On March 1, 2010, researchers funded in part by The Michael J. Fox Foundation announced that they had developed a vaccine that reverses an experimental form of Parkinson’s disease in a pre-clinical model.

The Michael J. Fox Foundation spoke with Scientific Advisory Board member David Standaert, MD, PhD, to gain a clearer understanding of the news and what it may mean for people with PD. Dr. Standaert is the John and Juanelle Strain Professor of Neurology and Director, Center for Neurodegeneration and Experimental Therapeutics, at the University of Alabama at Birmingham.

MJFF: According to the researchers who did this work, the dopamine neuron degeneration seen in Parkinson’s disease is linked to an immune system response. Can you provide some background on how this might occur?

DS: Sure. This really is part of a longer story about the role of the peripheral immune system in Parkinson’s disease. We often view Parkinson’s as a brain disease that occurs in isolation from the rest of the body. But I think we’ve all learned in the last couple of years that that’s probably not true. There are symptoms of PD linked to the gastrointestinal system and other areas of the body and there are probably other interplays between the rest of the body and the brain.

One of the aspects that we’ve gotten interested in is the interplay between the immune system and the brain in Parkinson’s. In some ways this is an old story — researchers have known for a long time that there is an inflammatory aspect of Parkinson’s disease. If you look in postmortem Parkinson’s brain tissue, there are activated microglia, which are the brain’s intrinsic immune cells, and there are also B- and T immune cells, specialized cells that play major roles in the body’s immune response. They come from the bone marrow and make their way, ultimately, into the brain in Parkinson’s disease. Several people have shown this over the years.

But I think, until recently, researchers haven’t paid much attention to this. It’s been viewed as a consequence: There was degeneration into the brain, some cells died and so, of course, there was an immune response to this cell death — the immune cells are there cleaning things up and taking away the debris. The new research, by Howard Gendelman and R. Lee Mosley at the University of Nebraska, is part of is a very different view: Maybe the immune system’s role isn’t just cleaning up after the fact, but maybe the immune system is actually driving the degeneration in the first place. So that’s the most important scientific shift that’s going on now, in several labs, and this recent work is the latest evidence that the immune system may be driving the disease rather than the disease driving the immune system.

MJFF: So what is the working hypothesis of this new paper?

DS: The idea here is that, in Parkinson’s disease, somehow, an immune response is created in the brain. The original cause of this response is very likely one of the things that we talk about all the time in PD, such as alpha-synuclein toxicity or oxidative stress — one of these triggers that we think is involved in the pathogenesis of Parkinson’s.

That trigger event produces an antigen that leads to an immune response involving both antibodies and B- and T-cells that come into the brain. They attack the source of this abnormal antigen and promote the degeneration of the brain. This hypothesis boils down to separating PD pathogenesis into two different events: first an original trigger, followed by the progressive part of the disease process which is driven by the immune response to this trigger.

What’s new in this study is that the researchers show that a specific kind of peripheral T-cell is critical for regulating the process of degeneration in an MPTP mouse model of PD. Earlier papers have shown that by transferring T-cells from one model to another you can confer resistance or increase susceptibility to injury from MPTP. Here, they have taken it several steps further and have identified a specific type of T cell, the Th17 cell, as the key player. They also show that a vaccination strategy can be used to increase the numbers of Th17 cells, and reduce the loss of dopamine cells in this model. These results add weight to the idea that the peripheral T-cell system really is important in modulating the cell death that occurs in the context of Parkinson’s progression, and point to a way in which you could use a vaccine to change the T cell response and slow the disease.

It’s exciting to think about it this way: Genetics and environment may be important for triggering PD, but they are hard to undo. If we can figure out the trigger that caused PD in a given individual, we may be able to prevent that trigger in the life of a future person, but if you yourself have already been exposed to it, we can’t undo that. The inflammatory response, on the other hand, is something that we can modify in an ongoing way.

What’s also exciting is the potential of this approach to lead to a possible biomarker of PD, something critically needed for the development of disease-modifying PD treatments. If you could develop a clinical test that would reveal T-cell abnormalities, that is something that we might be able to develop into a biomarker going forward.

MJFF: Is this the only vaccine approach to PD currently in development?

DS: Actually there are a couple of different therapeutic approaches to Parkinson’s that are referred to as “vaccines” — it’s important that we not muddy the waters between the recent news and some of this other work.

One approach labeled a “PD vaccine” is borrowed from Alzheimer’s disease (AD) drug development. In AD there is a whole line of research designed around trying to remove beta-amyloid, which is one of the proteins that is key to the pathogenesis of Alzheimer’s. There have been human clinical trials that have used antibodies to clear amyloid from the nervous system. For Parkinson’s, the same approach has been proposed for alpha-synuclein, which is the protein that builds up in nervous cells in PD. That’s a whole different strategy, but it is also referred to as a vaccine.

The vaccine strategy here is different — they are proposing to use a vaccine that triggers changes in the body’s T-cell composition, and leads to a downstream effect on the immune reaction in the brain. The types of vaccines that would be used for this strategy would not necessarily have anything to do with the PD proteins we are familiar with — they would come from the very extensive research that has already been done on other immune system disorders, and would be targeted at enhancing the numbers of particular types of T-cells.

MJFF: If this immune-based vaccine approach were successful, what kind of treatment would it be?

DS: Based on similar treatment approaches in other diseases, there is some likelihood that the treatment would consist of injections, maybe once a week or so, at home.

MJFF: Other diseases have benefited from this type of treatment?

DS: Yes — in fact, this is an area where we have a lot of knowledge from other diseases, most notably multiple sclerosis (MS), where we are able to immunize individuals with a protein that impacts their bodies’ cellular response to inflammatory events. Just in the past week the results of a 15-year clinical study of one such MS drug (Teva’s Copaxone) came out, and highlighted the drug’s long-term safety and efficacy.

MJFF: Are there possible side effects or complications that can come from modulating the immune system?

DS: Yes. With any new treatment, there is always the possibility of unexpected consequences, and working in the immune system is no exception. Possibly the best example comes from the MS drug Tysabri, which blocks T-cells from entering the brain. In clinical studies it was highly promising against MS. But when the drug came to market and was used by a much larger population, some patients — a very, very small percentage — developed a fatal viral infection in the brain. Nonetheless, Tysabri remains on the market today, because it is so effective against MS. Patients who take it are closely monitored for signs of infection. But overall, the benefit of the drug outweighs the risk.

MJFF: What are the next steps in developing this immune-based vaccine approach to PD?

DS: It’s important to keep in mind is that the results published this week were achieved in the MPTP model of Parkinson’s disease, which is created by introducing a one-time toxic insult into a pre-clinical model of PD. While this model is widely used in PD research, it has limitations in recapitulating the human condition of Parkinson’s, particularly aspects involving disease progression. We need to move quickly to gather as much data as we can and determine whether we can validate these results in additional pre-clinical models.

There is also a need for detailed immunology on the human side. Our group at UAB is collaborating with Dr. Gendelman to gather clinical data and screen for T-cell abnormalities in blood collected from PD patients — this would be another set of preliminary data toward a possible larger clinical study. We have a clinical protocol approved and are enrolling about 40 patients over the next two to three months.

MJFF: If this strategy continues to show promise, what is your best estimate on a time horizon to patient-relevance?

DS: It’s always hard to say, but in general I’m optimistic that this approach could advance quickly. The technology for immune modulation is well developed from work in other diseases. If we can establish a connection between immune response and ongoing PD pathogenesis, we may see clinical testing in patients in as soon as three to five years.

NOTE: The medical information contained in this article is for general information purposes only. The Michael J. Fox Foundation has a policy of refraining from advocating, endorsing or promoting any drug therapy, course of treatment, or specific company or institution. It is crucial that care and treatment decisions related to Parkinson’s disease and any other medical condition be made in consultation with a physician or other qualified medical professional.