The research team in question is a large one that includesDrs. Stephen Miller and Lonnie Shea from Northwestern University, as well as researchersat the University of Sydney and the Myelin Repair Foundation in Saratoga,Calif. The team was supported by the National Institute of Biomedical Imagingand Bioengineering (NIBIB) at the National Institutes of Health, with resultsof their work appearing in the Nov. 18 online edition of Nature Biotechnology.
This new approach is based on a natural mechanism of thebody by which apoptotic, or dying, cells are cleared from the body. As a celldies, the body releases immune cells known as macrophages, which gather up thedying cell and carry it to the spleen, where it presents self-antigens to Tcells. To keep auto-reactive T cells from being activated, the macrophages thenrepress any T cells capable of binding to the self-antigens.
This approach has been in the work for some time, saysMiller, who notes that they originally noticed years ago that "administeringantigens covalently complex to apoptotic leukocytes by the intravenous routewas a pretty powerful way to induce antigen-specific tolerance for theprevention and treatment of ongoing autoimmune diseases in mouse models." Thelab recently completed a Phase I clinical trial in human patients with multiplesclerosis (MS), an autoimmune disease in which the immune system attacksmyelin, the insulating material that protects nerve fibers. The patients werehooked up to a leukocytapheresis apparatus that separated white blood cellsfrom purple blood, then linked "a cocktail of seven different myelin antigenspeptides" to the cells, which induces the cells to undergo apoptosis. Theclinical trial, says Miller, showed the procedure to be safe.
"We were able to administer up to three billionantigen-coupled leukocytes back into the same patients from which they wereoriginally derived without retriggering any diseases or any adverse events,"says Miller, director of the Interdepartmental Immunobiology Center atNorthwestern. "And more encouraging is we compared their T cell responses fromtheir purple blood cells to the myelin auto-antigens that are associated withmultiple sclerosis, a month prior to treatment and again three months aftertreatment. What we were able to show was, at a certain dose of cells that werere-administered coupled cells, that we could specifically diminish theirauto-reactive responses to the myelin peptides."
Despite the success, the researchers decided that the costand complexity of cellular therapy "would be a hindrance to the widespreadclinical translation of the therapy," says Miller, and began a search insteadfor inert nanoparticles that could act as "surrogates of apoptotic cellulardebris," a search that lead them to Shea, a bioengineer at Northwestern.
They eventually settled on nanoparticles made ofpolylactide-co-glycolide (PLG), a biodegradable material already approved bythe U.S. Food and Drug Administration and used in resorbable sutures. Whenbound with myelin antigens, the particles proved highly effective at inducing Tcell tolerance in animal models of MS, preventing initiation of the disease andinhibiting progression when administered immediately after symptoms appear.
"I think we've come up with a very potent way to inducetolerance that can be easily translated into clinical practice. We're doingeverything we can now to take this forward," said Miller in a pressrelease.
MS isn't the only autoimmune disease the researchers testedthis approach in, as it was also seen to have potential in treating diabetes aswell. In a mouse model of type 1 diabetes, Miller notes, the PLG nanoparticlesattached to insulin, "and insulin peptides are highly tolerogenic to preventthe induction of that disease." They also have preliminary data of potentialuse in allergy, in preventing the production of IgE antibodies, which mediateallergic disease.
"The real beauty of the system is it provides a universalcarrier substance to attach antigens for the treatment of autoimmune diseases,allergic diseases and even there's a potential of using this in inducingtolerance for transplantation of organs and tissues and cells," says Miller,adding that the potential of translating this approach "for multipleimmune-mediated disease applications is quite exciting."
Accordingto Miller, the plan moving forward is to partner with a biotech or pharmacompany, or start up their own, in order to carry out initial toxicologystudies for this approach. Miller adds that they are in the process of speakingwith some companies already, and are partnering with the Juvenile DiabetesResearch Foundation and the Myelin Repair Foundation to try and carry thisapproach forward in hopes of translating it into a treatment for type 1diabetes or MS.