Selective Repression of the Immune System
About This Podcast
Drs. Stephen Miller and Lonnie Shea of Northwestern University, Evanston describe how they used antigen-coupled microparticles in mice to repress the part of the immune responsible for causing multiple sclerosis while leaving the rest of the system intact. The technique could potentially be adapted to treat other autoimmune diseases and prevent rejection of transplants.
Health TermsDrug Delivery, Nanotechnology, Stroke
Narrator-Kern: This is a production by the National Institute of Biomedical Imaging and Bioengineering—part of the National Institutes of Health
Shea: The body has natural mechanisms for kind of shutting down an immune response that’s inappropriate and we’re really just looking to tap into those natural mechanisms.
Narrator-Kern: That’s Dr. Lonnie Shea, professor of bioengineering at Northwestern University referring to a recent advance in the pursuit of a safer, more efficient way to treat autoimmune diseases. Shea, in collaboration with Dr. Stephen Miller, also of Northwestern, have come up with a way to selectively inhibit the part of the immune system responsible for causing these diseases. Their most recent work, published in Nature Biotechnology, describes an innovative method for treating multiple sclerosis in mice. Dr. Miller explains just how the immune system is involved in the development of MS:
Miller: The immune response starts to attack the myelin membrane in the central nervous system. As a part of the disease, activated T cells enter the CNS and cause the destruction of myelin that leads to impairment of electrical function from the central nervous system to the muscles resulting in paralysis.
Narrator-Kern: Miller went on to explain that self-reactive T cells are responsible for generating a host of autoimmune diseases including rheumatoid arthritis and type 1 diabetes. Currently, autoimmune diseases are treated with a class of drugs called immunosuppressants, but Miller says these drugs have major drawbacks.
Miller: You’re not only trying to treat the autoimmune disease, you also make the individual susceptible to what we call opportunistic infections, or infections that those of us with healthy immune systems can normally deal with quite readily.
Miller: People on long-term immunosuppressant drugs are also susceptible to higher rates of cancer development because their immune system is not properly used to patrol the body looking for mutant cells that might become cancers.
Narrator-Kern: Miller says the holy grail of treating autoimmune disease is by a phenomenon called tolerance.
Miller: And what tolerance simply means is, in order to treat the disease, what you’re trying to do is specifically inactivate only the T cells that are responsible for damaging the self-tissue
Narrator-Kern: Miller’s lab has spent the past several decades developing a novel method for inducing tolerance. In the late 70’s, the lab discovered that if they attached antigens (or tiny portions of a protein) to dying white blood cells and then injected these antigen-coupled cells into a mouse, the mouse’s immune systems would become tolerant to the antigen.
Narrator-Kern: The method works because the body is constantly helping the immune system distinguish between antigens that belong to the body and those that are foreign and should be attacked. One way it does this is by presenting bits of protein found within dying cells to T-cells located in the spleen. Any T-cells capable of binding to these proteins become suppressed. Using this method, Miller’s lab was able to treat various animal models of autoimmune disease over the years, simply by changing the antigen coupled to the dying cells.
Narrator-Kern: But Miller anticipated problems translating his results in the lab to a potential treatment for humans. The issue was the need to use dying cells as antigen carriers:
Miller: Using the cellular therapy is extremely expensive and complex and requires that this therapy would be carried out at a large medical center.
Narrator-Kern: It was at this point that professor Lonnie Shea was pulled into the mix.
Shea: You know in our conversations, it became obvious that while his approach was incredibly successful and he’d done tremendous science in terms of understanding how that process worked that the translation would really be facilitated by using something other than the cell as the carrier for the peptide.
Narrator-Kern: That something ended up being microscopic biodegradable particles to which the lab attached specific antigens, in their case, a peptide of myelin.
Shea: A human hair is approximately a hundred microns in diameter, and so these particles are roughly 500 times smaller than a human hair.
Narrator-Kern: To their amazement, the antigen-bound particles worked just as well if not better than the apoptotic cell carriers. And, when they injected their particles intravenously into mice conditioned to develop an experimental form of MS, the vast majority of mice never developed it. They were also able to halt the progression of the disease by injecting the mice just after the first symptoms of MS emerged.
Narrator-Kern: Shea says one advantage of their particles is that they’re made from a substance that already has FDA approval
Shea: This particle has been used as biodegradable sutures for many years. The same material has been used in drug delivery microspheres for years. We’ve made them a different size, but ultimately the material is something that’s readily accepted by the body.
Narrator-Kern: Miller believes that the particles could be adapted to potentially treat a wide range of diseases and conditions involving the immune system:
Miller: We’ve also shown that these antigen-coupled nanoparticles can be used in animal models of allergic disease. We found in unpublished results that we can attach allergens onto these particles and inhibit the development of an allergic immune response. A third potential use for this, we’re envisioning being used to induce tolerance to to promote the acceptance of cell and tissue grafts between individuals.
Narrator-Kern: Shea points to the unique collaboration that lead to the successful development of these particles.
Shea: This is just a tremendous example of the opportunities of interdisciplinary work. My lab has the materials but we don’t have the biological expertise that Dr. Miller has. At the same time, he has tremendous biological expertise but necessarily didn’t have the tools by which to modify or create a particle of our own that would have all the properties we would want.
Narrator-Kern: Miller’s hopeful that years of manipulating the immune system in a lab environment might soon yield a treatment for patients.
Miller: I’ve been working in the field of immune tolerance my whole scientific career. It took 30 years to get from animal experiments to our initial phase 1 clinical trials using the antigen-coupled apoptotic cells. We’re hoping it only takes a year or two to get into the phase 1 clinical trial using the particles.