How immunotherapy may treat multiple sclerosis
"Breakthrough hope for MS treatment as scientists discover how to 'switch off' autoimmune diseases," reports the Mail Online.
Autoimmune disorders, such as multiple sclerosis (MS), occur when the body's immune system attacks and destroys healthy body tissue by mistake.
The "holy grail" of treatment is to make the immune system tolerant to the part of the body it's attacking, while still allowing the immune system to work effectively.
Previous studies in mice have shown tolerance can be achieved by repeatedly exposing mice with autoimmune disorders to fragments of the components the immune system is attacking and destroying.
The immune cells that were attacking the healthy tissue convert into regulatory cells that actually dampen the immune response. This process is similar to the process that has been used to treat allergies (immunotherapy).
It's known that doses of the fragments of the components the immune system attacks need to start low before increasing – this is known as the dose-escalation protocol.
A new mouse study found that a carefully calibrated dose-escalation protocol caused changes in gene activity (gene expression). This then causes the attacking immune cells to express regulatory genes and become suppressive. So rather than attacking healthy tissue, they're now ready to protect against further attacks on healthy tissue.
The researchers hope some of the changes in immune cells and gene expression they've identified can be used in clinical studies to determine whether immunotherapy is working.
Where did the story come from?
The study was carried out by researchers from the University of Bristol and University College London. It was funded by the Wellcome Trust, MS Society UK, the Batchworth Trust, and the University of Bristol.
The study was published in the peer-reviewed journal Nature Communications. This article is open-access and can be read for free.
Although most of the media reporting was accurate, this study focused on how dose-escalation therapy works rather than revealing it as a new discovery. The principles underpinning immunotherapy and similar treatments have been known for many years.
What kind of research was this?
This animal study aimed to improve the understanding of how dose-escalation therapy works so it can be made more effective and safer.
Animal studies are the ideal type of study to answer this sort of basic science question.
What did the research involve?
Most of the experiments were performed in mice engineered to develop autoimmune encephalomyelitis, which has similarities to multiple sclerosis (MS).
In this mouse model, more than 90% of a subset of immune cells called CD4+ T cells recognise myelin basic protein, which is found in the myelin sheath that surrounds nerve cells. This causes the immune system to attack the myelin sheath, damaging it, which causes nerve signals to slow down or stop.
The researchers injected the mice under the skin (subcutaneously) with a small protein called a peptide that corresponded to the region of myelin basic protein recognised by the CD4+ T cells.
The researchers initially wanted to see what the maximum dose of peptide that could be tolerated was, and what dose was most effective at inducing tolerance.
They then did further experiments in which they increased the dose of peptide and compared that with just giving the same dose of peptide on multiple days.
Finally, they looked at what genes were being expressed or repressed in CD4+ T cells during dose-escalation.
What were the basic results?
The researchers found the maximum dose of peptide that could be tolerated safely by the mice was 8µg (micrograms).
The tolerance to the peptide increased as peptide dose increased. This means that when the mice were re-challenged with peptide, the immune response was lower in mice that received 8µg of peptide compared with mice that had received lower doses.
The researchers found that dose escalation was critical for effective immunotherapy. If mice received 0.08µg on day 1, 0.8µg on day 2, and 8µg on day 3, they could then tolerate doses of 80µg with no adverse effects. This dose escalation protocol also suppressed activation and proliferation of the CD4+ T cells in response to the peptide.
The researchers then looked at the gene expression within CD4+ T cells during dose escalation. They found each escalating dose of peptide treatment modified the genes that were expressed. Genes associated with an inflammatory response were repressed, while genes associated with regulatory processes were induced.
How did the researchers interpret the results?
The researchers concluded that, "These findings reveal the critical importance of dose escalation in the context of antigen-specific immunotherapy, as well as the immunological and transcriptional signatures associated with successful self-antigen escalation dose immunotherapy."
They go on to say that, "With the immunological and transcriptional evidence provided in this study, we anticipate that these molecules can now be investigated as surrogate markers for antigen-specific tolerance induction in clinical trials."
Conclusion
This mouse study used a mouse model of MS and found that the dose-escalation protocol is extremely important for inducing tolerance, in this case a small fragment of myelin basic protein.
Escalation dose immunotherapy minimised immune system activation and proliferation during the early stages, and caused changes in gene expression that caused the attacking immune cells to express regulatory genes and to become suppressive.
The researchers hope that some of the changes in immune cells and gene expression they've identified can be used in clinical studies of tolerance-inducing treatments for autoimmune disorders to determine whether therapy is working.
