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Investigators reporting that T cells isolated from multiple sclerosis patients proliferated significantly less in response to myelin peptides delivered transdermally than those from placebo-treated patients, suggesting that the patch modulated the immune system to suppress autoreactive responses.
DR. KRZYSZTOF SELMAJ: “Our idea was that maybe we can use endogenous autoantigens to induce tolerance, similar to allergens.”
Transdermal delivery of myelin peptides can modulate the immune system to suppress autoreactive responses, according to a new clinical study in the Annals of Neurology. While these findings indicate the promise of antigen-specific therapy in multiple sclerosis (MS), experts wonder if the field has room for any more new drugs.
Currently approved therapies for MS “aim for general suppression of the immune system,” according to lead researcher Krzysztof Selmaj, MD, PhD, professor of neurology at the Medical University in Lodz, Poland. The therapies are non-selective, down-regulating the entire system, rather than targeting the autoreactive lymphocytes believed to be the cause of the disease.
“We have been very interested in antigen-specific therapy, because it is a selective therapy,” which leaves intact the immune system's ability to combat legitimate targets. This has the potential to reduce the risk of serious adverse events, he said, including opportunistic infections.
Antigen-specific therapy has been attempted in the past, but with little success. Because of the apparent ineffectiveness of oral and intravenous administration of myelin antigens, Dr. Selmaj chose a novel approach — delivering myelin peptides transdermally using an adhesive patch.
Antigen presentation can either induce or down-regulate the immune response, he said. “It very much depends on the environment in which the presentation is being done.” The skin has many antigen-presenting cells, called dendritic Langerhans cells, and is constantly in touch with the outside environment. This may make it a more tolerance-inducing context than internal tissues, he suggested. “If all the agents the skin came in contact with induced an immune response, we would be in a constant state of immune hyper-reactivity.”
While dendritic cells can induce an immune response, they can also lead to down-regulation, a phenomenon immunologists take advantage of when they desensitize an allergy patient with subcutaneous injection of the allergen. “Our idea was that maybe we can use endogenous autoantigens to induce tolerance, similar to allergens,” Dr. Selmaj said.
DR. LAWRENCE STEINMAN: “We have a whole arsenal of such powerful drugs for relapsing-remitting MS. The landscape is full of successful therapies, which makes it very difficult for people to take it the next step.”
To test the hypothesis, Dr. Selmaj conducted a one-year, randomized, placebo-controlled trial in 30 patients with relapsing-remitting multiple sclerosis. Patients had had one or more relapses within the past year, and had to have received no immunomodulatory therapy within the past three months (one month for intravenous steroids). Adhesive patches containing either placebo or a mixture of three myelin peptides were applied to the skin. The patches were placed on the upper arm and changed monthly.
Biopsies of skin and axillary lymph nodes were performed to assess the cellular effects of treatment. The researchers found that treatment with myelin peptides, but not placebo, activated dendritic Langerhans cells at the site of the patch application. Antigens applied to the skin are known to induce reactivity in the peripheral lymphoid organs, Dr. Selmaj said, and indeed, samples from patients receiving active treatment showed a population of large, highly granular cells rarely seen in placebo-treated patients. Their cell surface markers suggested “a capacity for antigen presentation.” This, he said, is “a new population of dendritic cells. We are not sure at the moment if these are skin dendritic cells that travel to the lymph nodes, or whether dendritic cells in the skin can induce this population in the lymph nodes,” but the question is under investigation.
Whatever their origin, Dr. Selmaj believes these cells are the key to the rest of their observations. “Dendritic cells ‘re-educate’ autoreactive cells that enter the lymph nodes,” he said. Evidence of that re-education came in several forms.
T cells isolated from patients receiving active treatment proliferated significantly less in response to myelin peptides than those from placebo-treated patients, beginning four months after commencement of treatment and continuing to the end of the study. Active treatment also increased the regulatory cytokine interleukin-10, and decreased the inflammatory cytokines interferon-gamma and TGF-beta, signs of immunotolerance.
“We hypothesize that the dendritic cells which are induced by epidermal peptide therapy can contribute to diminished activity of the autoreactive lymphocytes, re-educating them to behave in a less aggressive way,” Dr. Selmaj said.
Clinical and imaging measures were not reported in the current study, but Dr. Selmaj has presented preliminary clinical findings elsewhere, and is preparing to publish those results as well. Both the clinical and MRI results “were very encouraging and very promising,” he said, particularly the imaging results. “After one year, the MRI results are already very positive, both in terms of new T2 lesions and enhancing lesions.” He noted that while a one-year study is a limited time to see a strong effect on clinical measures, the effect on relapses and progression was nonetheless “very positive.”
Patch site reactions, often a vexing problem in transdermal therapies, have been very mild. Much depends on the compound in the patch, he suggested, noting that protein is unlikely to be the same kind of irritant as other transdermally delivered chemicals.
Neurology Today advisory board member John Corboy, MD, professor of neurology at the University of Colorado, Denver, called the results “significant and interesting.” Transdermal delivery of MS treatment may be advantageous for patients over injected with therapy. But the key feature of the study, he said, was the specificity of the response. Previous efforts in the field have been “remarkably unsuccessful.”
Progress in developing specific therapy would be valuable not only for its clinical implications, but perhaps also for understanding the multiple sclerosis disease process. “The evidence supporting an autoimmune response against myelin has been hard to generate,” he noted. If the clinical results from this study support the histological evidence, it may put doubts about the significance of the myelin auto-response to rest.
The results presented are “exciting,” said Lawrence Steinman, MD, professor of neurology and Program Chair in Immunology at Stanford University. Antigen-specific therapy is “the so-called Holy Grail” of MS therapy, “but we haven't seen enough efficacy in the past.”
But whether even a very successful antigen-specific therapy can make it in the current market is “a vexing question,” he said.
“We have a whole arsenal of such powerful drugs for relapsing-remitting MS. The landscape is full of successful therapies, which makes it very difficult for people to take it the next step.”
That next step would be a phase 2 trial, costing approximately 20 million dollars; a phase 3 trial program would cost an additional 100 million dollars. “The next bet is going to have to be a very expensive bet. The problem these days is that in the face of so many potent and effective therapies, companies are reluctant to make that bet.”
“Unless and until the existing therapies destruct,” Dr. Steinman said, perhaps because of serious complications, “what we have is what we are going to see for the next 10 to 20 years.”
DR. JOHN CORBOY said transdermal delivery of MS treatment may be advantageous for patients over injected with therapy. But the key feature of the study, he added, was the specificity of the response, noting that previous efforts in the field have been “remarkably unsuccessful.”