hadn’t attempted it; who were depressed but not suicidal, and who were neither depressed nor suicidal.

The researchers found that most of the participants who had attempted suicide were able to learn the initial choice rule on the task, but had great difficulty re-learning it when the rule changed and were more sensitive to the misleading feedback.

A smaller group of suicide attempters tended to continue following the old rule despite negative feedback for wrong answers.

The researchers discovered that participants who had attempted suicide focused excessively on the last trial, ignoring their experiences. Participants who were depressed but had never attempted suicide did not show the same problem and resembled healthy volunteers.

“We consider this an important advance in understanding the decision processes in those elderly depressed patients who may be at high risk of attempting suicide,” said Dombrovski. “Older adults vulnerable to suicide seem to make overly present-focused decisions, ignoring past experiences. This may explain why people in a suicidal crisis fail to consider important deterrents and see suicide as the only solution. We are now using brain imaging to look at brain activity in suicidal older adults as they make decisions. We hope that this research will help doctors develop talk therapies, medications and brain stimulation treatments for suicidal, depressed older people.”

Pitt co-authors of the study were Katalin Szanto, Greg J. Siegle, Meryl A. Butters and Naho Ichikawa, all from the Department of Psychiatry and Western Psychiatric Institute and Clinic.

The study was supported in part by funding provided by the National Institute of Mental Health, the American Foundation for Suicide Prevention and the John A. Hartford Foundation.

WPIC named HIV study site

Western Psychiatric Institute and Clinic is among nine sites chosen for a multi-center trial that will study 5,000 high-risk patients to determine whether rapid HIV testing and counseling produce healthier results for those who test negative for the virus than testing alone.

Researchers at Western Psychiatric Institute and Clinic, in conjunction with the Allegheny County Health Department, will evaluate the effect of routine counseling at screening on two primary outcomes: the incidence of sexually transmitted infections and acceptance of HIV testing. Researchers also will measure reduction of risky sexual behaviors and substance use during sex after six months, and cost-effectiveness of counseling and testing.

Public health experts encourage everyone between the ages of 13 and 64 to be HIV tested. However, there currently is little scientific evidence to guide decisions on the benefit of providing prevention counseling for those who test negative for the disease.

Psychiatry faculty member Antoine Douaihy, who will be the Pittsburgh site’s lead research investigator, said, “We are excited about participating in this study that has such significant public health implications. This study in the STD program and clinic at [the health department] will provide important and timely data on the impact of HIV counseling in high-risk populations tested in health care settings.”

Health department director Bruce Dixon said, “This study will give us the opportunity to contribute to a better understanding of the role of counseling for all Allegheny County Health Department patients undergoing HIV screening and potentially improve care.”

The research is funded through a $12.3 million American Recovery and Reinvestment Act grant to the National Institute on Drug Abuse.

New mesh thwarts toxins

In an ongoing effort to mirror the ability of biological tissues to respond rapidly and appropriately to changing environments, scientists from the McGowan Institute for Regenerative Medicine have synthesized a single, multifunctional polymer material that can decontaminate both biological and chemical toxins. They described the findings recently in Biomaterials.

Senior investigator Alan Russell, University Professor of Surgery in the School of Medicine and director of the McGowan Institute, said: “Our lab applies biological principles to create materials that can do many things, just like our skin protects us from both rain and sun. Typically, labs engineer products that are designed to serve only one narrow function.”

Conventional approaches might not provide the best responses for weapons of mass destruction, which could be biological, such as the smallpox virus, or chemical, such as the nerve agent sarin, he noted. Terrorists aren’t going to announce what kind of threat they unleash in an attack.

“That uncertainty calls for a single broad-spectrum decontamination material that can rapidly neutralize both kinds of threats and is easily delivered or administered, and it must not damage the environment where it is applied,” Russell said. “Much work has gone into developing ways to thwart either germ or chemical weapons, and now we’re combining some of them into one countermeasure.”

He and his team have devised a polyurethane fiber mesh containing enzymes that lead to the production of bromine or iodine, which kill bacteria, as well as chemicals that generate compounds that detoxify organophosphate nerve agents.

Lead investigator Gabi Amitai of the McGowan Institute and the Israel Institute for Biological Research said the mesh could be developed into sponges, coatings or liquid sprays, and could be used internally or as a wound dressing that is capable of killing bacteria, viruses and spores. “The antibacterial and antitoxin activities do not interfere with each other, and actually can work synergistically,” Amitai said.

In their experiments, the material fended off Staph aureus and E. coli, which represent different classes of bacteria. After 24 hours, it restored 70 percent of the activity of acetylcholinesterase, an enzyme that is inhibited by nerve agents leading to fatal dysfunction of an essential neurotransmitter.

The researchers continue to develop alternate decontamination strategies to address chemical and biologic weapons.

Co-authors of the paper included Hironobu Murata and senior research technician Jill Andersen, both of the McGowan Institute, and Richard Koepsel of the McGowan Institute and the Department of Surgery.


The University Times Research Notes column reports on funding awarded to Pitt researchers as well as findings arising from University research.

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