Targeted Response

Professor David Shepherd and researcher Fanny Diaz examine a cell culture in a UM biomedical lab. Team members working under biohoods are Celine Beamer (left) and Ben Seaver.

Pollutants lead researchers toward novel therapy for immune system-related diseases

By Bess Pallares

When the body turns against itself, it can strike with debilitating and deadly accuracy.

The war raging inside people with autoimmune disorders can be devastating, and the current gold standard of care involves complete demilitarization of the body’s defenses by highly immunosuppressive drugs. Because one part of the immune system can’t be trusted, the whole thing is brought down, leaving the body highly susceptible to increased and more severe infections, as well as unchecked growth of cancerous cells.

But now UM researchers are developing a more targeted response.

When he started at the University in 2002, Professor David Shepherd was researching how chemicals that pollute the environment affect the immune system. Thousands of chemicals make up a class of environmental contaminants called halogenated aromatic hydrocarbons, which include dioxins and PCBs. Exposure to these pollutants can have profound immunosuppressive effects, producing an ineffective immune system that doesn’t work like it should to protect the body.

“These chemicals are global environment pollutants, and everyone’s exposed to them,” Shepherd says. “We asked what level of exposure do you need to have to see toxic effects in the immune system and other parts of the body, and how do the exposures produce these toxic effects?”

The immune system is made up of two branches: innate and adaptive. The innate is the frontline defense, while the adaptive is usually a secondary response that is called into action when the innate response doesn’t initially clear an infection. Both branches are vital, and it takes coordinated communication between them for the immune system to function properly.

Dendritic cells (Photo courtesy of William Bowers)Shepherd and his team of researchers keyed in on one particular immune cell that plays a pivotal role in this communication: dendritic cells. These cells bridge the innate and adaptive branches of the immune system. They are found in nearly every tissue in the body and play a prominent role in detecting pathogens, allergens, cancer cells and more.

“We like to think of them as the James Brown of the immune system – the hardest working cells in the immune system,” Shepherd says.

Within the dendritic cells is a protein called the aryl hydrocarbon receptor (AHR), which mediates the toxic effects of exposure to many environmental pollutants.

With initial support from the UM Center for Environmental Health Sciences and the Department of Biomedical and Pharmaceutical Sciences, Shepherd’s research team was able to secure a five-year, $1.6 million grant from the National Institutes of Health to investigate what happens when the AHR protein activates in dendritic cells.

Through that research, they found potential that goes far beyond the body’s response to environmental toxins.

“One of the really significant findings of the research is that exposure of chemicals that can bind and activate the AHR – both man-made pollutants and natural chemicals from plants – caused the dendritic cell to not become a stimulating immune cell anymore, but conversely to be a highly potent regulatory, suppressive immune cell,” Shepherd says.

His team is using this information to develop a highly targeted approach to intentionally generate AHR-activated dendritic cells that carry specific antigens – things that stimulate the immune system – that will generate regulatory dendritic cells that lead to disease-specific suppression.

“This approach can be done either directly in the body or indirectly via the transfer of cultured dendritic cells isolated from a patient,” he says. “Importantly, both approaches ultimately lead to highly targeted immune effects that work to suppress immune-mediated diseases such as autoimmune diseases, severe allergic responses and organ/tissue transplants,” he says.

To create this chain of events, it is helpful to be able to identify auto-antigens, the pieces of our own cells and tissues that the body recognizes and attacks in autoimmune diseases such as multiple sclerosis, systemic lupus or rheumatoid arthritis.

Nanoparticles may be used to suppress unwanted immune responses.Shepherd’s lab is working to deliver specific auto-antigens or allergens (antigens that induce allergic responses) with nontoxic compounds that activate the AHR in dendritic cells and do that in a selective manner using liposomal nanoparticles.

“If that happens, we will have generated a very targeted missile that suppresses unwanted immune responses, rather than using current immunosuppressive drugs that are more like carpet bombing that lacks specificity,” he says.

This highly specific approach will leave the rest of the immune system fully functional. So this new type of targeted therapy will still allow people to be protected from infectious diseases and cancerous cells by their immune system. This represents a significant advancement in the treatment of patients.

But the best thing about this treatment is what the body does with the response: The adaptive immune system generates memory cells, such as what happens with vaccination. And similar to how the body can be trained to attack a disease, it can be taught to ignore one.

“Instead of generating stimulatory immune cells, we can generate memory suppressive cells,” Shepherd says. “Moving forward, these suppressive cells in your body will remember the auto-antigen or allergen and respond – or rather not respond – to a future occurrence of the disease. Effectively, this treatment should cure the immune-mediated disease and put a patient into remission – likely for their lifetime.”

Though this method of treatment has not yet reached human clinical trials, Shepherd says researchers at Harvard Medical School using gold nanoparticles have successfully treated mice with experimental autoimmune encephalitis, a mouse model of multiple sclerosis. The method works for both disease prevention and treatment.

“In collaboration with Dr. Fanny Astruc-Diaz and Dr. Celine Beamer at UM, we’re trying to build off of the findings from Harvard by using different liposomal nanomaterials that are significantly less toxic,” Shepherd says. “We hope to better target this treatment so it gets specifically taken up by the dendritic cells, eliminating collateral damage within the immune system and throughout the body.”

Based on the research progress from his initial NIH grant, Shepherd’s team was able to renew his grant last year for another $1.7 million over five years.

“We’re really excited about this because it has the potential to make huge strides in the treatment of people with all kinds of diseases,” he says. “It can also be used for establishing, to much higher levels, acceptance of tissue and organ transplants.”

Moving forward, Shepherd is collaborating with programs across the UM campus, including the School of Business Administration and the Office of Technology Transfer, and others throughout the country to look at the practical and commercial applications of this novel treatment.

“Shepherd’s research illustrates how important basic biomedical research is to not only understanding the underlying mechanisms of disease, but to the development of novel therapeutic approaches,” says Rich Bridges, chair of the biomedical and pharmaceutical sciences department at UM. “Beyond the long-range benefits to patients, having research efforts of this caliber in our college is also a great benefit to our students and our educational mission in the health sciences.”

After developing the technology and the best ways to deliver the treatments in the pre-clinical setting, Shepherd is moving toward obtaining financial support to start a small biotechnology company to put the treatment into production and hopefully move to human clinical trials.

“It’s very encouraging to hear this type of entrepreneurial thought process from our faculty members,” says Joe Fanguy, UM director of technology transfer. “Historically the focus for nearly all faculty has been only on the research, but we’re moving the commercialization needle thanks to more individuals like Dr. Shepherd who are open to the broader impacts.”

Shepherd credits the NIH, the UM Department of Biomedical and Pharmaceutical Sciences and the robust biomedical research happening on campus with helping to move the study forward.

“This research, which was initially intended to better understand how the environment affects human health via effects on the immune system, is now leading to a greater understanding of how the immune system works at a basic level,” Shepherd says. “With this new information, we are specifically developing new immunotherapeutics, which have the potential to have profound effects in the treatment of people suffering from debilitating diseases.

“As you might expect, this research is very exciting for us as scientists and our ultimate goal of helping to improve human health.”

For more information email david.shepherd@mso.umt.edu.

UM doctoral student Joanna Kreitinger performs an immune cell analysis with a flow cytometer.

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